Publication date
Selected human models of maternal smoking during pregnancy (MSDP).
Authors and Publication date | Prospective or Retrospective | Populations species and size | Measures | Brief results |
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Prospective – maternal smoking data collected “during pregnancy” | Dyads recruited from the NICHD Neonatal Research Network n = 9637 mother-infant dyads | Birth weight, intrauterine growth restriction | Maternal smoking associated with lower birth weight and intrauterine growth restriction | |
Retrospective – maternal smoking data collected the 3 or 4 day after delivery | Nationwide multicenter obstetric/pediatric survey in Italy n = 12,987 babies | Birth weight | Maternal smoking associated with lower birth weight in dose response relationship | |
Prospective – maternal smoking data collected at 36 weeks | Mother giving birth in one of two South Wales towns n = 1159 mothers | Maternal weight gain, fetal growth | Maternal smoking associated in a dose-response fashion with lower maternal weight gain, and lower birth weights, length, and head circumference | |
Unclear – presumably retrospective | Children of twins from two twin samples | Birth weight | Smoking during pregnancy covaries with offspring birth weight through a direct environmental pathway rather than genetic or shared environmental factors. | |
Retrospective – maternal smoking data collected in mothers of twins aged 11–19 years | Adolescent female twins pairs n = 1936 twin pairs | DSM-IV ADHD, low birth weight | No evidence for maternal smoking effects on ADHD status when covariates included. Maternal smoking associated with low birth weight. | |
Prospective – maternal smoking data collected at first antenatal visit (usually before week 15) | All singleton births in two Swedish hospitals were examined for very preterm birth n = 295 | Very preterm births (between 22 and 32 weeks) | Dose dependent association between maternal smoking and very preterm birth. | |
Prospective – maternal smoking data collected at first antenatal visit (typically weeks 8–12) | All cases in Swedish Medical Birth Registry between 1983 and 1997 with cleft palate or cleft lip excluding multiple births, immigrants, those with missing smoking data and recurrent cleft births and controls n = 872 with cleft palate, 678 with isolated cleft palate, 1456 with cleft lip and 1175 with isolated cleft lip 10% of 128,688 noncleft births used as controls | Cleft lip and cleft palate | Cleft palate associated with MSDP using multiple designs, cleft lip associated with MSDP only with case-control design | |
Prospective – Maternal smoking data collected at 11–25 weeks of gestation | Mothers and offspring from Danish National Cohort n = 76,768 births | Congenital malformations using EUROCAT criteria | No association of congenital malformations with maternal smoking, children born to nonsmokers using nicotine substitutes had increased congenital malformations (especially musculoskeletal malformations) | |
Prospective-“during pregnancy” | Participants in the Collaborative Perinatal Project n = 53,518 pregnancies at 12 hospitals in the United States | Birth weight, placental health, and length of pregnancy | Maternal smoking associated with lower birth weight, poorer placental health, and shorter pregnancies | |
Prospective-100ug/kg body weight over 20 minutes during pregnancy | 8 pregnant rhesus monkeys near term | Uterine arterial blood flow | Nicotine decreases uterine arterial blood flow | |
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Prospective –maternal smoking data collected at first antenatal visit, 32 week of gestation, and after birth | Offspring of women enrolled in the Port Pirie Cohort Study n = 548 children followed from birth to 4 years | Bayley Scales of Infant Development at 2 years and McCarthy Scales of Children’s Abilities at 4 years | No significant association between maternal smoking and neuropsychological development | |
Retrospective – maternal smoking data collected to mother’s of 2 year olds | Community sample of 99 toddlers and mothers. 52 smoked during pregnancy, 47 did not smoke during pregnancy | Negativity as measured by impulsivity, risk taking, and rebelliousness | Maternal smoking during pregnancy was associated with negativity | |
Prospective – maternal smoking data collected in each trimester | Children aged 2–8 days that had participated in the Ottawa Prenatal Prospective Study n = 250 babies | Brazelton Neonatal Behavioral Assessment Scale | Maternal smoking associated with increased tremors and poorer auditory habituation | |
Prospective – maternal smoking data collected in each trimester | Children aged 13 months days that had participated in the Ottawa Prenatal Prospective Study n = 84 offspring | Bayley Mental and Motor Scales | Maternal smoking associated with decreased motor scores, poorer verbal comprehension, and poorer fine motor skills | |
Unclear- maternal smoking data collected within 48 hours of birth | Smoking exposed neonates and controls taken from a larger study on early language development n = 8 exposed and 8 unexposed neonates | Newborn speech discrimination ability measured by event-related potentials | Infants of smoking mothers discriminated fewer syllables and began the discrimination process 150 ms later than matched controls. | |
Prospective –self report and biomarkers used during pregnancy | 27 nicotine exposed and 29 unexposed infants n = 56 mother offspring pairs | NICU Network Neurobehavioral Scale within 48 hours of birth | Offspring of mothers who smoked were excitable, showed greater asymmetrical reflexes and more hypertonia than unexposed infants. Exposed infants also had higher scores on the stress abstinence scale in a dose response fashion. | |
Prospective – Maternal smoking behavior reported at 16 weeks gestation | Singleton infants without disability n = 1871 | Babbling abilities at home visit lasting 1–1.5 hours | Trend of dose response relationship between maternal smoking during pregnancy and the likelihood of being a nonbabbling infant was found. | |
Unclear when assessed | 15 smokers and 17 nonsmokers | Brazelton Neonatal Behavioural Assessment Scale | Prenatally exposed children exhibited decrements to bell, and deficits in inanimate orientation (auditory), animate orientation (auditory), and consolability | |
Prospective – maternal smoking data collected during pregnancy | Subsamples of the Groningen Perinatal Project were identified and re-examined at age 5.5 – 11 years n = 1186 singleton births | Reading spelling and arithmetic and parent and teacher ratings of attention and level of internalizing/externalizing | Children of mothers who smoked showed increased attention problems, externalizing behavior, and did worse on arithmetic and spelling tasks | |
Prospective – maternal smoking data collected “during pregnancy” | 9–11-year old children who participated in the Child Health and Development Studies n = varies between 1745 and 3260 by longitudinal timepoint | Peabody Picture Vocabulary Test, Raven Coloured Progressive Matrices Test, Goodenough-Jarrios Drawing Test, and Quick test | Offspring of mothers who smoked during pregnancy but quit afterwards did not differ on language and matrices tasks from offspring not exposed to smoking during pregnancy. However, children exposed to MSDP and smoking after pregnancy scored lower than either group. | |
Retrospective – maternal smoking data collected to mother’s of 2 year olds | Community sample of 99 toddlers and mothers. 52 smoked during pregnancy, 47 did not smoke during pregnancy | Negativity as measured by impulsivity, risk taking, and rebelliousness | Maternal smoking during pregnancy was associated with negativity | |
Prospective – maternal smoking data collected from fourth prenatal month | 10 year old children n = 593 mother/offspring pairs | Wide Range Assessment of Memory and Learning Screening, Wisconsin Card Sorting Task, Stroop and Trail making Tasks, Pediatric Assessment of Cognitive Efficiency, Grooved Pegboard. | Maternal smoking associated with deficits in verbal learning, design memory, eye hand coordination, flexible problem solving, and increases in impulsivity | |
Mixed- mothers were initially assessed on smoking during pregnancy 4 years after entry into the study; mothers who had a child within these four years would be retrospective whereas those giving birth later would be prospective | Females from the National Longitudinal Survey on Youth and their children n = 11, 192 children form 4886 mothers | Behavioral Problem Index | Although smoking during pregnancy was associated in a dose response fashion with offspring conduct problems, oppositional defiant problems or attention deficit hyperactivity problems (especially in males), the relationship between conduct problems and oppositional defiant problems were not found when examined in siblings that differed in exposure to prenatal nicotine suggesting the possibility of environmental effects that vary between families confound this relationship. | |
Eskanazi & Trupin, (1995) | Prospective – maternal smoking data collected “during pregnancy” | 5-year old children who participated in the Child Health and Development Studies n = 2,124 | Peabody Picture Vocabulary Test, Raven Coloured Progressive Matrices Test and a behavioral rating scale | Maternal smoking during pregnancy was not significantly associated with differences on the neurobehavioral assessment |
Prospective – maternal smoking data collected in each trimester | Children aged 6 years that had been followed in the Ottawa Prenatal Prospective Study n = 135 60-month old children and 137 72-month old children | McCarthy Scales of Children’s Abilities and Home Observation for Measurement of the Environment (only a subset) | Maternal smoking associated with impaired cognitive and receptive language scores at both 60 and 72 months | |
Prospective – maternal smoking data collected in each trimester | Children aged 6 years that had been followed in the Ottawa Prenatal Prospective Study n = 126 children | The Gordon Diagnostic System, sustained attention, The Sentence Memory Test, McCarthy Scales of Children’s Abilities, Target Test and Conners Parent Rating Scale | Maternal smoking was associated with poorer performance on memory tasks (in particular those with verbal recall) | |
Retrospective – maternal smoking data collected when offspring were 13–21 years old. | Australian female twin pairs where at least one twin had a history of alcohol abuse or dependence (DSM-IV) and at least one twin had children between ages of 13–21 n = 536 twin mothers (268 pairs) and 922 children | Child ADHD assessed with items from Diagnostic Interview for Children and Adolescents and Semi-Structured Assessment of the Genetics of Alcoholism | MSDP associated with offspring ADHD but children-of-twin design suggests genetic transmission of risk for ADHD is not fully explained by MSDP | |
Prospective – maternal smoking data collection begun at first antenatal visit | 15 year old males and females n = 400,000 | Educational achievement: grade point summary score | Maternal smoking associated with increased risk of poor scholastic achievement OR = 1.59 for 1–9 cigarettes daily, OR =1.92 for 10+ cigarettes daily. However, within mother comparisons suggested that siblings exposed to MSDP also at increased risk for poor school performance. | |
Prospective – maternal smoking data collected in each trimester | Children between the ages of 6 and 9 years that had been followed in the Ottawa Prenatal Prospective Study N = 91 children | Test battery including Sound blending, Pegboard test, Conners parent Questionnaire, Developmental Drawings test. Peabody Picture Vocabulary Test, Wide Range, Achievement Test, and Hand Dominance | Maternal smoking associated with poorer performance on tests of speech and language skills, intelligence, visual/spatial abilities, and maternal rating of behavior | |
Retrospective-maternal smoking data collected one year after twins’ birth | High risk twin pairs at age 5 with 18-month follow-up n = 1116 twin pairs | Conduct problems on Achenbach instruments | Prenatal smoking associated with children conduct problems at age 5 and 7 years with dose response relationship for light, moderate and heavy smokers. However, once antisocial behavior in both parents, maternal depression, familial disadvantage, and genetic influences were controlled for, the effects of MSDP were substantially reduced. | |
Prospective – assessed in each trimester | Children aged 6–11 years that had participated in the Ottawa Prenatal Prospective Study n = 110 children | Central auditory processing task (SCAN) | Prenatal exposure associated with poorer performance on SCAN | |
Retrospective-maternal smoking data collected shortly after birth | 2–3 year old twin pairs from the Netherlands Twin Register n = 377 twin pairs | Child Behavior Checklist | Association of MSDP with externalizing (especially aggression) but not internalizing behaviors | |
Prospective-maternal smoking data collected to gain entry into smoking cessation study | 3 year old offspring of mothers who smoked during pregnancy n = 366 offspring | McCarthy Scales of Children’s Abilities and Minnesota Child Development Inventory (MCDI) | Offspring of mothers who quit smoking showed higher scores on the General Cognitive Index of the McCarthy Scales and MCDI scores compared with offspring of mothers who did not quit smoking | |
Retrospective – maternal smoking data collected when offspring were aged 8–16 years | Twins from the Virginia Twin Study of Adolescent Behavioral Development n = 1413 families | Conduct disturbance and smoking behavior form the Child and Adolescent Psychiatric assessment | Conduct disorder related to some other variable than smoking during pregnancy | |
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Prospective – mother reported smoking behavior in third trimester | Birth cohort of 4169 males at age 34 years | Adult criminal outcomes | Dose response relationship between maternal smoking behavior and arrests for nonviolent and violent crimes (especially persistent criminal behavior. | |
Prospective – maternal smoking behavior assessed at each prenatal visit | Offspring from the National Collaborative Perinatal Project n = 1248 | DSM III nicotine and marijuana dependence | Offspring of mothers who smoked during pregnancy were more likely to develop nicotine but not marijuana dependence compared with unexposed offspring | |
Prospective – maternal smoking data collected at fourth and seventh prenatal visit and at delivery | Low-SES birth cohort randomly sampled from an urban prenatal clinic n = 589 10-year olds | Questions about use of tobacco, alcohol and marijuana | Association of MSDP and early tobacco experimentation in preadolescence | |
Retrospective – maternal smoking data collected at birth | 18 year old offspring followed in a longitudinal study n = 1022 children | Mental health problems measured with Composite International Diagnostic Interview at age 18 | Offspring of mothers who smoked were more likely to have higher psychiatric symptom rates for conduct disorder, alcohol and substance abuse and depression | |
Retrospective – maternal smoking data collected at 4-year follow-up | Siblings of ADHD and non-ADHD probands n = 266 | DSM III- R | Maternal smoking associated with ADHD, | |
Retrospective – maternal smoking data collected at 4-year follow-up | Siblings of ADHD and non-ADHD probands n = 266 | DSM III- R | Maternal smoking associated with ADHD, CD, Major Depression and drug abuse | |
Retrospective- Maternal smoking data collected from mothers of ADHD probands and non-ADHD comparison probands (mean age of 13) | High risk-siblings ascertained through probands of ADHD and non-ADHD controls n = 174 siblings of ADHD probands and 129 siblings of non-ADHD probands | DSM III-R diagnosis of ADHD | Association of MSDP and ADHD. Association also found after controlling for SES, parental IQ, and parental ADHD status | |
Mixed - maternal smoking data collected during and in first few days after pregnancy | Assessment at mean age of 18.7 n = 3044 singleton males | Intelligence assessed by Børge Priens Prøve. | Negative association of maternal smoking with intelligence in a dose-response relationship for five levels of maternal smoking. | |
Unclear – appears to be prospective | Men from a general population cohort n = 5636 | Criminal records | Maternal smoking associated with violent and persistent (but not nonviolent) offenses. | |
Retrospective – maternal smoking data collected when offspring were aged 7–12 years | A longitudinal study of boys referred to one of two university outpatient clinics n = 177 boys | DSM-III-R using the Diagnostic Interview Schedule | Maternal smoking associated with conduct disorder | |
Retrospective-maternal smoking data collected when offspring were 2.5–5.5 years old | Preschoolers referred to Preschool Behavior Problems Clinic and controls n = 79 referred to clinic and 52 controls recruited from a general pediatric clinic | DSM-IV symptoms of ODD and CD assessed using K-SADS | Disruptive behavior disorder symptoms were associated with prenatal exposure to cigarettes | |
Retrospective – maternal smoking data collected when offspring were between 6 and 23 years old | Mother offspring pairs selected for presence or absence of lifetime history of major depression in parents N = 147 offspring whose mothers reported either never smoking during pregnancy (97) or 10+ cigarettes daily during pregnancy (50) | Schedule for Affective Disorders and Schizophrenia-Lifetime version (SADS-LA) and Peabody Picture Vocabulary Test (PPVT) | Male offspring of mothers who smoked during pregnancy had more than a 3-fold increased lifetime risk of conduct disorder, female offspring of mothers who smoked during pregnancy had a more than 5-fold increased risk of drug abuse/dependence |
Animal models tend to show the most consistent support of the effects, as well as the mode of action, of prenatal nicotine, which is just one toxic component of cigarettes. Importantly, animal studies do pinpoint nicotine, which partially mimics the actions of acetylcholine, as a neuroteratogen ( Slikker, Xu, Levin & Slotkin, 2005 ). The major outcome variables examined in prenatally exposed animals include birth weight, locomotor activity, and cognitive performance.
Similar to results in humans (e.g., Eskenazi, Prehn, & Christianson, 1995 ; Ricketts et al., 2005 ), findings in rats consistently show lower birth weight in offspring exposed to prenatal nicotine when compared with nonexposed offspring (see Ernst, Moolchan & Robinson, 2001 for review). Although prenatally exposed mice do not exhibit significantly lower birth weight, pups born to nicotine-administered dams show a significantly slower rate in postnatal weight gain ( Ajarem & Ahmad, 1998 ). These findings are of importance since, in humans, low birth weight has been shown to be associated with long-term cognitive deficits and ADHD (e.g., Botting, Powls, Cooke & Marlow, 1997 ; Bresleau & Chilcoat, 2000).
In general, animal studies tend to show increased locomotor activity in offspring who have been exposed to nicotine prenatally (see Ernst et al., 2001 for review). Studies in rats and mice have reported cognitive impairment, such as attention and memory deficits in various maze tasks, associated with prenatal nicotine exposure ( Levin, Briggs, Christopher & Rose, 1993 ; Liang, Poytress, Chen, Leslie, Weinberger & Metherate, 2006 ; Martin & Becker, 1971 ; Paz, Barsness, Martenson, Tanner & Allen., 2006 ; Peters & Ngan, 1982 ; Sorenson, Raskin & Suh, 1991 ; Yanai, Pick, Rogel-Fuchs, Zahalka, 1992 ). Mild deficits in learning have also been reported in rats (e.g., Liang et al., 2006 ; Martin & Becker, 1971 ), mice (e.g., Paz et al., 2006 ) and guinea pigs (e.g., Johns, Louis, Becker & Means, 1982 ; Johns, Walters & Zimmerman, 1993 ). These impairments in attention, memory, and learning are consistent with the cognitive deficits found in children diagnosed with, for example, ADHD ( Ernst et al., 2001 ). It has also been hypothesized that the observed deficits in operant learning found in animals, might translate to, and be associated with, dysfunction in reward or motivational processes, which could also predispose to substance abuse ( Ernst et al., 2001 ).
Prenatal exposure to nicotine evokes a spectrum of effects by discoordinating the timing of trophic events linked to a subset of cholinergic receptors, specifically nicotinic cholinergic receptors (nAChRs), present very early in the developing brain of rodents (embryonic day 10) and humans (4–5 weeks of gestation) ( Hellstrom-Lindahl, Seiger, Kjaeldgaard & Nordberg, 2001 ; Levin & Slotkin, 1998 ; Slikker et al., 2005 ; Slotkin, 1998 ; Slotkin, 1999 ; Slotkin, McCook, Lappi & Seidler, 1992 ; Slotkin, Orband-Miller & Queen, 1987 ). Once nicotine enters the fetal bloodstream it binds to nAChRs, which are found in the central and peripheral nervous system and can be found both postsynaptically (e.g., acetylcholine neurotransmission) and presynaptically influencing the release of other neurotransmitters ( Dani, 2001 ).
nAChRs are ligand-gated channels including five subunits, usually made of two alpha (a) and three beta (B) subunits. Several nAChR subtypes (or combinations of subunits) exist, each of which has a specific pharmacology, physiology, and anatomical distribution ( Pakkanen, Jokitalo & Tuominen, 2005 ). The two most abundant subtypes in vertebrate brain are: (i) α4, β2 combination, and (ii) α7. The different subtypes have important functional implications, particularly during development, as their relative distribution in the brain varies with developmental stage and age ( Ernst et al., 2001 ). nAChRs are significantly involved in brain development via promotion of cell division during gastrulation and subsequent promotion of the switch from cell replication to cell differentiation in terminal neuronal differentiation ( Shea & Steiner, 2008 ). The presence of these receptors in early embryogenesis ( Hagino & Lee, 1985 ) suggests that nicotinic signaling may be an important part of neural development. Reported changes in receptor density during normal development (e.g., high levels found at early gestation) might also imply windows of vulnerability to exogenous nicotine. In humans, periods of high density have been found in the frontal cortex, hippocampus, cerebellum, and brainstem during mid-gestation and neonatal periods ( Hellstrom-Lindahl, Gorbounova, Seiger, Mousavi & Nordberg., 1998 ; Hellstrom-Lindahl et al, 2001 ; Huizink & Mulder, 2006 ).
In the rat (e.g., Slotkin et al., 1987 ), and to a lesser extent in the mouse ( Van de Kamp & Collins, 1994 ), binding to the nAChR during development, whether during prenatal or early postnatal stages, is a necessary and key step leading to the adverse effects of nicotine. Several studies indicate that chronic prenatal nicotine exposure in rats and mice results in increased receptor density of fetal and neonatal cerebral nAChRs (for example, Slotkin, 1998 ; Van de Kamp & Collins, 1994 ). Upregulation of the nAChRs during development is conclusive evidence that the cell has experienced chronic nicotinic stimulation. The long-term effects of this up-regulation remain unclear ( Ernst et al., 2001 ); although the proposed mode of action suggests that this stimulation results in premature onset of cell differentiation, at the expense of replication, leading to (i) brain cell death, (ii) structural changes in regional brain areas, and (iii) altered neurotransmitter systems (i.e., acetylcholine, norephinephrine, epinephrine, dopamine, serotonin, as well as glutamate and gamma-aminobutyric acid; Shea & Steiner, 2008 ; Slikker et al., 2005 ). Such alterations could translate to physical deficits, such as impaired cardiac function associated with hypoxia, as well as deficits in later learning, memory, behavior, and development. Differences in developmental profiles of receptor binding between species and strains suggest that genetic factors regulate the maturation of the nicotinic receptor ( Van de Kamp & Collins, 1994 ). These genetic factors may explain interindividual differences in sensitivity to the effects of in utero exposure to nicotine ( Ernst et al., 2001 ).
There is no question that animal work is vital to the study of human problems; however the rat brain, for example, is obviously different from the human brain. Effects of MSDP in humans, for example, often show up in higher-level cognitive (executive) function, which are controlled by the prefrontal cortex. Functional and structural differences in the region of rat brain traditionally considered homologous to the dorsolateral prefrontal cortex in primates suggest that the rat may not have an equivalent region ( Preuss, 1995 ). Moreover, in humans, MSDP results in fetal exposure not only to nicotine, but to a large amount of other toxic components, such as carbon monoxide, ammonia, nitrogen oxide, lead, and other metals ( Huizink & Mulder, 2006 ). Thus, one should not limit the effects of MSDP in humans to nicotine alone. Importantly, while we can use the evidence of negative effects of prenatal nicotine exposure that we garner from animal work as a guide to narrow our focus on potential effects in humans, we cannot directly extrapolate from animal findings to the complex human condition.
As suggested earlier, the evidence for deleterious effects of MSDP on behavior and cognition later in life in human studies is muddied in the existing literature due to the inability to separate these effects from other confounding environmental and genetic factors. In a methodological review of the literature on effects of MSDP, Ramsay and Reynolds (2000) suggest that women who smoke during pregnancy may possess a constellation of personality traits that distinguishes them from other women. They focus on traits such as (i) increased depression and thus decreased motivation to quit smoking during pregnancy (Depression-Compulsivity model), (ii) elevated antisocial traits and thus reduced awareness of their consequences of MSDP as well as reduced concern for others (Antisocial model), and (iii) reduced attention to her own and, by extension, her infant’s nutrition and general well-being (Self-Care model). Thus, the personality of pregnant smokers may reflect a familial vulnerability for later disorders. Ernst and colleagues (2001) go on to outline numerous potential confounds, which include those suggested by Ramsay and Reynolds (2000) , as well as others: (1) parental characteristics: including IQ, psychiatric history (e.g., ADHD, antisocial personality disorder, substance abuse) and parenting; (2) maternal characteristics (e.g. health, height and weight (affecting metabolism of tobacco by-products)); and (3) smoking characteristics: intensity, gestational age at consumption ( Ernst et al., 2001 ). Importantly, a number of these confounds can be controlled for via alternative genetically sensitive designs. However, there is a surprising lack of comprehensive examination of the effects of MSDP within a genetically-informative framework. Specifically, the joint roles of environmental factors (e.g., MSDP) and genetic transmission in the risk for deficits, such as behavioral, learning, and cognitive dysfunction, are downplayed and there is a lack of control for differences between women who smoke during pregnancy and those who do not.
The offspring outcomes associated with MSDP cover broad cognitive and behavioral domains and are outlined thoroughly in several well laid-out and comprehensive reviews of the effects of MSDP (see Cnattingius, 2004 ; Ernst et al., 2001 ; Huizink & Mulder, 2006 ; Linnet et al., 2003 ; Shea & Steiner, 2008 ). These reviews are presented primarily from the phenotypic association point of view and say very little about how genetic factors may influence the reported associations between MSDP and offspring outcome. The main points of these reviews are presented briefly in this section, along with results from a few recent studies. The scope of results concerning the negative impact of MSDP, both suggestive and inconclusive, are presented. What is clear from these reviews is the need for more comprehensive study design as well as the lack of genetically informed studies on MSDP. The few studies that have considered genetic effects are reviewed in the final section of this report.
Epidemiological evidence from prospective and case-control studies show relatively high consistency for the association of adverse pregnancy outcomes (i.e., fetal growth restriction, hypoxia and placental effects, stillbirth, sudden infant death syndrome, etc) with MSDP (see Cnattingius, 2004 for detailed review ; Ernst et al., 2001 ); however, neurobehavioral outcomes have shown less consistency, indicating the potential need for more sensitive sampling designs and strategies.
MSDP is reported to increase rates of spontaneous abortion, stillbirth, sudden infant death syndrome, cleft palate, and most relevant to long-term neurobehavioral effects, preterm birth and low birth weight ( Bada et al., 2005 ; Conter, Cortinovis, Rogari & Riva, 1995 ; DiFranza & Lew, 1985; D’Onofrio et al, 2003 ; Ernst et al., 2001 ; Knopik et al., 2005 ; Kyrklund-Blomberg, Granath & Cnattinguis, 2005 ; Levin & Slotkin, 1998 ; Meyer, Williams, Hernandez-Diaz & Cnattinguis, 2004 ; Salihu, Aliyu & Kirby, 2006 ; Salihu et al., 2008 ; Sastry, 1991 ). Recent evidence also suggests that offspring of nonsmokers who used nicotine substitutes during pregnancy are at increased risk for congenital malformations ( Morales-Suarez-Varela, Bille, Christiansen & Olson, 2006 ).
These outcomes reported to be associated with prenatal exposure may be indirect or direct toxic consequences of MSDP. Nicotine produces anorexigenic, hypoxic, vascular, and placental effects that can adversely affect fetal development ( Cnattingius, 2004 ; Ernst et al., 2001 ). Existing theories focus on (i) maternal and fetal undernutrition due to the acute anorexigen effects of tobacco smoking ( Davies & Abernethy, 1976 ; Perkins, Sexton, DiMarco & Fonte, 1994 ); (ii) intrauterine hypoxia secondary to increased carbon monoxide and dioxide, reduced blood flow, and inhibition of respiratory enzymes ( Abel, 1980 , 1984 ; Byrd & Howard, 1995 ); (iii) disruption of the function of the placenta ( Huizink & Mulder, 2006 ; Naeye, 1978 ; Sastry, 1991 ; Suzuki, Minei & Johnson, 1980 ) via nicotinic activation of placental cholinergic systems which depresses transplacental amino acid transport, which may contribute to intrauterine growth retardation ( Cnattingius, 2004 ; Ernst et al., 2001 ). Thus, prenatal exposure may have direct teratogenic effects on the fetus leading to more readily observed adverse phenotypes; however, these effects most likely depend on the specific outcome measure of interest ( D’Onofrio et al., 2003 ).
The evidence for effects of MSDP on infant and toddler outcomes has been overall, inconsistent, perhaps due to the possibility that a certain level of brain maturation needs to be achieved before deficits become detectable ( Ernst et al., 2001 ; Huizink & Mulder, 2006 ). The inconsistency may also be due to less sensitive assessment tools for this age group. Data showing negative effects of MSDP suggest deficits in speech processing ability ( Key, Ferguson, Molfese, Peach, Lehman & Molfese, 2006 ), decreased scores in motor ability and verbal comprehension ( Gusella & Fried, 1984 ), reduced auditory acuity ( Saxton, 1978 ), increased hypotonicity, heightened tremors and startles ( Fried & Makin, 1987 ), and negative affect ( Brook, Brook & Whiteman, 2000 ) among infants who were prenatally exposed to nicotine. Since it has been shown that adverse birth outcome, such as preterm birth, is related to neurologic and developmental disabilities during the first two years of life ( Marlow, Wolke, Bracewell, Samara & EPI Cure Study Group, 2005 ), a recent study ( Law, Stroud, LaGasse, Niaura, Liu & Lester, 2003 ) adjusted their findings for factors relating to birth outcome and still found that newborns exposed to MSDP were more excitable and hypotonic and showed more stress/abstinence signs on a standard neurobehavioral assessment. Not all studies have found significantly negative relationships however. For instance, Obel, Henriksen, Hedegaard, Secher, and Ostergaard (1998) found mixed results when comparing babbling abilities in prenatally exposed 8-month olds to controls. When comparing nonbabblers to di- and polysyllable babblers, a trend toward a dose-response effect of MSDP was found, with those children exposed to more cigarettes per day showing less babbling ability. However, this trend was nonsignificant when comparing nonpolysyllable babblers to polysyllable babblers. Baghurst, Tong, Woodward, and McMichael (1992) also found no evidence for differences in verbal, perceptual, and motor scores due to prenatal exposure once adjusting for social class, home environment, and mother’s intelligence. Together, these findings suggest the possibility that MSDP is associated with motor, sensory, and cognitive deficits in infants and toddlers, which may indicate a pervasive toxic effect on early neurodevelopment.
Findings in children also seem to support a negative influence of in utero exposure to smoking on behavior and cognitive function; however, there are again some inconsistencies. MSDP has been associated with a significant increase in externalizing (e.g., oppositional, aggressive, overactive) scores but not internalizing behavior ( Brook, Zhang, Rosenberg & Brook, 2006 ; Day, Richardson, Goldschmidt & Cornelius, 2000 ; Orlebeke, Knol, & Verhulst 1999 ). Cognitive function has also been shown to be negatively affected by MSDP, with deficits in sustained attention ( Fried, O’Connell & Watkinson., 1992a ), response inhibition, memory, and impulsivity, overall cognitive function, receptive language ( Fried, Watkinson & Gray, 1992b ), verbal learning and design memory ( Cornelius, Ryan, Day, Goldschmidt & Willford, 2001 ), problem solving ( Cornelius et al., 2001 ), speech and language ( Makin, Fried, & Watkinson, 1991 ), school performance ( Lambe, Hultman, Torrang, MacCabe & Cnattinguis, 2006 ), and auditory processing ( McCartney, Fried & Watkinson, 1994 ). Dose-response relationships, in which the smoking-related relative risk increases with amount smoked, have also been reported for general cognitive ability ( Sexton, Fox & Hebel, 1990 ), arithmetic, and spelling ( Batstra, Hadders-Algra & Neeleman, 2003 ), suggesting the presence of vulnerable periods during fetal development ( Ernst et al., 2001 ).
As with infant and toddler outcomes however, some negative findings are also reported. For example, Bauman, Flewelling and LaPrelle (1991) reported that scores on receptive language and matrices tasks of more than 3000 9–11 yr olds exposed to MSDP but whose mothers quit afterwards, were similar to those of children not exposed to MSDP; however, both of these groups performed better than children exposed to both MSDP and smoking after pregnancy, suggesting the importance of also considering postnatal environment. No clear relationship was observed for MSDP and receptive language scores at 5 yrs or at 15–17 yrs. Eskanazi and Trupin (1995) also found no dose-response relationship of MSDP during the third trimester and cognitive performance in 5 yr olds. Moreover, despite findings of adverse effects of MSDP on school performance using a between family analysis ( Lambe et al., 2006 ), a within-sibling comparison of siblings exposed to differential amounts of MSDP (an example of a case-crossover design which is detailed below) indicated that if a mother had smoked during either pregnancy, both siblings were at increased risk of poor school performance ( Lambe et al., 2006 ); results suggesting that observed associations between MSDP and poor cognitive performance might not be causal.
In one of the most comprehensive analyses to date, D’Onofrio and colleagues (2008) analyzed data from the National Longitudinal Survey of Youth (NLSY), with particular attention to controlling for differences between women who do and do not smoke during pregnancy. They focused their efforts on the association between MSDP and offspring externalizing behavior [conduct (CP), oppositional defiant (ODP), attention deficit hyperactivity (ADHP) problems]. Their comparisons of unrelated children were consistent with the results of previous studies ( Wakschlag, Pickett, Cook, Benowitz & Leventhal, 2002 ) in several respects: (a) CP, ODP, and ADHP were significantly associated with MSDP; (b) each association followed a dose-response relationship; (c) the number of CP demonstrated by children exposed to MSDP was higher for males; and (d) each association remained significant after statistically controlling for associated maternal characteristics. In addition to the use of statistical covariates used in previous studies, D’Onofrio et al. (2008) utilized the clustered nature of NLSY data to account for unmeasured confounds. The hypothesis was that if MSDP caused higher externalizing, the relation would have been evident both when comparing related (e.g. within mothers) and unrelated children (e.g., Rodgers, Cleveland, van den Oord & Rowe, 2000 ). However, similar to Lambe et al. (2006) , when siblings who differed in exposure to MSDP (i.e., none/some vs. more exposure, a broad definition of discordance for MSDP ) were compared, the offspring did not differ significantly with respect to CP or ODP. These results suggest that previous studies found a relationship between MSDP and offspring CP not because MSDP causes increased risk for CP or ODP, but because environmental influences that vary between families confound associations between MSDP and offspring externalizing ( D’Onofrio et al., 2008 ). This finding is consistent with studies that have included more precise measurement of adult characteristics that may confound the relation, such as maternal and paternal antisocial characteristics ( Maughan, Taylor, Caspi, & Moffitt, 2004 ) and maternal delinquency during adolescence ( Silberg et al., 2003 ). It is also generally supportive of a recent children-of-twins study of maternal alcohol use disorder, MSDP and ADHD ( Knopik et al., 2006 ; detailed below).
Overall, it seems that behavioral and cognitive deficits associated with MSDP continue into late childhood and early adolescence and lead to increased risk for ADHD and Conduct Disorder (CD). MSDP has been associated with ADHD, CD, criminality and substance use (particularly smoking) in adolescence ( Ernst et al., 2001 ). Milberger and colleagues (1996 , 1997 , 1998) investigated MSDP as a risk factor for ADHD and found that 22% of children with ADHD had a history of MSDP, compared with 8% of controls. Significantly lower IQ scores were also found in children exposed to MSDP versus those who were not exposed ( Milberger, Biederman, Faraone & Jones 1998 ). Wakschlag and colleagues (1997 , 2001 , 2002) have consistently shown that MSDP is a robust, independent risk-factor for CD in males. Weissman, Warner, Wickramaratne and Kandel (1999) report similar findings reporting 4-fold increases in CD rates and 5-fold increases in adolescent drug abuse in children exposed to MSDP. Cornelius, Leech, Goldschmidt and Day (2000) and Buka, Shenassa and Niaura (2003) found increased risk for early tobacco experimentation and nicotine dependence, respectively, in children exposed to MSDP. Fergusson, Woodward and Horwood (1998) also suggested that MSDP contributes to children’s risk of later externalizing problems. Children exposed to MSDP had higher psychiatric symptom rate for CD, alcohol abuse, substance abuse, and depression compared with unexposed children. These childhood associations also appear to carry into adulthood. For example, Brennan, Grekin and Mednick (1999) and Rasanen et al. (1999) found relationships between MSDP and later criminality in male offspring up to age 28 and Mortensen, Michaelsen, Sanders and Reinisch (2005) reported a dose-response relationship between MSDP and adult intelligence.
MSDP is associated with offspring behavioral abnormalities, including increased evidence of attentional deficits, impaired learning and memory, lowered IQ, cognitive dysfunction, later childhood conduct problems, substance use, and early adult criminality; however, not all studies have reported a significantly negative relationship between MSDP and offspring outcomes.
What is clear from these reviews, however, is the need for more comprehensive study design in the study of MSDP. In short, there are a paucity of studies investigating gene-environment interplay in the proposed associations between MSDP and subsequent child outcomes. A key approach is to use a combination of strategies, such as twin, children-of-twin, and sibling-control designs, emphasizing both behavioral and molecular genetic methods, to elucidate the likely complex factors contributing to the association between MSDP and child outcomes. Preliminary findings from this work in the area of child externalizing problems ( Maughan et al., 2004 ; Knopik et al., 2006 ; D’Onofrio et al, 2008 ) indicate that, once genetic and environmental effects are accounted for, MSDP accounts for a much smaller effect than proposed by existing literature; however, while the effects were smaller, MSDP continued to be significantly linked to childhood behavior. Such results suggest that MSDP is unlikely to be a unique cause of early childhood behavior problems and illustrate the need for comprehensive study design.
The idea of joint roles of genetic and environmental factors can be referred to as gene-environment interplay. This is a broad term that encompasses several different concepts with different meanings and interpretations (see Rutter, Moffitt & Caspi, 2006 for detailed review). While a thorough and comprehensive review of gene-environment interplay is beyond the scope of this report, we will focus briefly on gene-environment interaction (G×E) and gene by environment correlation (rGE). G×E occurs when the effect of environmental exposure is conditional on a person’s genotype ( Moffitt, Caspi & Rutter, 2005 ). An example of G×E is phenylketonuria (PKU), a genetic disorder characterized by deficiency of the enzyme phenylalanine hydroxylase. Children who are homozygous (carry two copies) for a certain form of the phenylalanine hydrolylase gene are deficient in phenylalanine hydroxylase and cannot metabolize phenylalanine in food. Thus, phenylalanine accumulates and damages the developing brain. Phenylalanine has no harmful effects on other children who do not carry this particular genotype. However, PKU is one of the few genetic diseases that can be controlled by diet (an example of an environmental influence). A diet low in phenylalanine can be very effective treatment, yet this low phenylalanine diet has no harmful or beneficial effect on other children. Perhaps the most well-known example of G×E in the development of psychiatric disorders was reported by Caspi et al. (2002) who found that a functional polymorphism in the gene encoding the neurotransmitter-metabolizing enzyme monoamine oxidase A (MAOA) was found to moderate the effect of maltreatment, such that maltreated children with a genotype conferring high levels of MAOA expression were less likely to develop antisocial problems. These findings provided the basis for a growing literature suggesting that genotypes can moderate children’s sensitivity to environmental insults.
rGE can be thought of as genetic control of exposure to the environment or, in other words, an individuals genotype influences the probability of exposure to certain environments ( Caspi & Moffit, 2006 ; D’Onofrio et al., 2003 ; Jaffee & Price, 2007; Kendler & Eaves, 1986 ). rGE has been described as passive, active or evocative (see Jaffee & Price, 2007, for a full review). (i) Passive gene-environment correlation refers to the association between the genotype a child inherits from her parents and the environment in which the child is raised. Parents create a home environment that is influenced by their own heritable characteristics. (ii) Evocative (or reactive) gene-environment correlation happens when individuals are reacted to based on their genetic propensities or, in other words, an individual's (heritable) behavior evokes an environmental response (see Burt, 2008 ). (iii) Active gene-environment correlation occurs when an individual seeks out or creates certain environments based on their genetic propensity. rGE results in “the contamination of measures of environmental exposure with genetic variation and thus clouds interpretation of results” ( Caspi & Moffitt, 2006 , p.587).
One of the main limitations of studying familial and environmental influence and child development is that the parents are providing both the environment and the genes to their offspring ( D’Onofrio et al., 2003 ). In addition to prenatal environment, separate consideration should also be given to environmental exposure to second-hand smoke (see Eskenazi & Castorina, 1999 for review) since children born to smoking mothers are more likely to be exposed to environmental tobacco smoke ( Key et al., 2006 ), which could increase risk of developmental deficits ( Yolton, Dietrich, Auinger, Lanphear & Hornung, 2005 ). Most studies that have considered prenatal nicotine exposure have considered latent genetic variables or have examined the presence of measured G×E by focusing on the dopaminergic system and genes involved in the metabolism of tobacco by-products. These few studies are included in the review below.
At the time of this report, there have been no adoption studies that have specifically considered maternal smoking during pregnancy; however, two studies outlined in this section have considered prenatal drug exposure more generally ( Crea, Barth, Guo & Brooks, 2008 ; Neiderhiser et al., 2007 ). The lack of adoption studies in this arena does not preclude the potential importance of this design for MSDP. Adoption designs provide a direct way to disentangle genetic and environmental sources of variation. Adoption creates pairs of genetically related individuals who do not share a common family environment (and/or prenatal environment; i.e., biological siblings adopted apart and raised in different homes) and also creates family members who share family environment but who are not genetically related (i.e., non-biologically related children adopted into the same adoptive home). In both situations, any resemblance estimates the contributions of the family environment. A strong suit of the adoption design is the ability to study gene by environment interaction and additional processes through which gene-environment correlation creates the covariance between parents and children ( D’Onofrio et al., 2003 ). However, the adoption design does suffer from certain limitations. First, due to highly selective placement ensuring that the adoptive environment is excellent, there is an inherent difficulty in obtaining samples of children who are exposed to high-risk environments. Moreover, an assumption of this design is that there are no negative consequences of being adopted and that environmental processes operate similarly in adoptive and nonadoptive families ( D’Onofrio et al., 2003 ). Such an assumption is not needed in other genetically sensitive designs.
Crea et al (2008) did not focus on disentangling genetic and environmental influences on behavior per se, but rather examined behavioral trajectories for substance exposed adopted children, fourteen years after adoption. They found that prenatal exposure predicted elevated behavior problems but only slightly higher than those of nonexposed adopted counterparts. The overall rate of change in behavioral problems did not differ between exposed and nonexposed groups. This finding contradicts the argument that substance exposure alone is responsible for triggering a cascade of negative sequelae and encourages the investigation of protective familial environmental factors (e.g., positive rearing environment) that buffer the impact of this exposure ( Crea et al., 2008 ).
In a recent analysis of a sample from the Early Growth and Development Study ( Leve et al., 2007 ), Neiderhiser et al. (2007) examined 350 ‘yoked’ birth mothers, adopted children and adopted parents and 104 birth fathers. The focus was on toddler temperament and behavior problems at 18 months. The authors reported preliminary results suggesting that high levels of prenatal drug use significantly contributed to suppressed toddler affect and effects of genetic risk operated only via prenatal drug exposure ( Neiderhiser et al., 2007 ). Future planned work to extend these analyses in order to facilitate the disaggregation of prenatal exposure, genes (via DNA collection), as well as postnatal rearing environment will lend considerable and potentially important information to the effort to elucidate these complex relationships ( Leve et al., 2007 ).
The twin method compares the similarity between identical (monozygotic or MZ) twins and fraternal (dizygotic or DZ) twins (see Plomin, DeFries, McClearn & McGuffin, 2008 for details). If a trait is genetically influenced, MZ twins will be more similar than DZ twins; however, it is also possible that this greater similarity is due to environmental rather than genetic factors. This design can offer considerable knowledge in the genetic etiology of, not only outcomes of interest (e.g., ADHD or cognitive ability), but also risk factors (e.g., MSDP; see Agrawal et al., 2008 for genetic etiology of MSDP; D’Onofrio et al, 2003 , 2008 ;). It can also determine whether genetic effects differ in two environments; however, the models may only partially control for genetic factors since they assume that the specified environments represent ‘true’ or ‘pure’ environmental risk factors which are free from genetic influences (i.e., that there is no gene-environment correlation; Caspi, Taylor, Moffitt & Plomin, 2000 ; D’Onofrio et al., 2003 ; Purcell & Koenen, 2005 ). Classical twin studies, even those that add explicit measures of the environment, are also not able to delineate the processes involved in intergenerational processes ( D’Onofrio et al., 2003 ).
Four recent studies have tested the association between MSDP and ADHD or conduct problems/antisocial behavior within a twin design ( Button, Thapar & McGuffin, 2005 ; Knopik et al., 2005 ; Maughan et al., 2004 ; Thapar et al., 2003 ). As discussed in this section, using a twin design allows the genetic effects that contribute to the outcomes in children to be estimated (see Purcell & Koenen, 2005 for details on limitations involving environmental mediation in the classical twin study). In an examination of conduct problems in 5–7 year old twins, Maughan et al. (2004) report that, once genetic and environmental risks were controlled for, the effects of MSDP were substantially reduced. Thapar et al (2003) found that, in addition to substantial genetic influences on ADHD symptoms, MSDP explains additional variance above and beyond genetic effects. Button et al. (2005) report similar results when considering the covariation between antisocial behavior and ADHD stating that MSDP contributes small but significant amounts to the variance of both phenotypes. Knopik et al. (2005) suggest that prenatal and parental risk factors (e.g., maternal and paternal psychopathology) combine additively with the important genetic risk of developing ADHD, rather than interactively (i.e., no significant findings for G×E interaction). Thus, in summary it appears that, while genetic influences on these ADHD phenotypes are important, MSDP also has an independent effect on ADHD.
An extension of the classical twin study is the bivariate twin study that investigates the relationship between an environmental risk factor (considered as a phenotype) and an outcome of interest. A limitation of this extension is that the bivariate design cannot study all of the possible environmental risk factors that are involved in developmental psychology because the model can only include environments for which twins can differ (i.e., individual-specific environment; Purcell & Koenen, 2005 ). Thus, in the case of exposure to smoking during pregnancy (i.e., an obligatory shared environment in twin offspring exposed prenatally; Purcell & Koenen, 2005 ), this is a design that cannot be used. However, if one is considering the etiology of the behavior of smoking during pregnancy (i.e., twin mothers who can differ in their smoking behaviors), this design can be used to determine the covariation of MSDP and another outcome of interest. For example, Agrawal et al (2008) considered the genetic covariation of maternal smoking during pregnancy and nicotine dependence. Results indicated that women who smoked during an entire pregnancy reported heavier dependence and more unsuccessful quit attempts, compared with a community sample of mothers and with women who smoked during only part of a pregnancy. Educational attainment, weekly church attendance, spousal current smoking, and nicotine dependence also were associated with MSDP. The authors also found that heritable influences, even after adjustment for the above-stated significant psychiatric and sociodemographic covariates, explain nearly half of the variation in MSDP, with the remainder of the variance being due to environmental factors not shared by members of a twin pair. A large proportion of the genetic influences on MSDP were shared with nicotine dependence. These results, though not focused on childhood outcomes of MSDP, do have strong implications for treatment and intervention, in that a lifetime history of difficulty with smoking cessation, in conjunction with social background and psychiatric comorbidity, especially during pregnancy, needs to be considered by treatment providers when counseling expectant mothers about the potential risks of MSDP.
Another expansion of the classical twin study incorporates assessment of the twins’ parents. This design has the ability to estimate environmental effects while controlling for genetic effects on both parents and children ( D’Onofrio et al., 2003 ; Rutter et al., 1997 ). Limitations exist, as outlined in Rutter, Pickles, Murray, and Eaves (2001) . Specifically, the twin-family design requires identical measures for parents and children and also assumes that the same genetic and environmental structure influences both generations ( D’Onofrio et al., 2003 ).
The Children-of-Twins (COT) design can begin to elucidate the role that specific environments (such as prenatal exposure) play in the etiology of psychological and behavioral phenomena ( D’Onofrio et al., 2003 ), while studying intergenerational associations with fewer assumptions than the twin-family design. In the case of prenatal exposure, it allows one to begin to disentangle genetic, prenatal exposure, and other environmental effects on offspring outcomes. It also offers the additional advantage of including offspring sibling pairs that may differ in their amounts and/or timing of prenatal exposure (an obligatory shared environment in classical twin studies).
There are several approaches within this design: (i) children of discordant twins, which essentially involves (a) a comparison between the children of affected and unaffected MZ twins, and (b) a subsequent comparison of the rates of the disorder in children of the unaffected MZ and DZ cotwins; (ii) the MZ half-sib design ( Nance, 1976 ; Nance & Corey, 1976 ; Nance, Corey, & Boughman, 1978 ) which is a nested analysis of variance approach to the study of offspring of MZ twin pairs; (iii) a structural equation model fitting approach as outlined in D’Onofrio et al. (2003) which is a variation on the twin-family study and examines (a) within-generation, (b) cross-generation, same-family, and (c) cross-generation, cross-family correlations; and (iv) inferring genetic and environmental risk on offspring outcome from the co-twin’s (parental) history of the phenotype of interest ( Jacob et al., 2003 ; Knopik et al., 2006 ).
The COT design (see Jacob et al., 2003 for general discussion of the method) has been used less often in behavioral genetic studies, and has just recently been expanded to not only assess the potentially complex relationship between parental psychopathology (such as substance dependence) and child behavior, but to also consider the role of prenatal exposure in intergenerational associations ( D’Onofrio et al., 2003 ; Knopik et al., 2006 ). For example, in an attempt to understand the underlying processes associated with MSDP, D’Onofrio et al (2003) used the structural equation model approach within a COT sample to move beyond the straight phenotypic association between MSDP and birth weight. Their results suggested that MSDP appears to have a specific environmental association with offspring birth weight with no apparent confounding by genetic factors, common environment, or other measured covariates ( D’Onofrio et al., 2003 ).
Given evidence that mothers who abuse alcohol, who are alcohol dependent, or who have an alcohol dependent partner are more likely to smoke or drink during pregnancy (e.g., Knopik et al., 2005 ), Knopik et al (2006) used the COT design to examine the relationship between maternal psychopathology (specifically alcohol use disorder, AUD), MSDP, and child ADHD. This approach provides a powerful pseudo-adoption design in which genetic and environmental risk status is inferred from the co-twin’s history of, in this case, AUD. Importantly, children raised by an AUD monozygotic (MZ) or dizygotic (DZ) twin parent are at high risk for psychiatric disorders (e.g., ADHD) and other health problems because of high genetic and high environmental risk. In contrast, children raised by a non-AUD twin of an AUD MZ co-twin are at reduced environmental risk because they have not grown up with a mother with AUD, but these children are at the same (high) genetic risk as children raised by an AUD twin because the mothers have identical genotypes. In turn, children raised by the non-AUD twin of an AUD DZ co-twin are also at reduced (low) environmental risk but at only intermediate genetic risk because DZ twin pairs share on average 50% of their genes.
Thus, in the absence of any environmental effect of maternal AUD, after controlling statistically for psychopathology in the biological parents, the child of an AUD mother should be no more likely to develop ADHD than the child of a non-AUD parent who is the MZ co-twin of an AUD individual. Excess rates of ADHD in children of AUD mothers, after controlling for comorbid psychiatric disorders and pertinent variables, would imply an environmental impact of maternal AUD. Therefore, the COT design is a powerful design to disentangle the genetic and environmental effects on the association between maternal (or paternal) psychopathology and offspring outcome, while also estimating direct effects of measured environmental variables, such as prenatal exposure.
These data ( Knopik et al., 2006 ) yielded a pattern of results consistent with a genetic contribution to the association between maternal AUD and increased offspring risk of ADHD, but also reaffirmed the potential importance of MSDP. Compared to controls, rates of offspring ADHD were significantly elevated not only in families where the mother had a history of AUD, but also in families where the mother had no history of AUD, but had a monozygotic twin sister with AUD. In addition, rates of maternal regular smoking, and maternal regular smoking during pregnancy, were significantly elevated in those mothers who had a history of AUD, and in mothers who were unaffected, but had an affected monozygotic cotwin. This is consistent with a strong genetic correlation between alcoholism and smoking that has been found in other research, and implies a potential confounding of MSDP and genetic risk of alcoholism. Thus, genetic transmission and effects of MSDP are partially confounded. Models predicting ADHD outcome from family risk (of AUD) status, as well as other maternal and paternal psychopathology, indicated that even when maternal genetic risk of AUD and maternal regular smoking were controlled for, heavy MSDP remained a significant and strong predictor of offspring ADHD risk. Thus, while MSDP is likely contributing to the association between maternal AUD and offspring ADHD, the evidence for a significant genetic correlation suggests: (i) pleiotropic genetic effects, with some genes that influence risk of AUD also influencing vulnerability to ADHD; or (ii) ADHD is a direct risk-factor for AUD ( Knopik et al., 2006 ). Thus, these results from the COT design ( D’Onofrio et al., 2003 ; Knopik et al., 2006 ) yielded a pattern of results consistent MSDP having an independent effect on offspring outcomes even after controlling for potential confounders (e.g., genetic transmission, other environmental factors, and other covariates). The ability to begin to disentangle genetic and environmental intergenerational transmission in the domain of MSDP is critical for understanding the magnitude of risk that MSDP carries as this can have real implications for future research, intervention, and prevention efforts.
The cotwin-control design is a modification of the traditional case-control design where data is considered from twin pairs that are discordant for (i) the outcome of interest (e.g., ADHD), (ii) a variable related to the outcome of interest (e.g., schizophrenia in a model examining cognitive ability, see Kremen et al., 2006 ; early cannabis use in a model examining drug use as in Lynskey et al., 2003 ), or (iii) a environmental measure. The design controls for effects of age, gestational influences, and genetic factors ( D’Onofrio et al., 2003 ). It can also control for many environmental factors; however, similar to twin studies and as pointed out in D’Onofrio et al. (2003) , it is limited by methodological problems that prohibit the examination of many environmental risk factors that are commonly examined in epidemiological studies such as divorce, parenting practices, parental psychopathology, and MSDP (see D’Onofrio et al., 2003 for detail). The difficulties also lie in finding large enough samples of twins that are discordant for salient environmental factors that are under consideration. Thus, there is typically not enough power to draw definitive and meaningful conclusions ( D’Onofrio et al., 2003 ; Kendler & Gardner, 2001 ).
A variation on the cotwin-control study is the case-crossover design (or within-mother between-pregnancy design) which examines siblings discordant for prenatal exposure to MSDP. A form of this design was used in two studies discussed earlier in this report which compared siblings exposed to a broad definition of differential amounts of prenatal smoking (more vs less; D’Onofrio et al., 2008 ; Lambe et al., 2006 ). Meyer et al (2004) also used a case-crossover approach to examine the effects of MSDP on risk of oral cleft; however, their cases were those with cleft lip with or without cleft palate rather than defined by exposure to MSDP. More recently, Salihu et al. (2008) examined MSDP and risk of stillbirth using case-control and case-crossover designs. Similar to Meyer et al (2004) , case status was not defined by MSDP but rather as a stillbirth with controls being defined as live births ( Salihu et al., 2008 ).
In general, this method provides statistical control for confounding factors (e.g., heritable and sociodemographic characteristics of the mother that predict increased probability of MSDP) that might otherwise artifactually create, or alternatively mask, an association between MSDP and child outcomes. Moreover, this design, in combination with molecular genetic information (see examples below), could offer substantial information to the delineation of genetic and environmental factors in the relationship between MSDP and child outcomes. There are potential limitations of this case-crossover design, e.g., (i) mothers who are able to quit in one pregnancy but not all, may be, on average, less nicotine dependent and therefore smoke less than mothers who are unable to quit; (ii) smoking during pregnancy may be secondary to other life stressors that were present during pregnancy and these life events may not be readily captured during assessment (particularly if retrospective reporting is used); (iii) there may be a selection bias if more women give up rather than initiate smoking during the reproductive years ( Meyer et al., 2004 ); (iv) MSDP tends to be highly correlated in sequential pregnancies introducing possible bias due to autocorrelation ( Levy, Lumley, Sheppard, Kaufman, & Checkoway, 2001 ; Mittleman, Maclure, & Robins, 1995 ); and (v) the prevalence of smoking during pregnancy has, in general, declined over time ( CDC, 2004 ) which could affect results. Some of these limitations can be overcome with the use of bi-directional case-crossover designs, where controls (nonexposed siblings) are chosen from both sides of the exposed pregnancy (e.g., Lumley & Levy, 2000 ; Meyer et al., 2004 ). To control for exposure trends, a case-time-control design can also be used in conjunction with the case-crossover design (see Meyer et al., 2004 ). The case-time-control design estimates an exposure trend by explicitly matching cases with controls. This exposure trend is then used to adjust the case-crossover estimates by the trend estimate. There is also the issue of identifying such samples and acquiring large enough samples to make meaningful conclusions. Despite these limitations, this case-crossover design in combination with molecular genetic information holds promise in the study of adverse effects of MSDP.
Earlier it was suggested that prenatal exposure may have direct teratogenic effects on the fetus leading to more readily observed adverse phenotypes; however, these effects most likely depend on the specific outcome measure of interest. In fact, the effect of MSDP on the fetus may also interact with other factors, such as genetic factors. In an investigation of gene-environment interaction (G×E), Wang and colleagues (2002) investigated the modifying role of two maternal xenobiotic [i.e., corresponding to a chemical compound (such as a drug, pesticide, or carcinogen) that is foreign to a living organism] metabolism genes (CYP1A1 and GSTT1) in the association between MSDP and infant birth weight. Their research was prompted by the fact that tobacco smoke contains approximately 4000 compounds ( Brunnemann & Hoffmann, 1991 ); the most important carcinogens in tobacco smoke are polycyclic aromatic hydrocarbons (PAHs), arylmines, and N-nitrosamines ( Bartsch et al, 2000 ). The ability of an individual to convert toxic metabolites of cigarette smoke to less harmful ones is important for minimizing other adverse health effects. As outlined in Wang et al. (2002) , the metabolic processing of PAH (for example) in humans occurs in two phases. The phase 1 metabolism is an activation process, in which the inhaled, hydrophobic PAHs are converted mainly through aryl hydrocarbon hydroxylase activity into hydrophilic, reactive, electrophilic intermediates that can bind covalently to macromolecules, especially DNA ( National Research Council, 1983 ). These intermediates may be more toxic than the original form. Aryl hydrocarbon hydroxylase, encoded by the CYP1A1 gene, is a phase 1 enzyme and is particularly relevant to the metabolism of cigarette smoke. The phase 2 metabolism is a detoxification process, in which these metabolic intermediates are detoxified by enzymes such as glutathione S-transferases (GSTs) or uridine diphosphate (UDP)-glucuronosyltransferase through transformation into conjugated forms that are sufficiently polar to be excreted from the body ( Timbrell, 1991 ). GSTT1, encoded by the GSTT1 gene, is a major phase 2 enzyme. Both CYP1A1 and GSTT1 are highly polymorphic ( Ishibe et al., 1997 ; Nelson et al., 1995 ; Xu, Kelsey, Wiencke, Wain & Christiani, 1996 ) and their polymorphisms have been associated with their encoded enzyme activities (Kawaijiri et al., 1990; Wiencke, Pemble, Ketterer & Kelsey, 1995 ). Wang et al. (2002) found that, when considering the CYP1A1 genotype (i.e., the combination of alleles for the CYP1A1 gene), increased reduction in infant birth weight was seen in children born to mothers with the Aa/aa genotype (OR=3.2, 95% CI=1.6–6.4). When the GSTT1 genotype was considered, there was increased reduction in birth weight (OR=3.5, 95% CI=1.5–8.3) in children born to mothers with the absent genotype group. When both CYP1A1 and GSTT1 genotypes were considered, the greatest reduction in birth weight was found among smoking mothers with the CYP1A1 Aa/aa and GSTT1 absent genotypes (−1285g). These results suggest an interaction between maternal metabolic genes and MSDP with regard to infant birth weight.
More recently, Tsai et al. (2008) observed a significant joint association of maternal smoking, CYP1A1 (Aa/aa) and GSTT1 (absent) genotypes with gestational age and with preterm delivery. Such joint association was particularly strong in certain preterm subgroups, including spontaneous preterm delivery, preterm delivery < 32 weeks, and preterm delivery accompanied by intrauterine infection/inflammation. Taken together, maternal smoking significantly increased the risk of preterm delivery among women with high-risk CYP1A1 and GSTT1 genotypes. Findings were strongest among preterm delivery accompanied by intrauterine infection/inflammation suggesting that intrauterine infection/inflammation may be a potential pathogenic pathway by which MSDP affects preterm delivery. Specifically, the gene-MSDP interactions may exert their effects synergistically on preterm delivery through maternal and fetal inflammatory responses and raise the possibility of identifying women at high risk for certain pregnancy outcomes by accounting for environmental exposures and genetic polymorphisms ( Tsai et al., 2008 ).
Infante-Rivard, Weinberg, and Guiguet (2006) studied CYP1A1, GSTT1, as well as a set of ‘repair’ genes (XRCC1, XRCC3, and XPD), due to the fact that cigarette smoke can generate reactive oxygen species, which are capable of inducing double-strand breaks in DNA. These ‘repair’ genes can maintain the integrity of the genetic code. The authors investigated these genetic polymorphisms and their interaction with MSDP in the role of small-for-gestational-age births (birth weight below the 10 th percentile according to gestational age and gender). Results indicated that certain genetic variants (maternal CYP1A1, maternal XRCC3, and newborn GSTT1) increased the risk of small-for-gestational-age birth and modified the effects of MSDP by increasing or decreasing its risk ( Infante-Rivard et al., 2006 ). Of particular interest here is the fact that not only are maternal genotypes involved, but also newborn genotypes which emphasizes the importance of obtaining DNA from mother, child, and father if available and conducting family-based studies to further examine the roles of these genes.
There are also a few studies that have focused on, and claim evidence for gene-environment interactions (dopaminergic pathway genes and prenatal smoking) on externalizing behavior in children ( Kahn, Khoury, Nichols & Lanphear, 2003 ; Neuman et al., 2007 ). However, these causal relationships need to be considered carefully. These studies, to the best of my knowledge, do not control for the fact that prenatal smoking may be correlated with parental behaviors that could act as more proximal risk factors that are in turn transmitted to their offspring. In brief, Kahn et al. (2003) found that children with the DAT1 480/480 homozygous genotype who were exposed to prenatal smoking had significantly elevated hyperactive-impulsive and oppositional scores on the Conners' Parent Rating Scale Revised-Long Version. The most striking association was with oppositional defiant behavior. Consistent with Kahn et al. (2003) , Becker, El-Faddagh, Schmidt, Esser and Laught (2008) also reported evidence of an environmentally moderated risk for ADHD behaviors, suggesting that effects of MSDP were dependent on genetic susceptibility (as reflected by individuals’ DAT1 genotypes) and thus operating via G×E interaction. Specifically, males who were exposed to MSDP and who were homozygous for the DAT1 480 allele had higher hyperactivity-impulsivity than males in other groups. This G×E effect was not evident in females. Recently, Neuman et al (2007) also reported that the risk of diagnosis for any DSM-IV ADHD was greatest for children exposed to MSDP and whose genotype contained either the DAT1 440 allele [in contrast to Kahn et al (2003) and Becker et al (2008) ] or the DRD4 exon 3 7-repeat allele. In summary, these results suggest an interaction between dopaminergic genes (in offspring) and MSDP with regard to child externalizing behavior; however, the conflicting nature of reported findings also stress the need for highly refined phenotypes, the measurement of other potential confounding factors (such as the fact that MSDP might only be a marker for maternal ADHD or other important genes transmitted to the child), and the measurement of other gene variants that might be in linkage disequilibrium (non-randomly associated) with the dopaminergic genes investigated ( Becker et al., 2008 ). Futher, the multifactorial nature of many child outcomes underscores the importance of studying both genetic and environmental factors and their interaction ( Becker et al., 2008 ).
The few genetically-informed studies that have considered MSDP suggest that, for certain outcomes, MSDP does have a specific environmental effect that is not confounded with genetic factors, common environmental factors, and other covariates. GxE (measured gene) studies also indicate that there is suggestive evidence that certain genetic polymorphisms (both maternal and offspring) do moderate the teratogenic effects of prenatal smoking exposure on infant birth weight, preterm delivery, and externalizing behavior. Taken as a group, these results highlight the importance of including genetic and environmental variables in the study of the association between MSDP and offspring outcomes.
Ideally, studies assessing effects of MSDP would recruit participants while pregnant, with continued follow-up of offspring to investigate outcomes associated with MSDP and its correlates (e.g., maternal/paternal psychopathology, home environment, exposure to second-hand smoke, etc). This, however, is not always possible. Many studies must rely on retrospective report of smoking during pregnancy. There has been some question of the reliability of retrospective reporting, in that such reporting could result in underreporting due to social desirability or greater measurement error which could cause the importance of prenatal exposure to be underestimated. Petitti, Friedman, and Kahn (1981) state that the reliability of retrospective reports is similar to the recall of other substance use. More recent reports also indicate high reliability and stability of maternal reporting about their pregnancies, including smoking ( Heath et al., 2003 ; Patrick et al., 1994 ; Reich, Todd, Joyner, Neuman & Heath, 2003 ; Tomeo et al., 1999 ;). Moreover, there is a high correlation between self-reported smoking and serum cotinine measures ( Klebanoff, Levine, Clemens, DerSimonian & Wilkins, 1998 ; McDonald, Perkins, & Walker, 2005 ).
Despite advances in interview assessment and procedures, the use of retrospective reports of the prenatal and postnatal environment should be used with caution. Retrospective recall of environmental exposures are likely to give rise to artefactual gene-environment associations arising from behavioral ‘contamination’ of the reported events (Jaffee & Price, 2007). Specifically, such reports may be influenced by individual differences in personality, mood, or mental health, or may reflect the degree to which past environments were elicited by an individuals behavior ( Kendler, 1996 ; Jaffee & Price, 2007).
It is unlikely, given methodological limitations and the risk factor under consideration (MSDP which, in twin offspring, will not differ), that a single design will provide the answers to the complicated nature of the association between MSDP and subsequent outcomes. Over the past three decades, behavioral geneticists have begun to use designs that combine many of the methods outlined in this report in order to bring more power to bear on analyses. For example, a necessary first step in mapping complex traits to genetic loci is to establish the amount of genetic variation that underlies the phenotypic variation of the trait (i.e., heritability). This is accomplished via twin studies. If phenotypic variation in a trait is found to be caused in part by genetic sources (i.e., the trait is heritable), linkage and/or association studies can be conducted in order to characterize the effects of specific genes on phenotypic variation ( Posthuma & Boomsma, 2000 ). But, if the trait of interest is not found to be heritable, the search for the measured genetic effects (i.e., direct main effects or interactive effects of, for example, dopaminergic genes) will most likely not be initiated. Researchers need to not only (i) use the knowledge that we can gain from the designs presented here as well as the information that animal models of MSDP provide (i.e., the teratogenic effect of nicotine on the fetus), but also (ii) to consider pooling resources in order to conduct studies that are powerful enough to make meaningful conclusions. Only then will we gain insight into the underlying processes involved in MSDP.
The ultimate goal of future research in prenatal tobacco exposure is to attempt to derive a relatively unbiased estimate of the magnitude of the association between exposure and outcome – to determine a real vs. statistically spurious effect. Indeed, the fully unbiased estimate is an elusive concept that is never achieved but hopefully more closely realized through increasingly rigorous and comprehensive methods. Future research in this domain should attempt to achieve as accurate as possible an assessment of the magnitude of the association between MSDP and neuropsychological as well as other more physical outcomes. There is strong reason to believe that the established estimates of MSDP-risk on outcome in the literature are upwardly biased due to lack of control for heritable and other confounding factors. A comprehensive approach incorporating genetically-informed samples is of critical importance to obtain a more refined estimate of these associations. Indeed, the more refined effect size may be smaller than what is currently accepted. This, in and of itself, is of great public health significance, not because it will identify a new putative causal agent, but because it will more accurately assess the upper limit of the potential causal association between MSDP and outcomes important for public health, such as low birth weight, cardiorespiratory illness, and ADHD. This should not diminish concern regarding MSDP, but rather could help clarify what are and are not potential causes of ADHD, other neuropsychological, and physical deficits seen in children across the developmental spectrum. Thus, not only is there the potential that findings could provide yet one more incentive for pregnant women to overcome tobacco dependence and quit, but findings can also guide treatment providers to think more comprehensively about smoking during pregnancy and the potential correlates of said behavior. In other words, treatment providers may not only treat, or be concerned with, MSDP, but also correlated behaviors (e.g., maternal psychopathology, detrimental rearing environment, secondhand exposure to smoking) that might also increase risk of certain offspring outcomes. This more informed approach to treatment or general cessation efforts could, in theory, have significant effects on the major public health concern that is smoking during pregnancy and thus result in something that is of substantial value to the field of public health.
Admittedly getting a pregnant woman to stop smoking is perhaps the most straightforward intervention; however, we have ignored other potential confounding factors for far too long. The reality is that, in humans, we do not understand how much of the association between MSDP and offspring outcomes can be attributed to either nicotine or other smoking by-products. By putting more realistic boundaries on the impact of MSDP and not continuing to ignore confounding factors, we open the door for other avenues of treatment, intervention, and prevention – opportunities that heretofore have been missed. The first step around this hurdle – and elucidating real vs. statistically spurious effects of MSDP -- are genetically informed designs.
This work was supported by grant DA17671 from the National Institute of Drug Abuse.
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Exposure to cigarette smoking during foetal and early postnatal life may have implications for lung health. The aim of this study was to assess the possible effects of such exposure in utero on lower respiratory disease in children up to two years of age.
A birth cohort of 4089 newborn infants was followed for two years using parental questionnaires. When the infant was two months old the parents completed a questionnaire on various lifestyle factors, including maternal smoking during pregnancy and after birth. At one and two years of age information was obtained by questionnaire on symptoms of allergic and respiratory diseases as well as on environmental exposures, particularly exposure to environmental tobacco smoke (ETS). Adjustments were made for potential confounders.
When the mother had smoked during pregnancy but not after that, there was an increased risk of recurrent wheezing up to two years' age, OR adj = 2.2, (95% CI 1.3 – 3.6). The corresponding OR was 1.6, (95% CI 1.2 – 2.3) for reported exposure to ETS with or without maternal smoking in utero. Maternal smoking during pregnancy but no exposure to ETS also increased the risk of doctor's diagnosed asthma up to two years of age, OR adj = 2.1, (95% CI 1.2 – 3.7).
Exposure to maternal cigarette smoking in utero is a risk factor for recurrent wheezing, as well as doctor's diagnosed asthma in children up to two yearsof age.
Many children are exposed to tobacco smoking, both before and after they are born. Maternal smoking during pregnancy is believed to affect the utero-placental flow, leading to an impaired foetal nutrition and consequent intrauterine growth retardation [ 1 ]. The foetus of smoking women is exposed from the time of conception to the same levels of nicotine as active smokers [ 2 ]. Smoking during pregnancy affects foetal lung development, reflected in spirometric flow in the neonate, especially when there is a family history of asthma and hypertension during pregnancy [ 3 , 4 ] and causes abnormal airway function [ 5 , 6 ]. Effects of ETS due to parental smoking on respiratory health in early childhood have been described in epidemiological studies [ 7 – 10 ] but few have made an effort to discriminate between effects of prenatal and postnatal exposure. Recent studies, however, suggest that smoke exposure in utero may be at least as detrimental to respiratory health in early life as postnatal exposure to ETS [ 11 , 12 ].
This prospective birth cohort study focuses on maternal smoking during pregnancy as a risk factor for recurrent wheezing during the first two years of life.
From February 1994 until November 1996, 4089 newborn infants (2,024 girls and 2,065 boys) were included in a population based prospective study, BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiological survey). The children were born in predefined areas in Stockholm and recruited at their first visit to the Child Health Centre. During the recruitment period 7,221 infants were born in the study area and of these 1,256 were excluded because the families planned to move within a year, had insufficient knowledge of Swedish or an already enrolled older sibling. Another reason for exclusion was a serious disease in the neonate. For 477 infants correct addresses were not available. Thirteen hundred and ninety-nine declined participation. The final study cohort thus constituted 75 % of the eligible children. Details of the study design, inclusion criteria, enrolment and data collection are described in detail elsewhere [ 13 – 15 ].
The first questionnaire was filled in by the parents at the time of enrolment (Q0) at a median age of the children of 2 months (10 th percentile 0 months, 90 th percentile 5 months of age). The questionnaire aimed to assess the home environment as well as various indoor environmental exposures such as maternal smoking during pregnancy and smoking habits of both parents after birth of the child. A second part of the questionnaire covered the health of both parents with focus on allergic diseases i.e. asthma, allergic rhino-conjunctivitis and eczema. Socioeconomic status was classified according to the Nordic standard occupational classification (NYK) and Swedish socio-economic classification (SEI) [ 16 ]. The children were categorised on the basis of their parents' occupation into blue-collar workers, white-collar workers and others (students, unemployed). Identical questionnaires (Q1 and Q2) dealt with disease symptoms in the children and were distributed by mail to the parents when the children were one and two years of age. Combinations of reported symptoms were used to define criteria for different diagnoses (see below). Information on important exposure factors, such as parental smoking and breast-feeding, were also obtained from the questionnaires. The questions on symptoms and tobacco smoke exposure have been used in earlier studies [ 17 – 19 ]. Reminders for all three questionnaires were sent three times. The response rates to Q1 and Q2 were 96% and 94%, respectively. The median age for answering Q1 was 12 months and for Q2 24 months. Those who had responded to all three questionnaires (N = 3,791, 93%) before one, two and three years of age of the child, respectively, constituted the basis for this study.
Foetal exposure to maternal smoking was reported in Q0 and was defined as maternal daily smoking of one cigarette or more during any trimester of pregnancy. The degree of such exposure was quantified for each trimester separately. Information on paternal smoking during the period in utero was not collected.
ETS was defined from exposure to maternal smoking of one cigarette or more daily during the first months of life and/or maternal smoking at one year of age of the child. Quantitative information i.e. the number of cigarettes smoked both of mothers and fathers, was obtained in Q0 for the first two months, Q1 and Q2 for the first and second year of life, respectively. In Q0 the parents also indicated whether they smoked at home and when the answer was yes whether they smoked on the balcony/at an open window/under the fan, thus actively avoiding direct exposure of the child.
Recurrent wheezing up to two years of age.
Three episodes of wheezing or more after three months of age in combination with the use of inhaled glucocorticoids and/or signs of bronchial hyperreactivity (wheezing or severe coughing when playing or being excited, or disturbed coughing at night not associated with common cold).
Reported "asthma" diagnosed by a doctor during the first and/or second year of life of the child.
Wheezing and/or disturbing cough at night not associated with a common cold during the first and/or second year of life.
Odds ratios (ORs) and ninety-five percent confidence intervals (CIs) were calculated using logistic regression. To identify potential confounders several models including various covariates were tested (heredity, socioeconomy, maternal age, keeping of cat and/or dog, construction year of the home and duration of breastfeeding). Finally, adjustments were made for heredity (defined as doctor-diagnosed asthma and asthma medication and/or allergic rhino-conjunctivitis diagnosed by a doctor in combination with reported allergy to furred pets and/or pollen in one or both parents), exclusive breastfeeding during 4 months or more and maternal age ≥ 26 years, because these variables changed the OR estimates for smoking exposure. To test for interaction between smoking and other covariates an interaction term was included in the logistic regression model. The chi-square test and the Fisher exact test were used for statistical analyses of proportions.
Complete information on maternal smoking during pregnancy and answers on all three questionnaires were required to be included in the analyses and this was available for 3790 subjects.
Statistical analyses were made with the Stata Statistical Software: Release 8.0 (College Station, Texas, USA).
The study was approved by the ethical committee at the Karolinska Institutet, Stockholm, Sweden.
Short duration of breast-feeding, maternal age below 26 years, socio-economic status of the parents, the keeping of cat and/or dog and reported dampness were all associated with maternal smoking during pregnancy (table 1 ). In total, 469 infants were exposed to maternal smoking in utero. The prevalence of smoking decreased during pregnancy and reported smoking during the first, second and third trimester were 12%, 10 % and 9 % respectively. Twelve percent of the mothers reported to have smoked at least one cigarette daily during any part of or all through pregnancy. During the child's first two months the corresponding proportion was 8.0%, and when the child was one and two years old 9.4 and 10%, respectively. The corresponding reported postnatal exposure to paternal smoking was 16, 12 and 11%, respectively. Any exposure to ETS during the first two years of life of the children was reported for 25% of the children. In families with smoking fathers 34% of the mothers smoked compared to 8.3% in families with non-smoking fathers (p < 0.001). Most of the smoking parents (94%) reported in Q0 that they almost always smoked only outdoors, near open window or under the fan when at home.
The reported smoking of mothers with asthma or respiratory allergy (asthma requiring medication and/or doctor's diagnosed allergic rhino-conjunctivitis with reported allergy to furred pets and/or pollen) tended to be lower than that of mothers without such allergy both during pregnancy and the child's first two years (figure 1 ). This also held true for paternal smoking.
Smoking during pregnancy and the first two years of the child and parents with or without asthma and/or respiratory allergy.
The cumulative incidence of recurrent wheezing, doctor's diagnosed asthma and any wheezing up to two years of age were 8.5%, 6.5% and 27%, respectively. The reported smoking pattern of mothers of children with recurrent wheezing differed from that of the mothers with children without recurrent wheezing (figure 2 ). Maternal smoking of one cigarette daily or more was reported for 16 % of the children with recurrent wheezing at one year of age, compared to 8.7% for healthy children (p < 0.001). The corresponding proportions at two year's age were 17 and 9.4% (p < 0.001). Eleven percent of the mothers of the children with recurrent wheezing reported to have smoked ten cigarettes or more daily at one and 12% at two years age. The corresponding figures were 6.3% and 7.0% for mothers with healthy children.
Proportion of maternal smoking of one or more cigarettes daily during pregnancy and during the first two years of the child among children with and without recurrent wheezing.
A large majority of infants (85%) were reported neither to have been exposed to maternal smoking during pregnancy, nor to any maternal smoking during the first two months of life and/or at one year of age, and these constituted the reference group. One-hundred and thirty-three children (3.6%) had been exposed in utero, but not after being born. Eleven percent of the children were exposed to ETS with or without maternal smoking in utero. Only 2.4% of the children were reported to have been exposed exclusively to ETS.
Maternal smoking during any period of pregnancy, but not after giving birth was associated with an increased risk of recurrent wheezing at two years of age, (OR adj = 2.2, 95% CI 1.3–3.6), (table 2 ). The effect appeared most pronounced when there was maternal smoking during the first and/or second trimester, (OR adj = 2.5, 95 % CI 1.5–4.0), but not thereafter in a separate analysis using the entire material and adjusting for the effect of ETS (data not shown).
Exposure to ETS alone or in combination with exposure in utero tended to be associated with an increased risk of recurrent wheezing (OR adj = 1.6, 95 % CI 1.2 – 2.3). The risk estimates were similar in the different exposure groups for doctor's diagnosed asthma and any wheezing up to two years of age, respectively (table 2 ). These effects were independent of gender of the infant (data not shown).
Exposure to cigarette smoking during pregnancy and of maternal smoking during the child's first year of life increased the risk of recurrent wheezing as well as of doctor's diagnosed asthma and any wheezing, respectively, at one year of age, in a similar way as reported in table 2 . Reported paternal smoking during the child's first year of life had no additional effect on any of the outcomes under study (data not shown).
The results of dose-response analyses were not conclusive i.e. neither confirmed nor excluded a trend, mainly due to low numbers of subjects in the high exposure groups (data not shown). Furthermore, there was no clear evidence of interaction between smoking and heredity or gender (data not shown).
This study provides strong evidence that exposure in utero to maternal smoking is important for development of recurrent wheezing during the first two years of life, irrespective of exposure to ETS after birth. Similar results have been published by others, but generally without separating the effects of exposure in utero exposure to ETS during the first few years of life [ 20 , 21 ]. The study by Lux and coworkers, however, clearly indicates that maternal smoking restricted to pregnancy causes wheezing [ 11 ]. The design of their study is similar to ours and allows for separation of the effects of different exposure periods but data about smoking during pregnancy were only obtained for gestational weeks 30–32. In the present study information about maternal smoking during pregnancy encompassed the various trimesters in detail. Our data suggest an effect with exposure particularly during early pregnancy. If so, this is possibly a consequence of an effect on intra-uterine growth [ 1 ].
An effect of maternal smoking on the foetus has also been documented by several studies of pulmonary function in neonates [ 4 , 6 , 22 , 23 ]. Most of these studies indicate hampered expiratory flows as indices of a detrimental effect. In a study by Hoo and co-workers prematurely born infants, in average seven weeks, were investigated and maternal smoking was associated with reduced pulmonary function [ 24 ]. The spirometric data in neonates only give indirect evidence of a reduction in airway diameter. For obvious reasons no direct studies of morphological consequences of exposure to smoking in the neonate lung have been carried out in healthy term babies. However, in children with sudden infant death increased airway thickness has been associated with maternal smoking of more than 20 cigarettes daily [ 25 ]. To which extent this effect stems from exposure prior to or after birth is not clear.
In many studies the role of ETS, as a determinant of childhood asthma, has been investigated but in most of them without due consideration of the separate influence of maternal smoking during pregnancy [ 8 , 26 ]. In a meta-analysis by Strachan and Cook a pooled risk estimate of 1.57 was found for lower respiratory illness in relation to smoking by either parent [ 7 ]. The relative contributions of pre- and postnatal smoking were not disentangled. In the study by Lux, an OR of 1.3 was found for exposure to ETS exclusively [ 11 ]. Possibly, the effect of exposure in utero may be the more important which is also supported by our data.
In Sweden exposure of children to tobacco smoking has been reduced to levels which are low in an international perspective. This is probably a consequence of a very active health policy and an effective maternal and child health care. During the study there was also a campaign "Smokefree children" through the Child Health Centres which reached almost all (99.5%) of the families when the baby was new-born (Statistics from Child Health Centres, Stockholm County Council, 1995). The effects of ETS are possibly diminished because of an overall awareness of the detrimental effects of exposure. This is supported by the finding that 94% of the parents reportedly never exposed their children to ETS. Exposure of the foetus, on the other hand, cannot be avoided by the pregnant mothers who are active smokers.
Participation in the study is most likely to have been affected by parental awareness of health hazards associated with cigarette smoking. Thus, smokers may to a higher extent than non-smokers have chosen not to join the study. A study of non- responders and actively excluded families of the BAMSE study showed that these parents smoked more than those included in the cohort [ 15 ]. This would render the study base less representative of the population, but in relation to tobacco smoke exposure probably not affect the risk estimate of smoking related health effects. Furthermore, parents with allergic diseases would possibly be more willing to join the original cohort but we found no such selection. We had the advantage of a large sample, allowing for the assessment of effects of exposures in subgroups of infants. Yet, possible biases must be taken into account. Smoking tobacco was found to be associated with a negative family history of allergic disease. Furthermore, we based the risk estimation on maternal smoking only, for obvious reasons regarding smoking in pregnancy, but this may lead to some misclassification of exposure postnatally. The effects of the role of ETS will be studied more in detail in the future follow up if the cohort.
The main implication of this study is that smoking cessation programmes need to be targeted on childbearing ages. In maternal health care such efforts should focus not only on those who are already pregnant, but also on women who plan to conceive.
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Assistance by epidemiology assistant Lena Tollin, research nurse Inger Kull, research secretary Eva Hallner and data co-ordinator André Lauber, Department of Environmental Health, Stockholm County Council, and statistical support from Niklas Berglind. Institute of Environmental Medicine, Karolinska Institutet, are gratefully acknowledged.
The study was supported by: The Swedish Asthma and Allergy Association, Swedish Council for Building Research, Stockholm County Council, The Swedish Foundation for Health Care Sciences and Allergy Research (Vårdalstiftelsen), Sven Jerring Foundation and 3MPharma.
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Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
Eva Lannerö, Magnus Wickman & Goran Pershagen
Department of Paediatrics, Karolinska University Hospital, Huddinge, Sweden
Eva Lannerö
Department of Occupational and Environmental Health, Stockholm County Council, Stockholm, Sweden
Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
Magnus Wickman
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
Lennart Nordvall
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All four authors have made substantial intellectual contributions to this study and have also been involved in the BAMSE project since it started.
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Lannerö, E., Wickman, M., Pershagen, G. et al. Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE). Respir Res 7 , 3 (2006). https://doi.org/10.1186/1465-9921-7-3
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Smoking harms almost every part of your body. But if you smoke when pregnant, the toxic chemicals in tobacco will also harm your unborn baby, with new research showing that it could lead to reduced academic outcomes at school.
In a systematic review of 19 studies and 1.25 million participants, researchers at the University of South Australia along with a team at Curtin University, SAHMRI, Harvard University and others found that 79% of studies reported reduced academic achievement in children exposed to maternal prenatal smoking.
An additional meta-analysis of eight primary studies with 723,877 participants showed that children exposed to maternal prenatal tobacco smoking were 49% more likely to struggle with poor academic achievement in comparison to those who had not been exposed to smoking in utero.
In Australia, 8.7% (or 26,433) of all mothers who gave birth in 2021 smoked at some time during their pregnancy.
Lead researcher, UniSA's Dr. Bereket Duko, says that despite what is already known about smoking, research is still uncovering additional negative effects.
For decades, agencies across the globe have pushed anti-smoking campaigns about the dangers of smoking. But despite these efforts, tobacco smoking remains a pervasive global public health issue. Prenatal smoking is known to cause multiple pregnancy complications, including a higher risk of miscarriage, stillbirth, restricted growth and development, and serious birth defects. It is also linked with adverse mental health outcomes and behavioral issues. Our new research adds to this, by showing that maternal prenatal smoking has a significant risk of limiting a child's academic performance, putting them well behind their peers at school. We all want children to have the best start in life. But clearly, we must do better to educate mothers and families about the noxious effects of smoking while pregnant on mother and baby. Remember, the fight against smoking is not one we have already won. Yes, we have made big steps to reduce the number of people smoking, and we have made many aware of the health risks. But this is an ongoing battle, and we must continue to educate people about the dangers of tobacco so that the next generations do not unnecessarily suffer." Dr. Bereket Duko, Lead Researcher, UniSA
University of South Australia
Duko, B., et al . (2024). The effect of maternal prenatal tobacco smoking on offspring academic achievement: A systematic review and meta-analysis. Addictive Behaviors . doi.org/10.1016/j.addbeh.2024.107985 .
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University of South Australia
Maternal prenatal smoking has a significant risk of limiting a child’s academic performance.
Credit: "Cigarette" by Sudipto_Sarkar is licensed under CC BY-NC-ND 2.0.
Smoking harms almost every part of your body. But if you smoke when pregnant, the toxic chemicals in tobacco will also harm your unborn baby, with new research showing that it could lead to reduced academic outcomes at school.
In a systematic review of 19 studies and 1.25 million participants, researchers at the University of South Australia along with a team at Curtin University , SAHMRI , Harvard University and others* found that 79% of studies reported reduced academic achievement in children exposed to maternal prenatal smoking.
An additional meta-analysis of eight primary studies with 723,877 participants showed that children exposed to maternal prenatal tobacco smoking were 49% more likely to struggle with poor academic achievement in comparison to those who had not been exposed to smoking in utero.
In Australia , 8.7% (or 26,433) of all mothers who gave birth in 2021 smoked at some time during their pregnancy .
Lead researcher, UniSA’s Dr Bereket Duko , says that despite what is already known about smoking, research is still uncovering additional negative effects.
“For decades, agencies across the globe have pushed anti-smoking campaigns about the dangers of smoking. But despite these efforts, tobacco smoking remains a pervasive global public health issue,” Dr Bereket says.
“Prenatal smoking is known to cause multiple pregnancy complications, including a higher risk of miscarriage, stillbirth, restricted growth and development, and serious birth defects. It is also linked with adverse mental health outcomes and behavioural issues.
“Our new research adds to this, by showing that maternal prenatal smoking has a significant risk of limiting a child’s academic performance, putting them well behind their peers at school.
“We all want children to have the best start in life. But clearly, we must do better to educate mothers and families about the noxious effects of smoking while pregnant on mother and baby.
“Remember, the fight against smoking is not one we have already won. Yes, we have made big steps to reduce the number of people smoking, and we have made many aware of the health risks. But this is an ongoing battle, and we must continue to educate people about the dangers of tobacco so that the next generations do not unnecessarily suffer.”
Notes or editors:
*Additional partners include the University of Iceland, the University of Queensland, the Norwegian Institute of Public Health, and the University of Sydney.
…………………………………………………………………………………………………………………………
Contact for interview: Dr Bereket Duko M: +61 410 350 140 E: [email protected] Media contact: Annabel Mansfield M: +61 479 182 489 E: [email protected]
Addictive Behaviors
10.1016/j.addbeh.2024.107985
Meta-analysis
Not applicable
The effect of maternal prenatal tobacco smoking on offspring academic achievement: A systematic review and meta-analysis
15-Jun-2024
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.
BMC Medicine volume 20 , Article number: 418 ( 2022 ) Cite this article
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Enhancing pregnancy health is known to improve the mother’s and offspring’s life-long well-being. The maternal environment, encompassing genetic factors, impacts of social determinants, the nutritional/metabolic milieu, and infections and inflammation, have immediate consequences for the in utero development of the fetus and long-term programming into childhood and adulthood. Moreover, adverse pregnancy outcomes such as preterm birth or preeclampsia, often attributed to the maternal environmental factors listed above, have been associated with poor maternal cardiometabolic health after pregnancy. In this BMC Medicine article collection, we explore a broad spectrum of maternal characteristics across pregnancy and postnatal phenotypes, anticipating substantial cross-fertilization of new understanding and shared mechanisms around diverse outcomes. Advances in the ability to leverage ‘omics across different platforms (genome, transcriptome, proteome, metabolome, microbiome, lipidome), large high-dimensional population databases, and unique cohorts are generating exciting new insights: The first articles in this collection highlight the role of placental biomarkers of preterm birth, metabolic influences on fetal and childhood growth, and the impact of common pre-existing maternal disorders, obesity and smoking on pregnancy outcomes, and the child’s health. As the collection grows, we look forward to seeing the connections emerge across maternal, fetal, and childhood outcomes that will foster new insights and preventative strategies for women.
The extraordinary, foundational months of pregnancy are a time of emergence of a new life for the conceptus and remarkable physiological and psychological adaptation by the mother. The orchestration of mutual communication between the mother and fetus is the driver of long-term health. It is shaped primarily by the maternal environment, with its genetic, physiologic, nutritional, inflammatory/infection, and psychological components. It has been repeatedly recognized that the in utero environment programs the fetus for lifelong health—the Barker Hypothesis—and pregnancy complications such as preeclampsia and preterm birth impact maternal cardiovascular health [ 1 , 2 ].
This special collection of articles by BMC Medicine seeks to synthesize information related to maternal and offspring outcomes associated with in utero exposures across pregnancy phenotypes and complications. Among the most common maternal traits that impact multiple aspects of fetal outcomes are maternal undernutrition and, more often, maternal overnutrition/obesity, associated with complications from development in an obesogenic environment and influences of gestational diabetes mellitus. In addition, the mechanisms leading to abnormalities in gestational duration and an increased risk for adverse outcomes such as preterm birth are central research targets [ 3 ]. The growing opportunity to interrogate “big data” with artificial intelligence or machine learning tools will accelerate this research and help to determine pregnancy interventions that are both safe and effective [ 4 , 5 , 6 , 7 ].
The editors believe that providing novel insights on exposures and outcomes across pregnancy phenotypes will be mutually informative as many driving determinants are shared. In this editorial, we will highlight some initial contributions to this collection and the new information that has been revealed.
Revealing underlying mechanisms in preterm birth and potential links to polycystic ovary syndrome.
Adverse pregnancy outcomes are common and have generally been refractory to interventions designed to reduce their incidence. Of all obstetric complications, preterm birth towers above nearly all others as the most severe. Affecting 8–10% of all pregnancies, it is depressingly common and can leave the newborn with a lifelong legacy of health deficits [ 8 ]: from subtle decrements in developmental outcomes for those born “late preterm” to profound disabilities for those born “extremely preterm” (cerebral palsy, chronic lung conditions, major learning problems) [ 9 ].
Spontaneous idiopathic preterm birth has been among the greatest challenges. Until now, there are no generally effective therapeutic interventions, and predictive biomarkers, while beginning to emerge, are limited. The lack of mechanistic insight has resulted in preterm birth being a long-standing leading cause of infant mortality and mortality in children under 5 years of age [ 10 ]. However, research of the underlying mechanisms in preterm birth has been greatly accelerated by using hypothesis-free interrogation of large data sets across ‘omics platforms and medical record information using advanced bioinformatic strategies [ 4 , 5 , 6 , 7 ].
As part of this collection, Tiensuu and colleagues [ 11 ] present new data for a candidate biomarker for preterm birth that may also help unravel the underlying mechanisms and is a potential target for interventions. In this study, the investigators evaluated whether placental proteins associated with spontaneous preterm birth can be identified using proteomics. Intriguingly, protein and mRNA levels of alpha-1 antitrypsin (AAT)/SERPINA1 were found to be downregulated on both the maternal and fetal sides of the placenta. This finding served as a basis to investigate whether damaging genetic DNA variations in AAT were also associated with spontaneous preterm birth through whole exome sequencing—and indeed, they were. After revealing this association, the authors performed functional studies, indicating that the downregulation of AAT affects the actin cytoskeletal pathways and extracellular matrix organization.
Beyond identifying relevant biomarkers, there is a strong need for interventions to prevent adverse pregnancy outcomes. The Tiensuu study moves forward with one strong candidate for such an intervention. Moreover, their approach of utilizing multiple association strategies to provide further evidence for a particular finding can be applied across various disease phenotypes.
Major risk factors for preterm birth have long been elucidated [ 8 , 9 ], such as prior preterm birth, early rupture of membranes, or co-existing medical conditions such as polycystic ovary syndrome (PCOS), as reported by others in this special collection [ 12 ]. Rocha and colleagues address an interesting question: for those in their second pregnancy and birth preterm, do risk factors associated with their preterm birth differ depending on whether or not their first infant was born preterm?
To address this question, the authors examined a large retrospective dataset from Brazil representing 1.7 million births [ 13 ]. They focused on women who had a preterm birth in their second pregnancy and split them according to whether their first pregnancy was delivered at full term (> 37 weeks gestation, “incident preterm birth” cohort) or they previously had a preterm birth (< 37 weeks gestation, “recurrent preterm birth” cohort).
Interestingly, the incident but not the recurrent preterm birth cohort had significant associations with household overcrowding, variations in ethnicity (being black, mixed-race, or indigenous had raised risks), being a younger mother (14–19 years), and having had a prior cesarean section, with odds ratios ranging from 1.04 to 1.34. Both cohorts were associated with reduced prenatal visits with higher odds ratios in the incidence preterm birth cohort. Notably, many of these risk factors likely reflect socioeconomic deprivation, stress, low educational attainment, and smoking—established risk factors for preterm birth [ 8 ].
Surprisingly, in both cohorts, being single or a widow conferred a 10–15% reduced risk of preterm birth compared to those who were married or in a civil union. While interesting, this finding is difficult to explain, and we do not suggest encouraging women to be single is a promising public health strategy to reduce preterm birth rates.
In another contribution to this collection, Subramanian and colleagues [ 12 ] present data indicating a convincing link between preterm birth and PCOS, a condition affecting 10% of women. While defined by a varied constellation of signs and symptoms—cysts on the ovary, biochemical or clinical evidence of androgen excess, oligo/anovulation [ 14 ]—PCOS is, at its heart, a metabolic disorder [ 15 ]. As a chronic condition that never retreats, those affected incur the risk of developing metabolic-related conditions as they age, especially diabetes and obesity [ 15 ].
Given PCOS is the most common endocrine disorder among women of reproductive age, it will invariably intersect with many pregnancies. In their retrospective study, Subramanian et al. examined the link between a pre-specified set of serious obstetric complications, including preterm birth, fetal size, mode of birth and stillbirth, and PCOS based on just under 140,000 pregnancies in the UK, of which 27,586 were affected by PCOS. While the lift in preterm birth risk in women affected by PCOS was modest (an 11% relative rise on the adjusted odds ratio), it could be substantiated by further sub-analyses. These findings concur with a recent study in a Swedish population, indicating an apparent doubling in the risk of extreme preterm birth < 28 weeks gestation in women suffering from PCOS and, thus, an even larger effect size [ 16 ].
But how is the link between PCOS and preterm birth explained? The authors muse over potential causes such as a shared genetic polymorphism between preterm birth and PCOS or a dysregulated hypothalamic-pituitary-adrenal axis tipping off a biological cascade that ends in spontaneous preterm birth. However, as the team did not adjust for important pregnancy-induced complications strongly associated with both PCOS and preterm birth (such as gestational diabetes and hypertensive disorders), more likely, the presence of such complications led to the excess in preterm births. They also found PCOS associated with a modestly increased risk of a cesarean section but no apparent link with stillbirth. While this finding seems reassuring, the study was likely underpowered to explore this outcome.
Finally, there may be a fascinating biological message buried within their apparently plain finding that PCOS is not associated with the birth of babies that are either small or large for gestational age. It suggests placental function may be surprisingly resistant to the multiple metabolic perturbations occurring within the mother, which would be a reassuring finding.
In addition to adverse obstetric outcomes such as preterm birth and associated risk factors, obesity during pregnancy is of great concern. Obesity rates continue to increase across the globe in all age groups in the population, including women of childbearing age [ 17 ]. Consequently, in a growing number of countries, over half of the pregnant women are now either obese or overweight.
Obesity is associated with immediate detrimental consequences for the mother and baby, including increased risk of gestational diabetes, preeclampsia, and the need for a caesarian section [ 18 ]. In addition, it is established that children born to obese women are at increased risk of becoming obese and developing type 2 diabetes and cardiovascular diseases. Furthermore, evidence suggests that at least part of this transmission of poor cardio-metabolic health from mother to child is driven by non-genetic factors. Notably, the latter provides an opportunity for early intervention before disease pathology is established [ 19 ].
Currently, it is not known which children born to obese mothers will follow a higher-than-normal body mass index growth trajectory and become overweight and ultimately obese. In this article collection, Gomes and colleagues address this knowledge deficit using the mother-child cohort study Programming of Enhanced Adiposity Risk in Childhood–Early Screening (PEACHES), which comprised 1671 mothers with pre-conception obesity and without (controls) and their offspring. They identified a “high-risk” subpopulation of offspring born to obese mothers susceptible to early upper deviations from healthy weight gain trajectories present within the first few months of life and progressing to overweight/obesity by 5 years of age. Hence, they established a novel sequential prediction system to allow early-risk stratification and re-evaluation to prevent a “higher-than-normal BMI growth pattern” at a subclinical stage preceding overweight. Maternal smoking and excessive gestational weight gain were the strongest predictors of a higher-than-normal BMI growth pattern by 3 months of age. Importantly, they validated these findings in the independent Perinatal Prevention of Obesity (PEPO) cohort, comprising 11,730 mother-child pairs recruited around 6 years of age. These findings take us a step closer to developing cost-effective and personalized advice and measures, counteracting the risk of early excess weight gain and ultimately preventing childhood obesity.
Several articles in this collection have focused on the metabolic environment in utero and the impact of environmental exposures in pregnancy on the mother’s and offspring’s long-term metabolic health. For example, the large mother-offspring Asian cohort study Growing Up in Singapore Towards healthy Outcomes (GUSTO), consisting of 1247 women from Singapore, studied the changes of 480 lipid species in the plasma of women during pregnancy (antenatal vs postnatal) and their offspring during development (cord blood and 6-year-old child plasma) [ 20 ]. This study demonstrated that around 36% of the profiled lipids increased in circulation during pregnancy, with phosphatidylethanolamine levels changing the most compared to pre-pregnancy. Compared to the gestating mother, the cord blood showed a lower concentration of most lipids, and a higher concentration of lysophospholipids, suggesting the specific developmental needs of the growing fetus. Pre-pregnancy BMI was specifically associated with a decrease in the levels of phospholipids, sphingomyelin, and several triacylglycerol species in pregnancy, highlighting the importance of managing obesity before pregnancy. Notably, lipid species associated with the child’s BMI were very similar to those associated with the adult’s BMI. This overlapping effect of adiposity, as observed in 6-year-old children and postnatal mothers in this study, may be influenced by the similarities in the diet apart from other factors such as genetics and shared lifestyle. The findings of this study were validated in an independent Caucasian birth cohort and provide an important resource for future research targeting early nutritional interventions to benefit maternal and child metabolic health.
Also focusing on the influencing factors on metabolic health, a Swedish nationwide register-based study investigated the association between maternal smoking during pregnancy and type 1 diabetes in the offspring [ 21 ]. The cohort consisted of nearly three million children born between the years 1983 and 2014, with follow-up until 2020. In addition, a nested case-control study was performed comparing children with type 1 diabetes to their age-matched siblings. A total of 18,617 children developed type 1 diabetes. Interestingly, maternal smoking during pregnancy was associated with a 22% lower risk of offspring type 1 diabetes in the full cohort. Although these data suggest a protective effect of maternal smoking on the risk for offspring to develop type 1 diabetes, mechanistic studies are needed to elucidate the underlying pathways behind this link. Despite these findings, we emphasize that smoking during pregnancy should be strongly advised against since it has severe effects on fetal and childhood health [ 21 ].
For example, a longitudinal study by Howell and colleagues in this collection provides evidence that maternal smoking is also associated with shorter offspring telomere length [ 22 ]. Acting as a mitotic clock to the cell, these hexameric repeat sequences found at the ends of chromosomes shorten with cell division [ 23 ] and, as shown recently, as a consequence of oxidative damage. Therefore, they represent good biomarkers of cellular aging and also exposure to oxidative damage [ 23 ]. Accelerated aging has been suggested as one potential mechanism linking suboptimal in utero exposures to long-term health. However, most evidence has primarily come from studies of suboptimal in utero nutritional exposures [ 24 ].
Howell et al. demonstrated that maternal prenatal smoking predicted greater telomere shortening by measuring the telomere length in buccal cells in infants from 4 to 18 months of age. They also showed that the relationship between maternal prenatal smoking and offspring attention-deficit/hyperactivity disorder (ADHD) was modulated by telomere length. Paradoxically, ADHD was associated with less telomere attrition for children whose mothers smoked. It is not known if these differences in buccal cell telomere length are reflective of the differences in other cell types, such as those in the brain. However, if similar differences are also present in brain tissue, this finding could indicate delayed maturation of cortical cells, which could provide a mechanistic link to ADHD.
As demonstrated by the initial series of articles published in this collection, the ability to utilize now more refined technologies to elucidate the underlying mechanisms that drive adverse pregnancy outcomes, such as preterm birth and metabolic risks for both the mother and fetus, has revealed new insights and potential pathways for intervention. Moreover, a deeper understanding of how these diverse outcomes are influenced by maternal co-morbidities such as maternal PCOS or smoking status is emerging.
However, to have a real impact on public health, these robust, reliable data and their implications need to be implemented in physician practice and be used for therapy development for a historically under-explored and invested group—pregnant women.
It will be essential to figure out how these findings can be used to tackle challenges related to lifestyle factors such as maternal obesity or smoking that have been refractory to preventive strategies and interventions. As the recognition of these influencing factors on maternal, fetal, and childhood outcomes across the lifespan emerges, we are encouraged that it will ultimately benefit the mother’s and child’s health.
We have enjoyed learning from this initial set of articles and look forward to future contributions to this collection.
All data discussed in this editorial are included in this published article.
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We thank Dr. Susanne Kröncke for her outstanding editorial support.
KB is the recipient of a “Fundamenteel Klinisch Navorserschap FWO Vlaanderen.”
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Louis J. Muglia
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Katrien Benhalima
University of Melbourne, Melbourne, Australia
Stephen Tong
Mercy Perinatal, Heidelberg, Australia
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Active and passive maternal smoking during pregnancy and birth outcomes: a study from a developing country.
Background: Smoking is one of the modifiable risk factors for adverse maternal and neonatal outcomes and is associated with low birth weight, preterm birth, respiratory, antepartum and intrapartum stillbirth, and perinatal death as well as long-term morbidity in offspring and sudden unexpected infant death. The rate of smoking in low- and middle-income countries is still relevantly high, and Jordan is no exception.
Objective: To investigate the effect of active and passive smoking during pregnancy on adverse pregnancy outcomes.
Methods: The case-control study was conducted in Jordan in June 2020. Healthy women with full-term singleton pregnancy (n = 180) were interviewed and stratified into three groups: Group I, active smokers; Group II, passive smokers; and Group III, nonsmokers. The study variables included demographic data, current pregnancy history, cotinine level of mothers and newborns, and perinatal outcomes. Statistical analysis was performed using the application package IBM SPSS 25. Various algorithms of statistical analysis were used depending on the type of distribution of feature and data quality. The threshold for statistical significance was set at p < 0.05.
Results: Active smokers had significantly lower gestational age at delivery compared to passive and nonsmoking women ( p = 0.038 and p = 0.003, respectively). Neonates from active smoking mothers had significantly lower birth weight compared to neonates from passive and nonsmoking women ( p = 0.016 and p = 0.019, respectively), significantly lower head and chest circumferences compared to babies from passive smokers ( p < 0.001 and p = 0.036, respectively), and significantly lower first-minute Apgar score compared to those from nonsmoking women ( p = 0.023). The urine cotinine level was significantly higher in both active and passive smoking women (both p < 0.01), and it was significantly higher in newborns who had been exposed to smoking in utero despite maternal active or passive smoking status (both p < 0.001). There was a weak negative correlation between urine cotinine level and birth weight: r = –0.14 for maternal cotinine level and r = –0.15 for neonate cotinine level.
Smoking is a modifiable risk factor for adverse maternal and neonatal outcomes and is associated with maternal, fetal, and infant morbidity and mortality [ 7 ].
As shown in previous research, active and passive maternal smoking during pregnancy increases the risk of having a child with low birth weight [ 27 , 34 ] and significantly increases other negative pregnancy outcomes, such as preterm birth [ 17 , 21 ], respiratory distress [ 1 ], antepartum and intrapartum stillbirth [ 5 ], perinatal death [ 24 ], long-term morbidity in offspring [ 32 ], and sudden unexpected infant death [ 3 ].
Birth weight, length, and head and chest circumference at birth are the main indicators of fetal growth suppressed by maternal smoking [ 15 ]. It is not clear from the current body of evidence whether maternal smoking specifically affects head growth, though maternal smoking during pregnancy negatively affects fetal brain development [ 16 ].
The Apgar score is used as a standardized index of newborn health at birth and is strongly associated with the risk of neonatal and infant death [ 4 ]. According to [ 35 ], babies of smoking mothers had lower Apgar scores compared to those of nonsmokers. However, smoking during pregnancy is not an independent predictor of the Apgar score. It remains unclear whether quitting smoking during pregnancy affects the Apgar score [ 35 ].
The rate of smoking in low- and middle-income countries is still relevantly high [ 22 , 23 , 29 ]. The prevalence of active and passive smoking in Jordan is high [ 9 , 10 , 11 , 13 ], and it mirrors the husbands’ active smoking patterns [ 11 , 29 ]. Paternal smoking is considered an independent risk factor for fetal growth restriction [ 6 ] and stillbirth despite the maternal smoking status [ 28 ].
This study aimed to investigate the effects of active and passive smoking during pregnancy on adverse pregnancy outcomes.
The case-control study was conducted at the main hospital in Jordan (King Abdullah University Hospital (KAUH)) using a semistructured questionnaire in June 2020.
Inclusion criteria for the study were as follows: full-term singleton pregnancy, absence of chronic diseases (e.g., cardiovascular, kidney, endocrine diseases) and pregnancy complications (gestational hypertension and diabetes mellitus), accommodation at the north of Jordan, prenatal car, and delivery and postnatal care at KAUH Obstetrics and Gynecology Department as well as an agreement to participate in research and completion of at least 75% of the questionnaire.
The Institutional Research Board (IRB) at Jordan University of Science and Technology (University Review Committee for Research on Human) approved all study activities. All participants in this research were voluntary, and anyone could stop participating in the interview at any time. The consent form was prepared to get the agreement of the participants to be interviewed, and only those who agreed to participate in this study were interviewed. The consent form excluded the possibility of unjustified deception, undue influence, and intimidation. The agreement was signed only after prospective subjects were adequately informed. Their decision on whether to participate did affect the doctor-patient relationship or any other benefits to which they are entitled. Personal information about subjects will never be disclosed, and the data collected will remain confidential.
All women included in the study (n = 180) were interviewed according to the questionnaire designed and developed by our team and included yes/no questions, select from a list questions, and short answer questions in the Arabic language. All participants were stratified into 3 groups according to their smoking status: Group I, current active smokers; Group II, women with current exposure to secondhand smoke; and Group III, nonsmoking women, neither active nor passive.
The study variables included demographic information (maternal age, education, work status, environment status, smoking behavior and attitudes), current pregnancy history (parity, mode of delivery), and perinatal outcomes (birth weight, length, head and chest circumferences, Apgar score at 1 and 5 minutes, NICU admission).
Data for this study came from a face-to-face survey with pregnant women and laboratory reports. Data was entered into a unified computer database and analyzed by our team.
Statistical analysis was performed using the application package IBM SPSS 25 (SPSS: An IBM Company, New York, USA). The character of data distribution was evaluated with the W-criterion of Shapiro-Wilk. Various algorithms of statistical analysis were used depending on the type of distribution of feature. Absolute and relative indicators (%) were used to represent the qualitative characteristics. Quantitative data were presented by central tendency and dispersion: the mean value (M) with a 95% confidence interval (CI). A comparison of three independent groups on one or several signs, having at least one of the groups of distribution different from the normal or if the type of distribution was not analyzed, was carried out by checking the statistical hypotheses about the equality of middle rank using the Mann-Whitney U-test. Analysis of contingency tables (χ2) was used to assess the differences in relative values. Fisher exact test ( p ) was applied at frequencies less than 5. The threshold for statistical significance was set at p < 0.05.
All women who participated in the study were married. The average maternal age was 30.23 ± 1.47, 28.85 ± 1.50, and 31.1 ± 1.34 years among active smokers, passive smokers and nonsmokers, respectively. It was significantly lower in the group of passive women smokers compared with women who do not smoke ( p = 0.027). Active smokers were significantly less educated than passive smokers and nonsmokers ( p < 0.001), and most of them did not work compared to nonsmokers ( p = 0.037). Additionally, their family monthly income was significantly lower than in the group of passive smokers ( p = 0.006). Approximately 13% of active smoking women were nulliparous, while 43% of passive smokers were nulliparous women ( p < 0.001). Both active and passive smoking groups were less likely to follow up with perinatal care clinics compared to women who did not smoke ( p = 0.029). Brief characteristics of the studied groups are represented in Appendices Table 1.
Most smoking women (both active and passive) reported their husband is also a smoker and smokes at home (63% [50.68–74.38] and 80% [68.22–88.17], respectively), while only 2% (0.30–8.86) of nonsmoking women declared about a smoking husband ( p < 0.001).
We found that most women started to smoke at the age of 20, and more (43% [31.57–55.89], 33% [22.73–45.94]) classified themselves as moderate and heavy smokers. All of them smoke at home, and 20% (11.83–31.78) smoke at the workplace.
Our study revealed that many smoking women received information about the hazardous effects of smoking during perinatal visits (43% [31.57–55.89]), and 83% (71.96–90.68) were aware of the effects of smoking on perinatal outcomes. However, only 13% [6.91–24.16] of women quit smoking cigarettes before or in the early termination of pregnancy. Approximately 23% (14.44–35.43) decreased the frequency of smoking during their pregnancy, 13% (6.91–24.16) continued to smoke with the same frequency as before, and 23% (14.44–35.43) of women tried to stop their habit, but without success.
Active smoking women had significantly lower gestational age at delivery compared to passive smoking and nonsmoking women ( p = 0.038 and p = 0.003, respectively). There were no differences in the rate of cesarean section between study groups ( p > 0.05).
Neonates from active smoking mothers had significantly lower weight at birth compared to neonates from passive smoking and nonsmoking women ( p = 0.016 and p = 0.019, respectively) as well as significantly lower head and chest circumferences compared to babies from passive smoking mothers ( p < 0.001 and p = 0.036, respectively). Additionally, we found that neonates from active smoking women had a significantly lower 1-minute Apgar score compared to those from nonsmoking women ( p = 0.023), while there were no differences in the 5th-minute Apgar score. The rate of NICU admission did not differ among the 3 groups.
The main pregnancy outcomes are represented in Appendices Table 2.
The urine cotinine level was significantly higher in both active and passive smoking women compared to nonsmoking women—43.27 ± 15.57 ng/mL, 1.08 ± 0.68 ng/mL, and 0.17 ± 0.05 ng/mL, respectively (both p < 0.01). Additionally, the urine cotinine level was significantly higher in newborns who had been exposed in utero (despite maternal active or passive smoking status)—42.53 ± 15.81 ng/mL, 0.42 ± 0.14 ng/mL, 0.15 ± 0.04 ng/mL for the active, passive, and nonsmoking group, respectively (both p < 0.001). A Pearson correlation test revealed there was a weak negative correlation between urine cotinine level and birth weight— r = –0.14 for maternal cotinine level and r = –0.15 for neonate cotinine level.
Smoking is considered one of the preventable risk factors for poor perinatal outcomes. Over the past several decades, many studies related to this issue have been conducted worldwide. Moreover, most of them have shown that smoking is a serious threat to public health, and this problem needs to be addressed at the level of the health care system [ 6 , 7 ].
This study, aimed at identifying the effects of smoking on perinatal outcomes, underscores the importance of smoking cessation interventions, especially in the context of high smoking rates among men and women of childbearing age [ 10 , 11 , 13 ].
Our study revealed that active smoking women were less educated and had less monthly family income compared to passive smoking and nonsmoking women. These findings replicate those of a similar study, where pregnant women with less than a high school education were more likely to smoke as compared to women with bachelor’s degree or higher [ 19 ].
The current study showed that active smoking women were likely to deliver an earlier gestational age compared to passive smoking and nonsmoking women. This finding is also suggested by several studies on the risk of preterm birth in smoking mothers [ 17 , 21 ]; however, we cannot equate these studies, since, in our study, the inclusion criterion was a full-term pregnancy.
According to Li and colleagues (2019), smoking women were more likely to have a caesarean section for nonreassuring fetal status [ 20 ]. However, in our study, there were no differences in the mode of delivery between women despite their smoking status.
We found a significantly lower 1-minute Apgar score in newborns from active smoking mothers compared to those from nonsmoking women, while the 5-minute Apgar score did not differ by maternal smoking status. The rate of NICU admission was similar between the study groups. Similar results were shown by Kharkova and colleagues (2017) [ 18 ], though another study found a significant increase in NICU admission in the smoking cohort [ 20 ]. Thus, we cannot accept smoking as the only factor that affects the Apgar score and the need for NICU admission [ 35 ].
Our study revealed the birth weights of newborns from active smoking mothers were significantly less than those from passive smoking and nonsmoking women, and secondhand exposure did not influence birth weight. Additionally, we found a tendency for smaller length and head and chest circumferences in newborns from active smoking women compared to those from nonsmoking mothers. These findings are strongly supported by similar studies, where maternal active smoking was associated with a lower mean birth weight [ 14 , 25 ], smaller length and head circumference [ 1 , 2 , 33 ], and abnormal body proportions [ 18 , 30 ].
We found that urinary cotinine levels in women and newborns were negatively associated with birth weight. However, this association was very weak. The only study that assessed the relationship between cotinine levels and anthropometric data in newborns found that the level of urine cotinine in newborns had a strong negative association with birth weight [ 8 ].
Furthermore, there is a high rate of smoking among Jordanian pregnant women, approximately 18% [ 9 ], and many were exposed to tobacco smoking by their husbands [ 9 ]. The smoking rate in Jordan is among the highest rates in the world, with a high exposure of smoking indoors and a lack of policy restrictions in developing countries [ 9 , 11 , 12 , 13 , 31 ]. This is a leading factor for stillbirths and sudden deaths among infants, which need more intervention programs [ 9 , 11 , 13 , 29 ]. Moreover, comprehensive smoke-free policies must be ensured in developing countries. In particular, for some health outcomes that are strongly influenced by active and passive smoking, keep in mind that smoking is a common habit and rates are higher among developing country communities [ 9 , 11 , 13 , 26 ].
The small sample size and the fact that the study sample excluded high-risk pregnant women and women with preterm birth means our results cannot be extrapolated to all pregnant women in general or other regions of Jordan. These groups of women require additional study.
We discussed limited perinatal outcomes as per our exclusion criteria and did not take into account pregnancy complications such as preterm delivery, gestational diabetes mellitus, gestational hypertension, placental abruption, and fetal malformations, which can be caused by smoking. So, further studies should be directed to these issues too.
Our information on smoking behavior during pregnancy was based on self-reporting. Consequently, underreporting of maternal smoking may have occurred, resulting in potential for misclassification. However, to address this, we measured cotinine in mother-baby couples to assess the accuracy of self-reported data. This was a major strength of our study.
Take into consideration the necessary contribution to the literature on prenatal smoke exposure and risks on obstetric outcomes for women and children in Jordan. The main strength is the inclusion of laparotomy cotinine levels. Furthermore, this study was the first of its kind in Jordan and therefore provides necessary baseline information for further improvement on tobacco control research in the developing countries and the Middle Eastern regions.
The current study illustrated that smoking during pregnancy leads to offspring with reduced birth weight, birth length, and head and chest circumference as well as reduced delivery gestational age and lower Apgar score. Moreover, we may conclude that argileh smoking (e.g., hookah) during pregnancy can also contribute to a reduction in newborns’ anthropometric measurements.
Our study findings highlight the need for continued study of the effects of smoking on perinatal outcomes and the need for targeted interventions to reduce and prevent tobacco smoking and tobacco smoke exposure during pregnancy. Further studies are needed to increase awareness of these adverse effects, to develop cessation interventions in the preconception period, and to evaluate useful interventions to enhance a smoking-free environment during pregnancy.
The additional file for this article can be found as follows:
Appendix Table 1 and Appendix Table 2. DOI: https://doi.org/10.5334/aogh.3384.s1
The authors acknowledge the Jordan University of Science and Technology support for this research. Thanks to all the mothers participating in this study. Thanks and appreciation to King Abdullah University Hospital.
This study was partially funded by the Jordan University of Science and Technology Scientific Research Fund.
The authors have no competing interests to declare.
Dr. Shereen Hamadneh:
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28 August 2024
In a systematic review of 19 studies and 1.25 million participants, researchers at the University of South Australia along with a team at Curtin University , SAHMRI , Harvard University and others* found that 79% of studies reported reduced academic achievement in children exposed to maternal prenatal smoking.
An additional meta-analysis of eight primary studies with 723,877 participants showed that children exposed to maternal prenatal tobacco smoking were 49% more likely to struggle with poor academic achievement in comparison to those who had not been exposed to smoking in utero.
In Australia , 8.7% (or 26,433) of all mothers who gave birth in 2021 smoked at some time during their pregnancy .
Lead researcher, UniSA’s Dr Bereket Duko , says that despite what is already known about smoking, research is still uncovering additional negative effects.
“For decades, agencies across the globe have pushed anti-smoking campaigns about the dangers of smoking. But despite these efforts, tobacco smoking remains a pervasive global public health issue,” Dr Bereket says.
“Prenatal smoking is known to cause multiple pregnancy complications, including a higher risk of miscarriage, stillbirth, restricted growth and development, and serious birth defects. It is also linked with adverse mental health outcomes and behavioural issues.
“Our new research adds to this, by showing that maternal prenatal smoking has a significant risk of limiting a child’s academic performance, putting them well behind their peers at school.
“We all want children to have the best start in life. But clearly, we must do better to educate mothers and families about the noxious effects of smoking while pregnant on mother and baby.
“Remember, the fight against smoking is not one we have already won. Yes, we have made big steps to reduce the number of people smoking, and we have made many aware of the health risks. But this is an ongoing battle, and we must continue to educate people about the dangers of tobacco so that the next generations do not unnecessarily suffer.”
Notes or editors:
*Additional partners include the University of Iceland, the University of Queensland, the Norwegian Institute of Public Health, and the University of Sydney.
…………………………………………………………………………………………………………………………
Contact for interview: Dr Bereket Duko M: +61 410 350 140 E: [email protected] Media contact: Annabel Mansfield M: +61 479 182 489 E: [email protected]
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BMC Pregnancy and Childbirth volume 21 , Article number: 254 ( 2021 ) Cite this article
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Smoking during pregnancy (SDP) and the postpartum period has serious health outcomes for the mother and infant. Although some systematic reviews have shown the impact of maternal SDP on particular conditions, a systematic review examining the overall health outcomes has not been published. Hence, this paper aimed to conduct an umbrella review on this issue.
A systematic review of systematic reviews (umbrella review) was conducted according to a protocol submitted to PROSPERO ( CRD42018086350 ). CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science, CRD Database and HMIC databases were searched to include all studies published in English by 31 December 2017, except those focusing exclusively on low-income countries. Two researchers conducted the study selection and quality assessment independently.
The review included 64 studies analysing the relationship between maternal SDP and 46 health conditions. The highest increase in risks was found for sudden infant death syndrome, asthma, stillbirth, low birth weight and obesity amongst infants. The impact of SDP was associated with the number of cigarettes consumed. According to the causal link analysis, five mother-related and ten infant-related conditions had a causal link with SDP. In addition, some studies reported protective impacts of SDP on pre-eclampsia, hyperemesis gravidarum and skin defects on infants. The review identified important gaps in the literature regarding the dose-response association, exposure window, postnatal smoking.
The review shows that maternal SDP is not only associated with short-term health conditions (e.g. preterm birth, oral clefts) but also some which can have life-long detrimental impacts (e.g. obesity, intellectual impairment).
This umbrella review provides a comprehensive analysis of the overall health impacts of SDP. The study findings indicate that while estimating health and cost outcomes of SDP, long-term health impacts should be considered as well as short-term effects since studies not including the long-term outcomes would underestimate the magnitude of the issue. Also, interventions for pregnant women who smoke should consider the impact of reducing smoking due to health benefits on mothers and infants, and not solely cessation.
Peer Review reports
Smoking during pregnancy (SDP) is a significant public health concern due to adverse health outcomes on mothers and infants, such as miscarriage, low birth weight (LBW), preterm birth, and asthma [ 1 , 2 , 3 , 4 ]. The prevalence of SDP is around 10% in high-income countries (HICs) [ 5 , 6 , 7 ] and 3% in low- and middle-income countries (LMICs) [ 8 ].
Smoking during pregnancy generates a considerable cost burden and the annual cost of smoking-related pregnancy complications has been estimated to be between £8 and £64 million in the UK, depending on the estimation method chosen [ 9 ]. In addition, the costs associated with the health problems experienced by the infant during the first year following the birth were found to be between £12 and £23 million [ 9 ]. Smoking during pregnancy poses a considerable economic burden in the USA as well, since smoking-attributable neo-natal costs were estimated to be nearly $228 million in total [ 10 ]. When long-term impacts on the infant are considered, the actual figures are likely to be higher. Therefore, to have a comprehensive estimate of the health and cost impacts of SDP to inform policy decisions and ensure that scarce health resources are allocated optimally, it is necessary to review the evidence on the overall health effects for mothers and infants over the longer term.
A scoping review and a review of reviews by Godfrey and colleagues [ 9 ], and a scoping review by Jones [ 11 ] provided a picture of the health and cost outcomes associated with SDP, and several narrative reviews about the health outcomes have been published [ 12 , 13 , 14 , 15 ]. However, none of these papers were fully systematic and comprehensive. Moreover, a considerable number of systematic reviews have been published more recently on the impact of maternal SDP on separate health outcomes, which makes this overall review of the current evidence timely.
The present study aimed to investigate the overall health impacts of maternal smoking during pregnancy and the postpartum period on mothers and infants. Additionally, the evidence on the impact of the number cigarettes consumed and second-hand smoking (SHS) by partner during pregnancy was assessed [ 16 , 17 ].
The guideline provided by the Cochrane Handbook for Systematic Reviews of Interventions [ 18 ] was followed. The review was carried out according to a protocol which included a detailed description of the methodology [ 19 ]. Umbrella reviews have been increasingly used to summarise the existing evidence on an issue by analysing all systematic reviews conducted [ 18 , 20 ]. Considering the large number of original studies about health outcomes of SDP, an umbrella review was the appropriate design for this research.
Searches were undertaken of CINAHL, EMBASE, MEDLINE, PsycINFO, Web of Science, CRD Database (includes DARE, NHSEED and HTA) and HMIC databases. The search strategy for MEDLINE is presented in the Additional file 1 . All systematic reviews published in English and by December 2017. Two independent reviewers conducted the study selection and quality assessment. The data extraction toll is provided in the Additional file 1 : Table S1. The quality of included studies was assessed with a tool developed from the Centre for Reviews and Dissemination (CRD) checklist, which covers a range of issues including prior protocol use, bias in study selection, and consideration of publication bias and inclusion of a quality assessment [ 21 ]. Main outcome measures were odds ratios and relative risks for smoking women and their children compared to non-smoking women and their children.
To evaluate the causal link between SDP and the identified conditions which were found to have an association with SDP, a causal link analysis was conducted using established methods [ 11 ]. The evidence on the identified conditions was assessed and categorised using the following criteria:
Strong evidence - one systematic review with ≥8 studies (group 1) or more than one systematic review (group 2);
Weak evidence – more than one systematic review reported conflicting findings (group 3) or one systematic review reported limited number of studies (< 8) which found a relationship (group 4).
A validity assessment was conducted by reducing the threshold of eight studies to seven, and increasing it to 10 and 12. As discussed by Jones [ 11 ], this strength of evidence analysis fulfilled five of the nine items proposed by Hill [ 22 ] as conditions of a causal link (strength, consistency, specificity, temporality, and plausibility). In addition, the dose-response association was also considered. The remaining requirements (coherence, experiment, and analogy) of the Hill [ 22 ] criteria were irrelevant to this review as laboratory studies were not included and no causes other than smoking of the identified conditions were considered.
The database search yielded 744 studies and an additional five studies were found through hand searching the references of included studies. Following the removal of duplicates and abstract screening, 64 studies were selected for full-text analysis Fig. 1 .
PRISMA Diagram for Study Selection
Most reviews ( n = 46) were published since 2010. Only 13 reviews investigated a health condition related to mothers; the other 49 reviews analysed infant-related conditions, except two [ 23 , 24 ] which evaluated the impacts on both. Key characteristics of the included reviews are provided in Additional file 1 : Table S2.
In most reviews ( n = 27 reviews), the included studies were predominantly from HICs, and 22 of the included reviews covered studies from HIC only. In two reviews [ 3 , 25 ] most of the included studies were concerned with upper-middle-income countries.
In 12 reviews, the country of focus of the included studies was not provided. However, one of them [ 26 ] conducted a meta-analysis of the studies from Europe only, and in five reviews, the language of the included studies was either only English [ 27 , 28 , 29 ] or languages [ 30 , 31 ] which are only spoken by HICs. In the remaining six reviews [ 32 , 33 , 34 , 35 , 36 ] there was no indication of whether the studies focussed on LMICs or HICs. Nevertheless, when interpreting the results of these reviews, the possibility that studies which were conducted in LMICs have been included in addition to HICs should be born in mind.
The quality scores of the reviews are provided in Additional file 1 : Table S2. The highest achievable score was 16, and most reviews ( n = 46) scored between nine and 14 while two reviews [ 25 , 32 ] achieved very low scores of 4 and 5. Therefore, most of the included reviews were moderate or high quality studies according to the criteria used.
Study selection was made by two reviewers independently in almost half of the reviews ( n = 31) to minimise bias. The majority of the studies ( n = 50) assessed publication bias. Heterogeneity was measured in all reviews although causes of heterogeneity were not analysed in some ( n = 17). However, only seven reviews reported protocol publication [ 3 , 26 , 33 , 37 , 38 , 39 , 40 ].
Overall, of the 14 reviews that reported the impact of smoking on mothers, all except two [ 41 , 42 ] conducted meta-analyses (Additional file 1 : Table S3). The reviews presented consistent findings, suggesting a significantly increased risk associated with smoking and seven health conditions. The highest risks were reported for spontaneous miscarriage in assisted reproduction (OR = 2.65, 95% CI, 1.33–5.30, 28) and ectopic pregnancy (OR = 2.30, 95% CI, 2.02–2.80, 30). Two conditions (preeclampsia and hypremesis gravidarum) were found to be negatively associated with SDP. Hence, women who smoked whilst pregnant were less likely to experience these two conditions.
Studies found a smoking-related increased risk for 20 conditions and the highest impact was observed for sudden infant death syndrome (SIDS) (OR = 2.98, 95% CI, 2.51–3.54) [ 24 ], asthma (OR = 1.85, 95% CI, 1.35–2.53) [ 1 ], LBW (OR = 1.75, 95% CI, 1.42–2.10), stillbirth (OR = 1.55, 95% CI, 1.36–1.78) [ 38 ] and obesity (OR = 1.60, 95% CI 1.37–1.88) [ 43 ]. Studies did not find any significant association between 15 conditions and SDP, including autism, brain tumors, breast cancer in daughters and testicular cancer in sons. On the other hand, a protective impact on skin defects was observed in one review [ 44 ].
Most studies ( n = 42) investigating the impacts of SDP on infants conducted a meta-analysis (Additional file 1 : Table S4), and only nine did not include this (Additional file 1 : Table S5). In these studies, there was no significant relationship between maternal SDP and lung functions, or Tourette’s syndrome.
The age group of study participants varied between studies; for example, some conditions were assessed amongst infants while some were measured in adults. In some reviews, participants were both infants and adults. Table 1 lists health conditions by the life stage they were assessed.
The reviews included in this study indicated that maternal smoking increased the risk of death for the child during the prenatal period, neonatal period and infancy. The evidence showed maternal SDP did not only have short-term impact but also some long-term outcomes which could be detrimental for offspring. Moreover, some of the conditions measured in early life stages could continue later in life. For instance, some birth defects and intellectual disability would affect later stages of life.
To understand the impact of reductions in smoking, the relationship between the number of cigarettes consumed and the health implications for infants or mothers were investigated. Although a dose-response impact of SDP was reported in 27 reviews (22 related to infant conditions), it was statistically tested in just 17 studies. Among them, four found no significant impact of SDP and their dose-response tests showed similar results. In addition, one review [ 62 ] reported a dose-response association for SIDS but did not provide the odds ratios. Findings of the remaining 12 studies are summarised in the Additional file 1 : Table S6.
To define light, moderate and heavy smokers, most studies [ 38 , 39 , 46 , 62 , 63 , 64 ] chose smoking 10 cigarettes daily as a cut-off point to distinguish light smokers from moderate and heavy smokers. In some studies [ 4 , 39 , 46 , 61 , 64 ], both 10 cigarettes daily and 20 cigarettes daily were utilised as the thresholds. In one review the number of cigarettes consumed daily for each category was inconsistent [ 65 ]. All studies estimated the risk ratios compared to non-smokers [ 66 ], except for one review, in which light smokers were compared to moderate smokers.
Included reviews showed that the risk of stillbirth, birth defects, preterm birth and perinatal death elevated as the number of cigarettes increased [ 4 , 38 , 39 , 46 ]. In contrast, smoking not only protected against pre-eclampsia but the risk reduced as exposure increased [ 67 ].
A dose-response relationship was found in five reviews although a pooled estimation was not calculated. They reported an increased risk for placental abruption [ 68 ], and for the offspring the risk of being overweight [ 57 ], having oral clefts [ 29 , 50 ], or a decrease in cognitive abilities [ 53 ] increased along with the number of cigarettes that the mothers consumed. Five reviews included studies reporting a dose-response relationship along with others that did not find any relationship [ 1 , 41 , 51 , 56 , 69 ]. Therefore, it was not clear whether or not the risk for some conditions (pre-eclampsia, and in the offspring asthma, attention deficit hyperactivity disorder, and vision difficulties) was affected by the number of cigarettes consumed.
Six reviews observed no significant association between the number of cigarettes consumed and the risk of health conditions for the children exposed to maternal SDP, although overall they reported a significantly increased risk. These studies covered congenital heart diseases [ 65 ], central nervous system tumors [ 64 ], childhood neuroblastoma [ 63 ], lower respiratory infections (LRI) [ 37 ] and lymphoblastic leukaemia [ 66 ], and reduced menarche age in daughters [ 61 ].
The main findings of the reviews which investigated the impact of postnatal smoking on the infants are shown in Additional file 1 : Table S7. The reviews showed an increased impact on asthma, LRI, SIDS and wheezing but not on leukaemia and obesity. However, in some studies, it was not clear whether or not the mothers included in the studies smoked during the whole pregnancy as well as the postpartum period. This is a significant consideration as one study reported by Oken et al. [ 57 ] found no increase in the prevalence of obesity when the mother smoked only after birth, whereas smoking before and throughout pregnancy were found to be related with an increased risk [ 70 ].
In addition to active smoking, SHS during pregnancy could have health implications. It was important to understand whether the health-related risks were higher when partners smoked during pregnancy. Therefore, partner-related findings of the included reviews were analysed. Partner smoking was considered in only 12 reviews of which six did not assess the impact of SHS specific to the pregnancy period (Additional file 1 : Table S8). None of the studies reported the combined impact of SDP and SHS by the partner during pregnancy. Two reviews reported an increased risk of SIDS [ 71 ] and delay in mental development [ 25 ] when the partners of non-smoking women smoked during pregnancy, while no association was found for brain tumors [ 72 ] or breast cancer risk in daughters [ 73 ].
The reviews conducted sub-group analyses to assess the impact of study design, sample size, the duration of the infant exposure to smoking (i.e. pre-pregnancy, first trimester or the whole pregnancy) and adjustments for confounding factors. The study findings did not differ significantly in most of the analyses except for adjustments for confounding and study quality. The evidence was not sufficient to make a comparison based on country income groups because most studies were from high-income countries.
Although the included meta-analyses utilised the most adjusted estimations of observational studies when pooling their results, only 10 of the included reviews provided risk ratios for adjusted and unadjusted estimations (Additional file 1 : Table S9). Studies with unadjusted ratios estimated greater values for miscarriage, perinatal death, SDIS, overweight and obesity.
Sub-group analyses based on quality appraisal of the included studies were conducted in 14 reviews (Additional file 1 : Table S10). The results showed that high-quality studies reported higher ratios for some conditions (overweight, obesity, placenta previa) as opposed to lower or insignificant ratios for some others (e.g. LBW, miscarriage, stillbirth).
Two reviews [ 46 , 74 ] compared the type of smoking status data and found similar results for biochemical and self-reported data. The exposure period was researched in five reviews [ 40 , 41 , 46 , 64 , 75 ], and the results showed no significant difference between women who quit early in pregnancy and those who did not smoke.
The causal link analysis identified a range of health conditions found to have strong association with SDP; these are presented in Table 2 , grouped according to the strength of evidence.
Nearly all of the conditions for which a strong association was identified fulfilled the criteria for a causal link. The health conditions were largely reported by moderate- or high-quality reviews and there were consistent findings in the sub-group analyses. There was not a sufficient biological explanation to the correlation found between hyperemesis gravidarum and SDP, hence although there was a strong association, a causal link could not be confirmed.
This study analysed the health impacts of smoking during pregnancy and during the postpartum period on mothers and infants. The 64 included reviews covered 1744 studies relating to SDP or smoking during the postpartum period. The review found that maternal SDP has short-term and long-term health consequences, suggesting a positive association between 20 infant-related and seven mother-related conditions, and a negative association with two maternal conditions. The review did not find a statistically significant impact of SDP on 15 infant-related conditions while conflicting findings were reported for leukaemia and lymphoma.
The causal link analysis of the conditions that were found to have an association with SDP suggested that five mother-related and 10 infant-related conditions had a causal link with SDP. PPROM and intellectual disability in children did not fulfil the criteria for the casual link although meta-analyses reported a statistically significant relationship with SDP.
Some health conditions were assessed in multiple meta-analyses and they reported conflicting results. For instance, the increased risk of having any type of birth defect was statistically significant despite being small in the effect size (OR = 1.18, 95% CI, 1.14–1.22) in one review [ 39 ] as opposed to a borderline ratio (OR = 1.01, 95% CI, 0.96–1.07) reported in another [ 44 ]. The main difference was the reduced risk of skin defects (OR = 0.82, 95% CI, 0.75–0.89) which was included in the latter [ 44 ] while omitted in the former [ 39 ] without any justification. All five studies included in this meta-analysis reported a negative relationship and the heterogeneity was low ( P = 0.00001, I 2 = 0%). Therefore, the evidence suggested an increased risk of birth defects except for skin defects amongst SDP exposed children. However, there was no biological explanation for the potential protective impact of SDP on skin defects.
Another health condition with mixed findings was leukaemia. One meta-analysis [ 64 ] including 19 studies indicated an insignificant decreased risk (OR = 0.99, 95% CI, 0.92–1.06) whereas another review [ 66 ] of 21 studies found an increased risk (OR = 1.10, 95% CI, 1.02–1.19). The difference could be explained by the different studies included, since there were only five studies common to both, and the association between SDP and leukaemia is unclear.
Similarly, the reviews reported different results for lymphoma. One meta-analysis [ 55 ] found an insignificant association between any lymphoma and SDP based on eight studies (OR = 1.10, 95% CI, 0.96–1.27), although positive relationship for non-Hodgkin lymphoma was reported (OR = 1.22, 95% CI, 1.03–1.45, n = 8). Another review [ 64 ] which included six studies found an increased risk for any lymphoma (OR = 1.21, 95% CI, 1.05–1.34). Hence, SDP increases the risk of non-Hodgkin lymphoma but for other types of lymphoma the impact is unclear.
To the best of the authors’ knowledge, this is the first umbrella review on the topic and provides the most systematic and comprehensive assessment of the current evidence. The criteria to assess any causal links are an important consideration. The tool developed by Hill [ 22 ] is widely recognised for assessing causation. In addition to these criteria, this study considered the quality of reviews and the findings of sub-group analyses. Hence, the conditions identified by the causal link analysis are very likely to have a causal link with SDP.
The review has some limitations. Firstly, although systematic reviews are accepted as the highest in the evidence hierarchy [ 76 , 77 ], the focus on systematic reviews alone meant some health conditions were not covered. Some original studies have indicated the impact of SDP on other infant-related conditions, such as diabetes [ 78 ], hypomania [ 79 ], otitis [ 80 ] and pervasive development disorder [ 81 ], which were not assessed in a systematic review, and as a result were not included in this study. Furthermore, SDP has been shown to be related to the smoking uptake of the offspring [ 82 , 83 ]. There are also some maternal health conditions found to be related to smoking whilst pregnant in one study; vein thrombosis, myocardial infarction, influenza or pneumonia, bronchitis, gastrointestinal ulcers [ 84 ]. However, the current study focused on the conditions for which there was strong evidence from systematic reviews.
The methodological limitations of the original studies covered in the included reviews should be born in mind when interpreting the results of the current review. First, long-term implications of SDP were often tested retrospectively by asking mothers whether or not they had smoked during pregnancy. This clearly has limitations as these studies were not designed to compare the offspring of smoking mothers with the children of non-smoking mothers to determine differences in their health, but rather to compare the exposure in children with particular conditions and those without these conditions. The second issue is the usual reliance on mother’s memory and openness about their smoking behaviour is unsatisfactory. The third issue is the impact of confounding factors. For example, a seven-year-old child with diagnosed asthma could have a mother who smoked during pregnancy only and a father who smoked during pregnancy and the postpartum period. To minimise the impact of this the most adjusted estimations were reported in this review.
Two previous scoping reviews were conducted to define the health outcomes of SDP although they did not focus on systematic reviews [ 9 , 11 ]. The scoping review by Jones et al. [ 11 ] was more comprehensive and included 32 health conditions. A quality assessment was not conducted but specific criteria were used to assess the strength of the evidence. According to the criteria, Jones et al. suggested that the evidence for a link between obesity and SDP was not strong [ 11 ]. However, the current analysis suggests a causal link due to the inclusion of two subsequently published systematic reviews [ 32 , 43 ].
Some of the health conditions covered in this study were also included in the review by Godfrey et al. but often higher ratios were reported [ 9 ]. This might be because they included narrative reviews which did not separate maternal SDP and postnatal passive smoke exposure while estimating the summary risk ratios [ 24 , 85 , 86 , 87 ]. Moreover, none of the previous reviews analysed the impact of the number of cigarettes consumed, partners’ smoking and postpartum smoking on infants. Therefore, the current review is more comprehensive and more systematic than previous studies.
The study identified important gaps in the literature which warrant further research. In particular, there is a need to further our understanding of dose-response association, the impact of postnatal smoking, and SHS during pregnancy. Current evidence on the impact of number of cigarettes consumed suggests that even low amounts of cigarette consumption during pregnancy have significant health outcomes and there is a clear gradient for some conditions. This indicates the importance of smoking cessation during pregnancy and if reduction in smoking which is often not addressed in smoking cessation interventions designed for pregnant women.
Only two studies assessed the impact of SHS by partners during pregnancy when the mother was a non-smoker. There was no review reporting the combined impact of SDP and SHS by partners during pregnancy while two reviews reported increased risks for SID [ 43 ] and delay in mental development [ 25 ] when only the partner smoked during pregnancy. Hence, more research is needed to understand the impacts of having a smoking partner during pregnancy.
This study has shown that smoking during pregnancy and the postpartum period has significant health consequences for mothers and infants. It is important to encourage pregnant smokers to quit smoking or reduce the number of cigarettes consumed if they are not prepared to quit entirely since the existing evidence indicates a dose-response association. Similarly, the impact of SHS needs to be considered to promote a smoke-free environment for the mother and infant.
Not applicable.
Low birth weight
Lower respiratory infections
High-income countries
Low and middle-income countries
Centre for Reviews and Dissemination
Second-hand smoking
Sudden infant death syndrome
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By Theresa Gaffney Aug. 28, 2024
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Good morning! Amid today’s news, two items on pregnancy that are interesting and eerie to read in tandem. And on top of that, two itchy pieces of mosquito-related news from STAT’s Helen Branswell.
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Take our money, the company said. We’ll handle the business side while you look after your patients, it said. Together we can create a future where primary care leads, it said. Those were the promises UnitedHealth Group made in 2014 to ProHealth Physicians, a reputable Connecticut-based primary care network with more than 50 clinics across the state.
But doctors say the promises weren’t kept — 10 years later, the group is a shell of its former self. “People cannot get the care that they need,” said Sharon Maloney, whose husband couldn’t get into his doctor’s office for three days, precipitating a chain of events that led to his death.
In Part 3 of STAT’s investigative series on UnitedHealth Group’s physician empire, reporters recount in detail how the story unfolded at ProHealth. My colleagues spoke with more than 15 former doctors, current and former patients, and experts. They also obtained documents through public records requests.
Read the story . And if you haven’t already, go back to read Part 1 and Part 2 .
The Biden administration announced yesterday that CDC will invest $118.5 million over five years to help identify and prevent pregnancy-related deaths. Specifically, the funds will go toward expanding a system of Maternal Mortality Review Committees from representing 46 to 52 states and U.S. territories. The groups review deaths within each state or territory that occur within one year of the end of a pregnancy to determine if the deaths were preventable, and recommend how the deaths could be prevented in the future. Funds will also be used to implement the White House Blueprint for Addressing the Maternal Health Crisis, according to the announcement.
Maternal mortality is tricky to measure , but by all expert accounts, the U.S. is in the midst of a crisis . It’s yet to be seen how additional funding from the federal government will affect the work done by MMRCs. “Increasingly, the reporting of those findings have become a political issue, and there have been efforts to suppress their findings,” researcher Greg Roth told STAT’s Nalis Merelli last summer. Between 2017 and 2019, only 36 state groups reported their findings to the CDC.
It happens — to about 3 to 5% of people who receive tubal sterilization, according to new estimates published yesterday in NEJM Evidence . Researchers used data from the National Survey of Family Growth collected in waves over the last two decades. Among women surveyed between 2013 and 2015, the researchers estimated that about 2.9% of those who had their tubes tied became pregnant within a year. But an estimated 8.4% had become pregnant within 10 years of the procedure.
The results indicate “nontrivial” rates of pregnancy after the purportedly permanent procedure, the authors write. It’s good to know, as data from the same survey show that about a third of women receive the surgery by the age of 44.
Twenty-one people in the U.S. have contracted the Oropouche virus during travels to Cuba over the summer, the CDC reported yesterday. The island country is experiencing its first ever recorded outbreak of the virus, which has also been spreading in several South American countries. But what exactly is Oropouche virus?
As usual, STAT’s Helen Branswell has us covered. The virus is spread through biting insects — specifically one species of midge, which is a small fly, and one type of mosquito. About 60% of people who become infected will develop symptoms like fever, severe headache, chills, muscle aches, and joint pains. And there isn’t a vaccine or specific drug treatment for the virus, so the best way to avoid it, as Helen writes, is to not get bit.
Read more on everything you need to know about the virus including how to pronounce its name.
In more mosquito news: New Hampshire has recorded the country’s first death this year from eastern equine encephalitis, a rare but dangerous disease spread through the bite of infected mosquitoes. The CDC says it has been informed of four human infections so far in 2024, with Wisconsin, Massachusetts, and New Jersey also reporting cases. All four involve neuroinvasive disease, meaning the virus moved into the brain. About 30% of Triple E cases are fatal, and survivors often have long-term neurological problems. Massachusetts has begun spraying mosquitoes in some communities, and is urging people to consider remaining indoors from dusk to dawn to avoid being bitten.
Triple E infections typically occur in late summer and early fall, before cool temperatures kill off the mosquitoes that spread it. The virus is most commonly found along the Gulf Coast, in the Atlantic states and around the Great Lakes. The number of cases varies by year, though most years fewer than 10 cases are reported. In 2019, however, a record 38 cases were reported.
—Helen Branswell
The National Institutes of Health has announced plans to devote over a quarter-billion dollars to researching substance use and drug overdose among indigenous tribes across the country. But there’s a community-driven twist: Tribes and tribal-serving organizations get to design and conduct the research themselves.
Of course, major initiatives promising to serve indigenous people can be tricky to execute, given the federal government’s track record of violence and broken promises — and broader mistrust of research projects aimed at historically marginalized communities, STAT’s Lev Facher reports.
But that context is the “foundation of this program,” said Kathy Etz, the director of Native American Programs at the National Institute on Drug Abuse. “Tribes want to lead research, they want to be directly funded to lead research, and they want the research to reflect the priorities of their communities,” she said. “What we’re doing here is supporting tribes and Native American-serving organizations to do what they want.” Read more from Lev.
What mental health care protections exist in your state? Pro Publica
America is doubling down on sewer surveillance, The Atlantic
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Background. Smoking during pregnancy (SDP) is a significant public health concern due to adverse health outcomes on mothers and infants, such as miscarriage, low birth weight (LBW), preterm birth, and asthma [ 1 - 4 ]. The prevalence of SDP is around 10% in high-income countries (HICs) [ 5 - 7] and 3% in low- and middle-income countries ...
Results. Nineteen thousand five hundred fifty-four pregnant women met the inclusion criteria and 2,714 (13.9%) of them were smokers. Even after adjusting for confounding factors, smoking during pregnancy was associated with preterm birth, birthweight < 2500 g, intrauterine growth restriction, neonatal respiratory and gastrointestinal diseases, transfer to the neonatal intensive care unit, and ...
Background It has been shown that active exposure to tobacco is associated with adverse pregnancy outcomes including, but not limited to, intrauterine fetal death, reduced fetal weight, and higher risk of preterm birth. We want to investigate these effects in a high-income country. Methods This cross-sectional study examined 20,843 pregnant women who delivered over 10 years at the Maternity ...
As shown in previous research, active and passive maternal smoking during pregnancy increases the risk of having a child with low birth weight [27,34] and significantly increases other negative pregnancy outcomes, such as preterm birth [17,21], respiratory distress , antepartum and intrapartum stillbirth , perinatal death , long-term morbidity ...
The maternal smoking status before childbirth was as follows: Never = 60.0%, Quit before recognising current pregnancy = 24.1%, Quit after finding out about current pregnancy = 12.3%, and Still ...
Research Article. Maternal cigarette smoking before and during pregnancy and the risk of preterm birth: A dose-response analysis of 25 million mother-infant pairs ... Maternal smoking during either the first or second trimester of pregnancy was associated with an increased risk of preterm birth. After adjustment for maternal age, race ...
Introduction. Maternal smoking during pregnancy is associated with a reduction in birth weight of approximately 250g and is known to adversely affect the health of both fetus and mother.[] Knowledge of the age at onset of faltering fetal growth in association with maternal smoking would be useful evidence to underpin public health advice for mothers not to smoke during pregnancy.
Associations of maternal smoking with fetal growth. Differences in mean fetal size across gestation by maternal smoking during pregnancy are presented in Fig 1, with estimates from multivariable adjusted analyses shown in S7 Table. Overall, trajectories of fetal growth varied according to maternal smoking status (p < 0.001 for each fetal ...
Maternal smoking is one of the most important preventable risk factors for infant morbidity and mortality and associated with increased risk of Sudden Infant Death Syndrome (SIDS). 1,2 SIDS is a ...
Smoking in pregnancy is known to be associated with a range of adverse pregnancy outcomes, yet there is a high prevalence of smoking among pregnant women in many countries, and it remains a major public health concern. We have conducted a systematic review and meta-analysis to provide contemporary estimates of the association between maternal smoking in pregnancy and the risk of stillbirth.
Background Maternal smoking during pregnancy may be associated with low birth weight (LBW) in offspring and global risk estimates have not been summarized previously. We aimed to systematically explore evidence regarding maternal smoking and the LBW risk in offspring globally and examine possible causes of heterogeneity across relevant studies. Methods Comprehensive search of PubMed, Ovid ...
The prevalence data are consistent with a recent analysis based on Demographic and Health Survey data from 54 countries, in which the global pooled estimate of tobacco smoking prevalence during pregnancy was 1·3% (95% CI 0·9-1·8). However, although this analysis included a higher number of reporting countries than in the study by Lange and ...
Articles were retained if they: consisted of original, quantitative research published in a peer-reviewed journal; reported the prevalence of smoking during pregnancy in the general population; and provided a measure of uncertainty (CI or SE) for the prevalence or at least two of the following: sample size, number of cases, or prevalence.
Here, we aim to investigate the effects of maternal prepregnancy smoking, reduction during pregnancy, and smoking during pregnancy on SUID rates. METHODS: We analyzed the Centers for Disease Control and Prevention Birth Cohort Linked Birth/Infant Death Data Set (2007-2011: 20 685 463 births and 19 127 SUIDs).
Research article. First published online October 2, 2018. Striving to Meet Healthy People 2020 Objectives: Trend Analysis of Maternal Smoking. ... (NHANES) to examine trends in maternal smoking and smoking cessation during pregnancy in the United States from 1985 through 2014 to (1) address the gap in data on national trends in pregnancy ...
In addition, more efforts should be made to investigate the causal nature of observed relations, given the confounding issues in research on maternal smoking during pregnancy and child outcomes. 8 Using paternal smoking as a negative control is a well-known approach to examine whether there is a direct intrauterine effect of a maternal exposure ...
Evidence regarding the negative effects of tobacco smoking on fetal development is widely documented in existing literature. The toxic effects vary from perinatal complications, such as low birth weight, to changes in adult behavior [1-5].Regarding the effects of maternal tobacco smoking on placental blood flow and vascular resistance, there still exists some controversy regarding which ...
3.2.3 Joint analyses of maternal smoking status during pregnancy and ASI with ACD. We found that for ACD, there was no interaction between MSDP and ASI (p values for interaction = 0.905). Then, according to the maternal smoking status around birth and the time starting to smoke, all participants were divided into eight groups (Groups 0 to 7).
Introduction. Maternal smoking during pregnancy (MSDP) is a major public health concern with nearly half of all women who smoke continuing to do so throughout their pregnancies (Centers for Disease Control (CDC), 2002, 2004; Ebrahim, Floyd, Merrit, Decoufle, & Holtzman, 2000).As a result, more than half a million infants per year are prenatally exposed to maternal smoking (CDC, 2004; Smith ...
The corresponding OR was 1.6, (95% CI 1.2 - 2.3) for reported exposure to ETS with or without maternal smoking in utero. Maternal smoking during pregnancy but no exposure to ETS also increased the risk of doctor's diagnosed asthma up to two years of age, ORadj = 2.1, (95% CI 1.2 - 3.7). Exposure to maternal cigarette smoking in utero is a ...
An additional meta-analysis of eight primary studies with 723,877 participants showed that children exposed to maternal prenatal tobacco smoking were 49% more likely to struggle with poor academic ...
image: Maternal prenatal smoking has a significant risk of limiting a child's academic performance. view more . Credit: "Cigarette" by Sudipto_Sarkar is licensed under CC BY-NC-ND 2.0.
Enhancing pregnancy health is known to improve the mother's and offspring's life-long well-being. The maternal environment, encompassing genetic factors, impacts of social determinants, the nutritional/metabolic milieu, and infections and inflammation, have immediate consequences for the in utero development of the fetus and long-term programming into childhood and adulthood. Moreover ...
Introduction. Smoking is a modifiable risk factor for adverse maternal and neonatal outcomes and is associated with maternal, fetal, and infant morbidity and mortality [].As shown in previous research, active and passive maternal smoking during pregnancy increases the risk of having a child with low birth weight [27, 34] and significantly increases other negative pregnancy outcomes, such as ...
28 August 2024 Smoking harms almost every part of your body. But if you smoke when pregnant, the toxic chemicals in tobacco will also harm your unborn baby, with new research showing that it could lead to reduced academic outcomes at school.. In a systematic review of 19 studies and 1.25 million participants, researchers at the University of South Australia along with a team at Curtin ...
More information: Bereket Duko et al, The effect of maternal prenatal tobacco smoking on offspring academic achievement: A systematic review and meta-analysis, Addictive Behaviors (2024). DOI: 10. ...
Smoking during pregnancy (SDP) is a significant public health concern due to adverse health outcomes on mothers and infants, such as miscarriage, low birth weight (LBW), preterm birth, and asthma [1,2,3,4].The prevalence of SDP is around 10% in high-income countries (HICs) [5,6,7] and 3% in low- and middle-income countries (LMICs) [].Smoking during pregnancy generates a considerable cost ...
Smoking even one or two cigarettes a day before or during pregnancy can lead to serious health problems for newborns, according to a new analysis of more than 12 million families.
Not so, found the new study, which tracked the health outcomes of more than 32,000 people diagnosed with heart disease over five years. Close to 15,000 had smoked at some point in their lives and ...
Read the story.And if you haven't already, go back to read Part 1 and Part 2.. CDC announces $118.5 million to investigate maternal deaths. The Biden administration announced yesterday that CDC ...