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1.  An investigation of the smoking behaviours of parents before, during and after the birth of their children in Taiwan 
BMC Public Health  2008;8:67.
Although many studies have investigated the negative effects of parental smoking on children and Taiwan has started campaigns to promote smoke-free homes, little is known about the smoking behaviours of Taiwanese parents during the childbearing period. To help fill the gap, this study investigated Taiwanese parents' smoking behaviours before, during and after the birth of their children, particularly focusing on smoking cessation during pregnancy and relapse after childbirth.
We used data from the Survey of Health Status of Women and Children, conducted by Taiwan's National Health Research Institutes in 2000. After excluding survey respondents with missing information about their smoking behaviours, our sample consisted of 3,109 women who were married at the time of interview and had at least one childbearing experience between March 1, 1995 and February 28, 1999. Data on parental smoking behaviour in the six months before pregnancy, during pregnancy, and in the first year after childbirth were extracted from the survey and analysed by descriptive statistics as well as logistic regression.
Four percent of the mothers and sixty percent of the fathers smoked before the conception of their first child. The educational attainment and occupation of the parents were associated with their smoking status before the first pregnancy in the family. Over 80% of smoking mothers did not quit during pregnancy, and almost all of the smoking fathers continued tobacco use while their partners were pregnant. Over two thirds of the women who stopped smoking during their pregnancies relapsed soon after childbirth. Very few smoking men stopped tobacco use while their partners were pregnant, and over a half of those who quit started to smoke again soon after their children were born.
Among Taiwanese women who had childbearing experiences in the late 1990s, few smoked. Of those who smoked, few quit during pregnancy. Most of those who quit relapsed in the first year after childbirth. The smoking prevalence was high among the husbands of these Taiwanese women, and almost all of these smoking fathers continued tobacco use while their partners were pregnant. It is important to advocate the benefits of a smoke-free home to Taiwanese parents-to-be and parents with young children, especially the fathers. The government should take advantage of its free prenatal care and well-child care services to do this. In addition to educational campaigns through the media, the government can request physicians to promote smoke-free homes when they deliver prenatal care and well-child care. This could help reduce young children's health risks from their mothers' smoking during pregnancy and second-hand smoke at home.
PMCID: PMC2289813  PMID: 18284702
2.  Increased Nicotine Self-Administration Following Prenatal Exposure in Female Rats 
There is a significant association between maternal cigarette smoking during pregnancy and greater subsequent risk of smoking in female offspring. In animal models, prenatal nicotine exposure causes persistent alterations in cholinergic and monoaminergic systems, both of which are important for nicotine actions underlying tobacco addiction. Accordingly, the current study was conducted to determine if there is a cause-and-effect relationship between prenatal nicotine exposure and nicotine self-administration starting in adolescence. Pregnant rats were administered nicotine (6 mg/kg/day) by osmotic minipump infusion throughout gestation and then, beginning in adolescence and continuing into adulthood, female offspring were given access to nicotine via a standard operant IV self-administration procedure (0.03 mg/kg/infusion). Gestational nicotine exposure did not alter the initial rate of nicotine self-administration. However, when animals underwent one week of forced abstinence and then had a second opportunity to self-administer nicotine, the prenatally-exposed animals showed a significantly greater rate of self-administration than did the controls. Prenatal nicotine exposure causes increased nicotine self-administration, which is revealed only when the animals are allowed to experience a period of nicotine abstinence. This supports a cause-and-effect relationship between the higher rates of smoking in the daughters of women who smoke cigarettes during pregnancy and implicates a role for nicotine in this effect. Our results further characterize the long-term liabilities of maternal smoking but also point to the potential liabilities of nicotine-based treatments for smoking cessation during pregnancy.
PMCID: PMC1797890  PMID: 17196243
Nicotine; Self-administration; Prenatal; Adolescent; Prenatal Nicotine Exposure
3.  Parental smoking during pregnancy and risk of overweight and obesity in the daughter 
Emerging evidence suggests that prenatal exposures may affect long-term health outcomes. In utero exposure to smoking is associated with an increased risk of overweight and obesity in children and adolescents. However, few studies have examined how prenatal exposure to parental smoking influences risk of obesity in adulthood and whether these associations are independent of childhood and adolescent adiposity. The aim of the current study was to investigate whether prenatal exposure to parental smoking influences body size in adulthood and whether any association may be mediated by childhood and adolescent body size.
We investigated the association between parental smoking during pregnancy and risk of overweight and obesity in adulthood and at age 18, and adiposity during childhood among 35,370 participants in the Nurses’ Health Study II. Data on smoking during pregnancy and socioeconomic variables were provided by the mothers, and anthropometric data and adult risk factors were reported by participants.
After adjustment for socioeconomic and behavioral variables, maternal smoking during pregnancy was associated with adiposity at ages 5–10, age 18, and during adulthood. For age 18 overweight the ORs (95% CIs) for 1–14, 15–24, and 25+cigarettes/day were 1.13 (1.18–1.50), 1.40 (1.20–1.64), and 1.15 (0.79–1.69) and for obesity were 1.41 (1.14–1.75), 1.69 (1.31–2.18), and 2.36 (1.44–3.86). The corresponding ORs (95% CIs) for obesity in adulthood were 1.26 (1.16–1.37), 1.46 (1.30–1.63), and 1.43 (1.10–1.86). Risk of adiposity was not increased among daughters whose mothers stopped smoking during the first trimester (OR [95% CI] for overweight (1.03 [95% CI 0.90–1.17] and obesity (1.12 [95% CI 0.97–1.30]). Women whose fathers smoked during pregnancy were also at increased risk of overweight and obesity in adulthood with covariate-adjusted ORs (95% CIs) for obesity of 1.19 (1.11–1.29) for 1–14 cigarettes/day, 1.27 (1.18–1.37) for 15–24 cigarettes/day, and 1.40 (1.27–1.54) for 25+ cigarettes/day compared to fathers who did not smoke (ptrend<0.0001). Paternal smoking during pregnancy was also associated with an increased risk of obesity at age 18 among those whose fathers smoked 15 or more cigarettes/day but was not associated with childhood body size.
Maternal smoking during pregnancy was associated in a dose-response manner with overweight and obesity in the daughter through adolescence and adult life. Smoking cessation during the first trimester appears to mitigate this excess risk.
Paternal smoking was also associated with risk of overweight and obesity of the adult daughter and this association persisted after adjustment for maternal smoking.
PMCID: PMC3795801  PMID: 23736356
pregnancy; prenatal programming; cigarette smoking; obesity
4.  Exposure to parental smoking and child growth and development: a cohort study 
BMC Pediatrics  2013;13:104.
Studies on adverse childhood health and development outcomes associated with parental smoking have shown inconsistent results. Using a cohort of Belarusian children, we examined differences in cognition, behaviors, growth, adiposity, and blood pressure at 6.5 years according to prenatal and postnatal exposure to parental smoking.
Using cluster-adjusted multivariable regression, effects of exposure to prenatal smoking were examined by comparing (1) children whose mothers smoked during pregnancy with those of mothers who smoked neither during nor after pregnancy and (2) children whose mothers smoked during and after pregnancy with those whose mothers smoked after pregnancy only; effects of postnatal smoking were examined by comparing (1) children whose mothers smoked after pregnancy only with those of mothers who smoked neither during nor after pregnancy and (2) children whose fathers smoked with those whose fathers did not smoke among children of non-smoking mothers after adjusting for a wide range of socioeconomic and family characteristics.
After adjusting for confounders, children exposed vs unexposed to prenatal maternal smoking had no differences in mean IQ, teacher-rated behavioral problems, adiposity, or blood pressure. Children exposed to maternal postnatal smoking had slightly increased behavioral problems [0.9, 95% CI: 0.6, 1.2 for total difficulties], higher body mass index [0.2, 95% CI: 0.1, 0.3], greater total skinfold thickness [0.4, 95% CI: 0.04, 0.71], and higher odds of overweight or obesity [1.4, 95% CI; 1.1, 1.7]. Similar magnitudes of association were observed with postnatal paternal smoking.
No adverse cognitive, behavioral and developmental outcomes were associated with exposure to maternal prenatal smoking. Observed associations with postnatal smoking of both parents may reflect residual confounding by genetic and family environmental factors.
PMCID: PMC3717101  PMID: 23842036
5.  Mother’s environmental tobacco smoke exposure during pregnancy and externalizing behavior problems in children 
Neurotoxicology  2012;34:167-174.
While the impact of active maternal smoking during pregnancy on child health has been well investigated, the association between maternal passive smoking, or environmental tobacco smoke (ETS), or second-hand smoke, and behavioral development of offspring is less clear. This study examines the association between maternal ETS exposure during pregnancy and child behavior problems.
Cross-sectional data of 646 mother–child pairs from the Jintan China Cohort Study were used in the analyses. Mother’s exposure to tobacco smoking at home, the workplace, and other places during pregnancy (for the determination of maternal ETS exposure) and children’s behaviors (via Child Behavior Checklist) were assessed when the children were 5–6 years old. Logistic regression models were constructed to examine associations between maternal exposure to ETS during pregnancy and internalizing and externalizing behavior problems, adjusting for potential cofounders including child sex and parental characteristics.
37% of mothers reported ETS during pregnancy. Children of mothers exposed to ETS during pregnancy had higher scores for externalizing and total behavior problems, with 25% of children whose mothers were exposed to ETS compared to 16% of children of unexposed mothers. After adjusting for potential confounders, ETS exposure was associated with a higher risk of externalizing behavior problems in offspring of exposed mothers (OR = 2.08, 95% confidence interval [CI] 1.27–3.43). Analysis after multiple imputations and sensitivity analysis further verified the association, but no dose–response relationship was found. ETS exposure, however, was not associated with internalizing or total behavior problems.
This study suggests that maternal ETS exposure during pregnancy may impact child behavioral development, particularly externalizing behaviors.
PMCID: PMC3587028  PMID: 23178460
Environmental tobacco exposure; Second-hand smoke; Child behavior problem; Externalizing behavior; Pregnancy exposure
6.  Association of Prenatal and Childhood Blood Lead Concentrations with Criminal Arrests in Early Adulthood 
PLoS Medicine  2008;5(5):e101.
Childhood lead exposure is a purported risk factor for antisocial behavior, but prior studies either relied on indirect measures of exposure or did not follow participants into adulthood to examine the relationship between lead exposure and criminal activity in young adults. The objective of this study was to determine if prenatal and childhood blood lead concentrations are associated with arrests for criminal offenses.
Methods and Findings
Pregnant women were recruited from four prenatal clinics in Cincinnati, Ohio if they resided in areas of the city with a high concentration of older, lead-contaminated housing. We studied 250 individuals, 19 to 24 y of age, out of 376 children who were recruited at birth between 1979 and 1984. Prenatal maternal blood lead concentrations were measured during the first or early second trimester of pregnancy. Childhood blood lead concentrations were measured on a quarterly and biannual basis through 6.5 y. Study participants were examined at an inner-city pediatric clinic and the Cincinnati Children's Hospital Medical Center in Cincinnati, Ohio. Total arrests and arrests for offenses involving violence were collected from official Hamilton County, Ohio criminal justice records. Main outcomes were the covariate-adjusted rate ratios (RR) for total arrests and arrests for violent crimes associated with each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration. Adjusted total arrest rates were greater for each 5 μg/dl (0.24 μmol/l) increase in blood lead concentration: RR = 1.40 (95% confidence interval [CI] 1.07–1.85) for prenatal blood lead, 1.07 (95% CI 0.88–1.29) for average childhood blood lead, and 1.27 (95% CI 1.03–1.57) for 6-year blood lead. Adjusted arrest rates for violent crimes were also greater for each 5 μg/dl increase in blood lead: RR = 1.34 (95% CI 0.88–2.03) for prenatal blood lead, 1.30 (95% CI 1.03–1.64) for average childhood blood lead, and 1.48 (95% CI 1.15–1.89) for 6-year blood lead.
Prenatal and postnatal blood lead concentrations are associated with higher rates of total arrests and/or arrests for offenses involving violence. This is the first prospective study to demonstrate an association between developmental exposure to lead and adult criminal behavior.
Kim Dietrich and colleagues find an association between developmental exposure to lead and adult criminal behavior.
Editors' Summary
Violent crime is an increasing problem in many countries, but why are some people more aggressive than others? Being male has been identified as a risk factor for violent criminal behavior in several studies, as have exposure to tobacco smoke before birth, having antisocial parents, and belonging to a poor family. Another potential risk factor for antisocial behavior as an adult is exposure to lead during childhood, although few studies have looked directly at whether childhood lead exposure is linked with criminal behavior in adulthood. Lead is a toxic metal that damages the nervous system when ingested or inhaled. It is present throughout the environment because of its widespread use in the past in paint, solder for water pipes, and gasoline. In 1978, 13.5 million US children had a blood lead level above 10 μg/dl, the current US Centers for Disease Control and Prevention blood lead level of concern (the average US blood lead level is 2 μg/dl). Lead paint and solder were banned in 1978 and 1986, respectively, by the US federal government; leaded gasoline was finally phased out in 1996. By 2002, only 310,000 US children had a blood lead level above 10 μg/dl. However, children exposed to lower levels of lead than this—through ingesting flakes or dust residues of old lead paint, for example—can have poor intellectual development and behavioral problems including aggression.
Why Was This Study Done?
Although some studies have suggested that childhood lead exposure is associated with later criminal behavior, these studies have often relied on indirect measurements of childhood lead exposure such as bone lead levels in young adults or a history of lead poisoning. Other studies that have measured childhood lead exposure directly have not followed their participants into adulthood. In this new study, the researchers investigate the association between actual measurements of prenatal and childhood blood lead concentrations and criminal arrests in early adulthood to get a clearer idea about whether early lead exposure is associated with subsequent violent behavior.
What Did the Researchers Do and Find?
Between 1979 and 1984, the researchers recruited pregnant women living in poor areas of Cincinnati, which had a high concentration of older, lead-contaminated housing, into the Cincinnati Lead Study. They measured the women's blood lead concentrations during pregnancy as an indication of their offspring's prenatal lead exposure and the children's blood lead levels regularly until they were six and half years old. They then obtained information from the local criminal justice records on how many times each of the 250 offspring had been arrested between becoming 18 years old and the end of October 2005. The researchers found that increased blood lead levels before birth and during early childhood were associated with higher rates of arrest for any reason and for violent crimes. For example, for every 5 μg/dl increase in blood lead levels at six years of age, the risk of being arrested for a violent crime as a young adult increased by almost 50% (the “relative risk” was 1.48).
What Do These Findings Mean?
These findings provide strong evidence that early lead exposure is a risk factor for criminal behavior, including violent crime, in adulthood. One possibility, which the authors were unable to assess in this study, is that lead exposure impairs intelligence, which in turn makes it more likely that a criminal offender will be caught (i.e., arrested). The authors discuss a number of limitations in their study—for example, they probably did not capture all criminal behavior (since most criminal behavior does not lead to arrest). Although both environmental lead levels and crime rates have dropped over the last 30 years in the US, the overall reduction was not uniform—inner-city children remain particularly vulnerable to lead exposure. The findings therefore suggest that a further reduction in childhood lead exposure might be an important and achievable way to reduce violent crime.
Additional Information.
Please access these Web sites via the online version of this summary at
A PLoS Medicine Perspective article by David Bellinger further discusses this study and a related paper on childhood lead exposure and brain volume reduction in adulthood
Study researcher Kim Dietrich can be heard talking about “The Lethal Legacy of Lead”, a brief MP3 about lead exposure and violent crime
Toxtown, an interactive site from the US National Library of Medicine, provides information on environmental health concerns including exposure to lead (in English and Spanish)
The US Environmental Protection Agency provides information on lead in paint, dust, and soil and on protecting children from lead poisoning (in English and Spanish)
MedlinePlus provides a list of links to information on lead poisoning (in English and Spanish)
The US Centers for Disease Control and Prevention provides information about its Childhood Lead Poisoning Prevention Program
The UK Health Protection Agency also provides information about lead and its health hazards
PMCID: PMC2689664  PMID: 18507497
7.  Active and passive maternal smoking during pregnancy and birth outcomes: the Kyushu Okinawa Maternal and Child Health Study 
In Western countries, active maternal smoking during pregnancy is recognized as the most important preventable risk factor for adverse birth outcomes. However, the effect of passive maternal smoking is less clear and has not been extensively studied. In Japan, there has been only one epidemiological study which examined the effects of active smoking during early pregnancy on birth outcomes although the effects of passive smoking were not assessed.
Study subjects were 1565 mothers with singleton pregnancies and the babies born from these pregnancies. Data on active maternal smoking status in the first, second, and third trimesters and maternal environmental tobacco smoke (ETS) exposure at home and work were collected with self-administered questionnaires.
Compared with children born to mothers who had never smoked during pregnancy, children born to mothers who had smoked throughout their pregnancy had a significantly increased risk of small-for-gestational-age (SGA) (adjusted odd ratio [OR] = 2.87; 95% confidence interval: 1.11 − 6.56). However, active maternal smoking only in the first trimester and active maternal smoking in the second and/or third trimesters but not throughout pregnancy were not significantly associated with SGA. With regard to the risk of preterm birth, the adjusted ORs for the above-mentioned three categories were not significant; however, the positive linear trend was significant (P for trend = 0.048). No significant association was found between active maternal smoking during pregnancy and the risk of low birth weight. There was a significant inverse relationship between active maternal smoking during pregnancy and birth weight; newborns of mothers who had smoked throughout pregnancy had an adjusted mean birth weight reduction of 169.6 g. When classifying babies by gender, a significant positive association between active maternal smoking throughout pregnancy and the risk of SGA was found only in male newborns, however, the interaction was not significant. Maternal ETS exposure at home or work was not significantly associated with any birth outcomes.
This is the first study in Japan to show that active maternal smoking throughout pregnancy, but not during the first trimester, is significantly associated with an increased risk of SGA and a decrease in birth weight. Thus, women who smoke should quit smoking as soon as possible after conception.
PMCID: PMC3750375  PMID: 23919433
8.  Impact of Scotland's Smoke-Free Legislation on Pregnancy Complications: Retrospective Cohort Study 
PLoS Medicine  2012;9(3):e1001175.
An analysis of pregnancy data for the whole of Scotland demonstrates a reduction in small-for-gestational-age births and preterm delivery since the introduction of legislation banning smoking in enclosed public spaces.
Both active smoking and environmental tobacco smoke exposure are associated with pregnancy complications. In March 2006, Scotland implemented legislation prohibiting smoking in all wholly or partially enclosed public spaces. The aim of this study was to determine the impact of this legislation on preterm delivery and small for gestational age.
Methods and Findings
We conducted logistic regression analyses using national administrative pregnancy data covering the whole of Scotland. Of the two breakpoints tested, 1 January 2006 produced a better fit than the date when the legislation came into force (26 March 2006), suggesting an anticipatory effect. Among the 716,941 eligible women who conceived between August 1995 and February 2009 and subsequently delivered a live-born, singleton infant between 24 and 44 wk gestation, the prevalence of current smoking fell from 25.4% before legislation to 18.8% after legislation (p<0.001). Three months prior to the legislation, there were significant decreases in small for gestational age (−4.52%, 95% CI −8.28, −0.60, p = 0.024), overall preterm delivery (−11.72%, 95% CI −15.87, −7.35, p<0.001), and spontaneous preterm labour (−11.35%, 95% CI −17.20, −5.09, p = 0.001). In sub-group analyses, significant reductions were observed among both current and never smokers.
Reductions were observed in the risk of preterm delivery and small for gestational age 3 mo prior to the introduction of legislation, although the former reversed partially following the legislation. There is growing evidence of the potential for tobacco control legislation to have a positive impact on health.
Please see later in the article for the Editors' Summary
Editors' Summary
The risks of smoking during pregnancy, both on mother and fetus, are well established: women who smoke during pregnancy are more likely to have a miscarriage. Smoking can cause placental problems, such as placental abruption, which can result in heavy bleeding during pregnancy, which is dangerous for both mother and baby. Other dangers of smoking during pregnancy include the baby being born too early (premature birth), the baby being below average weight (small for gestational age), birth defects, and infant death. Because of the serious damage to health caused by smoking, in 2005, under the auspices of the World Health Organization, countries adopted the Framework Convention on Tobacco Control to protect present and future generations from the devastating health, social, environmental, and economic consequences of tobacco consumption and exposure to tobacco smoke. Article 8 of the treaty obliges member states who have ratified the treaty—168 so far—to protect all people from exposure to tobacco smoke in indoor workplaces, public transport, and indoor public places. As a result, many countries around the world have banned smoking in public places.
Why Was This Study Done?
Scotland was the first country in the United Kingdom to ban smoking in public places, which was implemented as part of the Smoking, Health and Social Care (Scotland) Bill on 26 March 2006. Previous studies have shown that the introduction of the legislation led directly to a reduction in smoking and also a reduction in environmental tobacco smoke exposure in adults and children. Furthermore, the Scottish legislation has been accompanied by significant reductions in both cardiovascular and respiratory disease. Because of the known risks of smoking during pregnancy, the researchers wanted to investigate whether the change in policy on smoking in public places had positive benefits on the health of mothers and babies. They evaluated this by measuring the rates of preterm delivery and small for gestational age before and after the Scottish legislation went into effect.
What Did the Researchers Do and Find?
The researchers collected information on preterm delivery and small for gestational age in all single babies born live at 22–44 weeks gestation between 1 January 1996 and 31 December 2009 by using the Scottish Morbidity Record (SMR2), which collects relevant information on all women discharged from Scottish maternity hospitals, including maternal and infant characteristics and pregnancy complications. The researchers categorized preterm delivery into mild, moderate, and extreme depending on how much before 37 weeks the baby was born. They defined small for gestational age as the smallest 10% (below the 10th centile) for sex-specific birth weight at delivery, and very small for gestational age as the smallest 3% (below the 3rd centile), for all deliveries in Scotland over the study period. As some people may have stopped smoking in anticipation of the smoking ban, in their statistical model, the researchers included two possible breakpoints for the effect of the legislation—the actual date of implementation and 1 January 2006.
The researchers found that of the 716,968 pregnancies (the number eligible for inclusion in the study), 99.9% of women had their smoking status recorded, and among these 23.9% were current smokers, 57.6% never smokers, and 8.7% former smokers. However, following implementation of the legislation the researchers noted that there was a significant reduction in current smokers to 18.8%. In their statistical model, the researchers found that following 1 January 2006, there was a significant drop in overall preterm deliveries, which remained after adjustment for potential confounding factors. Likewise, there was a significant decrease in the number of infants born small, and very small, for gestational age after 1 January 2006. Furthermore, the researchers found that these significant reductions occurred in both mothers who smoked and those who had never smoked.
What Do These Findings Mean?
These findings suggest that the introduction of national, comprehensive smoke-free legislation in Scotland was associated with significant reductions in preterm delivery and babies being born small for gestational age. These findings are plausible and add to the growing evidence of the wide-ranging health benefits of smoke-free legislation, and support the adoption of such legislation in other countries that have yet to implement smoking bans.
Additional Information
Please access these websites via the online version of this summary at
More information is available on the World Health Organization's Framework Convention for Tobacco Control
More information on the Smoking, Health and Social Care (Scotland) Bill is available
The US Centers for Disease Control and Prevention has more information about the risks of smoking in pregnancy, as does the UK National Health Service's smokefree web page
NHS Health Scotland has a website that summarises all the studies to date evaluating the Scottish smoke-free legislation
PMCID: PMC3295815  PMID: 22412353
9.  Maternal Smoking Cessation and Reduced Academic and Behavioral Problems In Offspring* 
Drug and Alcohol Dependence  2011;121(1-2):62-67.
There is some debate whether smoking during pregnancy causes or is only a risk factor for negative academic outcomes and increased risk of psychopathology in offspring. This study evaluated whether maternal smoking cessation would reduce the risk of adverse outcomes in school-aged children.
Women completed an online survey that included items about child scholastic performance and the Child Behavior Checklist (CBCL). Mothers were divided based on pre-pregnancy and pregnancy smoking status into: 1) Nonsmokers (N=320); 2) Women that smoked in the three months preceding and throughout pregnancy (Smokers, N=83); and 3) Smoking before, but not during pregnancy (Quitters, N=72).
The Smokers and Quitters groups each had lower education and incomes compared to Nonsmokers but were indistinguishable from each other on these measures. The offspring of Smokers were more likely (p<.05) to be behind their peers on standardized tests in math (27.8%) relative to both Nonsmokers (17.4%) and Quitters (13.0%) with similar findings for reading. Smokers reported more behavioral problems by their children in several areas including Hyperactivity and Impulsivity, Social problems, and Externalizing problems including Aggression and Rule-Breaking. Further, the children of Quitters had significantly fewer Attention and Externalizing problems than Smokers. These outcomes were observed even after accounting for the variance attributable to maternal education and several other potential confounds.
Together, these findings indicate that smoking cessation is associated with reduced risk of having children with academic and neuropsychological difficulties. These outcomes are discussed within the framework that nicotine may be a neurobehavioral teratogen.
PMCID: PMC3262955  PMID: 21937170
aggression; attention; math; nicotine; psychopathology; prenatal
We previously reported an association between prenatal exposure to airborne PAH and lower birth weight, birth length and head circumference. The main goal of the present analysis was to assess the possible impact of co-exposure to PAH-containing of barbecued meat consumed during pregnancy on birth outcomes.
The birth cohort consisted of 432 pregnant women who gave birth at term (>36 weeks of gestation). Only non-smoking women with singleton pregnancies, 18-35 years of age, and who were free from chronic diseases such as diabetes and hypertension were included in the study. Detailed information on diet over pregnancy was collected through interviews and the measurement of exposure to airborne PAHs was carried out by personal air monitoring during the second trimester of pregnancy. The effect of barbecued meat consumption on birth outcomes (birthweight, length and head circumference at birth) was adjusted in multiple linear regression models for potential confounding factors such as prenatal exposure to airborne PAHs, child’s sex, gestational age, parity, size of mother (maternal prepregnancy weight, weight gain in pregnancy) and prenatal environmental tobacco smoke (ETS).
The multivariable regression model showed a significant deficit in birthweight associated with barbecued meat consumption in pregnancy (coeff = −106.0 g; 95%CI: −293.3, −35.8); The effect of exposure to airborne PAHs was about the same magnitude order (coeff. = −164.6 g; 95%CI: −172.3, − 34.7). Combined effect of both sources of exposure amounted to birth weight deficit of 214.3 g (95%CI: −419.0, − 9.6). Regression models performed for birth length and head circumference showed similar trends but the estimated effects were of borderline significance level. As the intake of barbecued meat did not affect the duration of pregnancy, the reduced birthweight could not have been mediated by shortened gestation period.
In conclusion, the study results provided epidemiologic evidence that prenatal PAH exposure from diet including grilled meat might be hazardous for fetal development.
PMCID: PMC3288524  PMID: 22079395
barbecued meat; pregnancy; birth weight; birth cohort study
11.  Cesarean Section and Rate of Subsequent Stillbirth, Miscarriage, and Ectopic Pregnancy: A Danish Register-Based Cohort Study 
PLoS Medicine  2014;11(7):e1001670.
Louise Kenny and colleagues conduct a population-based cohort study in Denmark to assess the likelihood of stillbirth, miscarriage, and ectopic pregnancy following cesarean section compared to women who gave birth by vaginal delivery.
Please see later in the article for the Editors' Summary
With cesarean section rates increasing worldwide, clarity regarding negative effects is essential. This study aimed to investigate the rate of subsequent stillbirth, miscarriage, and ectopic pregnancy following primary cesarean section, controlling for confounding by indication.
Methods and Findings
We performed a population-based cohort study using Danish national registry data linking various registers. The cohort included primiparous women with a live birth between January 1, 1982, and December 31, 2010 (n = 832,996), with follow-up until the next event (stillbirth, miscarriage, or ectopic pregnancy) or censoring by live birth, death, emigration, or study end. Cox regression models for all types of cesarean sections, sub-group analyses by type of cesarean, and competing risks analyses for the causes of stillbirth were performed. An increased rate of stillbirth (hazard ratio [HR] 1.14, 95% CI 1.01, 1.28) was found in women with primary cesarean section compared to spontaneous vaginal delivery, giving a theoretical absolute risk increase (ARI) of 0.03% for stillbirth, and a number needed to harm (NNH) of 3,333 women. Analyses by type of cesarean section showed similarly increased rates for emergency (HR 1.15, 95% CI 1.01, 1.31) and elective cesarean (HR 1.11, 95% CI 0.91, 1.35), although not statistically significant in the latter case. An increased rate of ectopic pregnancy was found among women with primary cesarean overall (HR 1.09, 95% CI 1.04, 1.15) and by type (emergency cesarean, HR 1.09, 95% CI 1.03, 1.15, and elective cesarean, HR 1.12, 95% CI 1.03, 1.21), yielding an ARI of 0.1% and a NNH of 1,000 women for ectopic pregnancy. No increased rate of miscarriage was found among women with primary cesarean, with maternally requested cesarean section associated with a decreased rate of miscarriage (HR 0.72, 95% CI 0.60, 0.85). Limitations include incomplete data on maternal body mass index, maternal smoking, fertility treatment, causes of stillbirth, and maternally requested cesarean section, as well as lack of data on antepartum/intrapartum stillbirth and gestational age for stillbirth and miscarriage.
This study found that cesarean section is associated with a small increased rate of subsequent stillbirth and ectopic pregnancy. Underlying medical conditions, however, and confounding by indication for the primary cesarean delivery account for at least part of this increased rate. These findings will assist women and health-care providers to reach more informed decisions regarding mode of delivery.
Please see later in the article for the Editors' Summary
Editors' Summary
Globally, increasing numbers of babies are being delivered by cesarean section (a surgical operation in which the baby is delivered through a cut made in the mother's abdomen and womb) instead of naturally through their mother's vagina. In England in 2010, for example, nearly 25% of all babies were delivered by cesarean section (also called C-section) compared to only 2% in the 1950s; in China and some parts of South America cesarean rates are now between 40% and 50%. A cesarean section is usually performed when a vaginal birth would endanger the life of the mother or her unborn child because, for example, the baby is in the wrong position. Some cesareans are performed as emergency procedures, but others are planned in advance when the need for the operation becomes clear during pregnancy (an elective cesarean). Some planned cesarean sections are also undertaken because the mother has requested a cesarean delivery in the absence of any medical reasons for such a delivery.
Why Was This Study Done?
Cesarean sections save lives but do they have any negative impacts on the outcome of subsequent pregnancies? With so many cesarean sections being undertaken, it is important to be sure that the procedure does not increase the rates of subsequent miscarriage, stillbirth, or ectopic pregnancy. Miscarriage—the loss of a fetus (developing baby) that is unable to survive independently—is the commonest complication of early pregnancy, affecting about one in five women who know they are pregnant. Stillbirth is fetal death after about 20–24 weeks of pregnancy; the exact definition of stillbirth varies between countries. About four million stillbirths occur each year worldwide. Ectopic pregnancy—development of the fetus outside the womb—occurs in 1%–2% of all pregnancies. In this population-based cohort study, the researchers investigate the rates of subsequent stillbirth, miscarriage, and ectopic pregnancy following a cesarean section among women living in Denmark. A population-based cohort study determines the baseline characteristics of the individuals in a population, and then follows the population over time to see whether specific characteristics are associated with specific outcomes.
What Did the Researchers Do and Find?
The researchers obtained data for 832,996 women from Danish national registers about their first live birth (including whether they had a cesarean) then followed the women (again using the registers) until they had a stillbirth, miscarriage, or ectopic pregnancy, or a second live birth. The researchers used these data and statistical models to estimate the risk of stillbirth, miscarriage, and ectopic pregnancy following a cesarean compared to a spontaneous vaginal delivery after controlling for the possibility that the cesarean was performed because of an indication that might increase the risk of a subsequent event (confounding). Women who had had a cesarean had a 14% increased risk of a stillbirth in their next pregnancy compared to women who had had a vaginal delivery, corresponding to an absolute risk increase of 0.03%. In other words, 3,333 women would need to have a cesarean to result in one extra stillbirth in subsequent pregnancy (a “number needed to harm” of 3,333). Compared to vaginal delivery, having a cesarean increased the risk of a subsequent ectopic pregnancy by 9% (an absolute risk increase of 0.1% and a number needed to harm of 1,000) but did not increase the rate of subsequent miscarriages.
What Do These Findings Mean?
These findings show that, among women living in Denmark, cesarean section is associated with a slightly increased rate of subsequent stillbirth and ectopic pregnancy. Part of this increase can be accounted for by underlying medical conditions and by confounding by the indication for the primary cesarean section. The accuracy of these findings may be affected by limitations in the study such as incomplete data on some factors (for example, the smoking history of the mother) that might have affected the risk of stillbirth, miscarriage, and ectopic pregnancy, and by misclassification or underreporting of the study outcomes. Given the global increase in cesarean rates, these findings suggest that cesarean delivery is not associated with an increased rate of subsequent stillbirth, miscarriage, or ectopic pregnancy, an important finding for both expectant mothers and health-care professionals that nonetheless needs to be confirmed in further large-scale studies. Finally, these findings highlight the need for women to consider all their options thoroughly before requesting a cesarean section on non-medical grounds.
Additional Information
Please access these websites via the online version of this summary at
The American Congress of Obstetricians and Gynecologists provides patient fact sheets on cesarean birth, miscarriage, and ectopic pregnancy
The US-based non-profit Nemours Foundation provides information about cesarean sections, miscarriage and stillbirth, and ectopic pregnancy (in English and Spanish)
The UK National Health Service Choices website provides information for patients about cesarean section, miscarriage, stillbirth, and ectopic pregnancy
MedlinePlus provides links to additional resources about cesarean section, miscarriage, stillbirth, and ectopic pregnancy (in English and Spanish)
The UK non-profit organization Healthtalkonline provides personal stories about cesarean delivery, miscarriage, and stillbirth
PMCID: PMC4077571  PMID: 24983970
12.  Does maternal smoking during pregnancy predict the smoking patterns of young adult offspring? A birth cohort study 
Tobacco Control  2006;15(6):452-457.
To examine the association between maternal smoking during pregnancy and the development of smoking behaviour patterns among young adult offspring.
Data were from the Mater‐University of Queensland Study of Pregnancy (MUSP), a birth cohort of 7223 mothers and children enrolled in Brisbane, Australia, in 1981. The development of smoking behaviours (early or late onset, or combination of onset and prevalence patterns) among offspring at age 21 years with different patterns of maternal smoking (never smoked, smoked before or after pregnancy but not during pregnancy, or smoked during pregnancy) were compared. Maternal smoking information was derived from the prospectively collected data from the beginning of pregnancy until the child was 14 years of age. Analyses were restricted to the 3058 mothers and children whose smoking status was reported.
The proportion of young adults who smoked regularly, either with early onset or late onset, was greater among those whose mothers had smoked during pregnancy compared with those whose mothers had never smoked. The smoking patterns among those adolescent offspring whose mothers stopped smoking during pregnancy, but who then smoked at other times during the child's life, were similar to those whose mothers had never smoked. This association was robust to adjustment for a variety of potential covariates.
The findings provide some evidence for a direct effect of maternal smoking in utero on the development of smoking behaviour patterns of offspring and provide yet another incentive to persuade pregnant women not to smoke.
PMCID: PMC2563674  PMID: 17130374
13.  Intergenerational transmission of maltreatment and psychopathology: the role of antenatal depression 
Psychological Medicine  2012;43(3):519-528.
Maternal experience of childhood maltreatment and maternal antenatal depression are both associated with offspring childhood maltreatment and offspring adjustment problems. We have investigated the relative impact of maternal childhood maltreatment and exposure to depression in utero on offspring maltreatment and psychopathology.
The sample included 125 families from the South London Child Development Study. A prospective longitudinal design was used. Data on maternal childhood maltreatment, maternal antenatal depression (36 weeks of pregnancy), offspring childhood maltreatment (age 11 years) and offspring adolescent antisocial behaviour and depression (ages 11 and 16 years) were obtained from parents and offspring through clinical interview.
Mothers who experienced childhood maltreatment were significantly more likely to be depressed during pregnancy [odds ratio (OR) 10.00]. Offspring of mothers who experienced only childhood maltreatment or only antenatal depression were no more at risk of being maltreated or having psychopathology; however, offspring of mothers who experienced both maternal childhood maltreatment and antenatal depression were exposed to significantly greater levels of childhood maltreatment and exhibited significantly higher levels of adolescent antisocial behaviour compared with offspring not so exposed. Furthermore, maternal childhood maltreatment accounted for a significant proportion of the variance in offspring childhood maltreatment in only those offspring exposed to depression in utero.
Maternal childhood maltreatment and maternal antenatal depression are highly associated. The co-occurrence of both insults significantly increases the risk of offspring adversity. The antenatal period is an optimum period to identify vulnerable women and to provide interventions.
PMCID: PMC3558981  PMID: 22694795
Adolescents; antisocial behaviour; maltreatment; pregnancy; prenatal stress
14.  A Common Genetic Variant at 15q25 Modifies the Associations of Maternal Smoking during Pregnancy with Fetal Growth: The Generation R Study 
PLoS ONE  2012;7(4):e34584.
Maternal smoking during pregnancy is associated with fetal growth retardation. We examined whether a common genetic variant at chromosome 15q25 (rs1051730), which is known to be involved in nicotine metabolism, modifies the associations of maternal smoking with fetal growth characteristics.
This study was performed in 3,563 European mothers participating in a population-based prospective cohort study from early pregnancy onwards. Smoking was assessed by postal questionnaires and fetal growth characteristics were measured by ultrasound examinations in each trimester of pregnancy.
Among mothers who did not smoke during pregnancy (82.9%), maternal rs1051730 was not consistently associated with any fetal growth characteristic. Among mothers who continued smoking during pregnancy (17.1%), maternal rs1051730 was not associated with head circumference. The T-allele of maternal rs1051730 was associated with a smaller second and third trimester fetal femur length [differences −0.23 mm (95%CI −0.45 to −0.00) and −0.41 mm (95%CI −0.69 to −0.13), respectively] and a smaller birth length [difference −2.61 mm (95%CI −5.32 to 0.11)]. The maternal T-allele of rs1051730 was associated with a lower third trimester estimated fetal weight [difference −33 grams (95%CI −55 to −10)], and tended to be associated with birth weight [difference −38 grams (95%CI −89 to 13)]. This association persisted after adjustment for smoking quantity.
Our results suggest that maternal rs1051730 genotype modifies the associations of maternal smoking during pregnancy with impaired fetal growth in length and weight. These results should be considered as hypothesis generating and indicate the need for large-scale genome wide association studies focusing on gene – fetal smoke exposure interactions.
PMCID: PMC3319619  PMID: 22496830
15.  Low-Level Prenatal Exposure to Nicotine and Infant Neurobehavior 
Neurotoxicology and teratology  2009;31(6):356-363.
To examine the association between prenatal exposure to nicotine from tobacco smoke and infant neurobehavior using tobacco biomarkers and a sensitive and comprehensive measure of infant neurobehavior.
Study design
Participants were 318 infants (206 White, 95 Black, 17 Other) and their mothers. Prenatal tobacco smoke exposure was measured twice during pregnancy and once at delivery using maternal serum cotinine. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scale at approximately five weeks after birth.
Prenatal tobacco smoke exposure was significantly associated with infant neurobehavior after controlling for important covariates, but the specific behaviors associated with exposure varied by race. In White infants, higher cotinine was associated with increased arousal (p=.030) and excitability (p=.034), and decreased self-regulation (p=.010). In contrast, among Black infants, higher cotinine was associated with decreased arousal (p=.001), excitability (p=.021), and special handling required to complete the assessment (p=.003), and increased self-regulation (p=.021) and hypotonicity (p=.016). In secondary analyses, we found racial differences in the effects of postnatal exposure to second hand smoke and low-level prenatal exposure.
Low-level prenatal tobacco smoke exposure is associated with infant neurobehavior at five weeks of age, but the specific effects differ by race. These effects may reflect racial differences in nicotine metabolism that are similar to differences reported in adult and child studies of tobacco.
PMCID: PMC2761996  PMID: 19619640
tobacco smoke; prenatal exposure; infant neurobehavior
16.  Maternal Overweight and Obesity and Risks of Severe Birth-Asphyxia-Related Complications in Term Infants: A Population-Based Cohort Study in Sweden 
PLoS Medicine  2014;11(5):e1001648.
Martina Persson and colleagues use a Swedish national database to investigate the association between maternal body mass index in early pregnancy and severe asphyxia-related outcomes in infants delivered at term.
Please see later in the article for the Editors' Summary
Maternal overweight and obesity increase risks of pregnancy and delivery complications and neonatal mortality, but the mechanisms are unclear. The objective of the study was to investigate associations between maternal body mass index (BMI) in early pregnancy and severe asphyxia-related outcomes in infants delivered at term (≥37 weeks).
Methods and Findings
A nation-wide Swedish cohort study based on data from the Medical Birth Register included all live singleton term births in Sweden between 1992 and 2010. Logistic regression analyses were used to obtain odds ratios (ORs) with 95% CIs for Apgar scores between 0 and 3 at 5 and 10 minutes, meconium aspiration syndrome, and neonatal seizures, adjusted for maternal height, maternal age, parity, mother's smoking habits, education, country of birth, and year of infant birth. Among 1,764,403 term births, 86% had data on early pregnancy BMI and Apgar scores. There were 1,380 infants who had Apgar score 0–3 at 5 minutes (absolute risk  = 0.8 per 1,000) and 894 had Apgar score 0–3 at 10 minutes (absolute risk  = 0.5 per 1,000). Compared with infants of mothers with normal BMI (18.5–24.9), the adjusted ORs (95% CI) for Apgar scores 0–3 at 10 minutes were as follows: BMI 25–29.9: 1.32 (1.10–1.58); BMI 30–34.9: 1.57 (1.20–2.07); BMI 35–39.9: 1.80 (1.15–2.82); and BMI ≥40: 3.41 (1.91–6.09). The ORs for Apgar scores 0–3 at 5 minutes, meconium aspiration, and neonatal seizures increased similarly with maternal BMI. A study limitation was lack of data on effects of obstetric interventions and neonatal resuscitation efforts.
Risks of severe asphyxia-related outcomes in term infants increase with maternal overweight and obesity. Given the high prevalence of the exposure and the severity of the outcomes studied, the results are of potential public health relevance and should be confirmed in other populations. Prevention of overweight and obesity in women of reproductive age is important to improve perinatal health.
Please see later in the article for the Editors' Summary
Editors' Summary
Economic, technologic, and lifestyle changes over the past 30 years have created an abundance of cheap, accessible, high-calorie food. Combined with fewer demands for physical activity, this situation has lead to increasing body mass throughout most of the world. Consequently, being overweight or obese is much more common in many high-income and low-and middle-income countries compared to 1980. Worldwide estimates put the percentage of overweight or obese adults as increasing by over 10%, between 1980 and 2008.
As being overweight becomes a global epidemic, its prevalence in women of reproductive age has also increased. Pregnant women who are overweight or obese are a cause for concern because of the possible associated health risks to both the infant and mother. Research is necessary to more clearly define these risks.
Why Was This Study Done?
In this study, the researchers investigated the complications associated with excess maternal weight that could hinder an infant from obtaining enough oxygen during delivery (neonatal asphyxia). All fetuses experience a loss of oxygen during contractions, however, a prolonged loss of oxygen can impact an infant's long-term development. To explore this risk, the researchers relied on a universal scoring system known as the Apgar score. An Apgar score is routinely recorded at one, five, and ten minutes after birth and is calculated from an assessment of heart rate, respiratory effort, and color, along with reflexes and muscle tone. An oxygen deficit during delivery will have an impact on the score. A normal score is in the range of 7–10. Body mass index (BMI) a calculation that uses height and weight, was used to assess the weight status (i.e., normal, overweight, obese) of the mother during pregnancy.
What Did the Researchers Do and Find?
Using the Swedish medical birth registry (a database including nearly all the births occurring in Sweden since 1973) the researchers selected records for single births that took place between 1992 to 2010. The registry also incorporates prenatal care data and researchers further selected for records that included weight and height measurement taken during the first prenatal visit. BMI was calculated using the weight and height measurement. Based on BMI ranges that define weight groups as normal, overweight, and obesity grades I, II, and III, the researchers analyzed and compared the number of low Apgar scoring infants (Apgar 0–3) in each group. Mothers with normal weight gave birth to the majority of infants with Apgar 0–3. In comparison the proportion of low Apgar scores were greater in babies of overweight and obese mothers. The researchers found that the rates of low Apgar scores increased with maternal BMI: the authors found that rates of low Apgar score at 5 minutes increased from 0.4 per 1,000 among infants of underweight women (BMI <18.5) to 2.4 per 1,000 among infants of women with obesity class III (BMI ≥40). Furthermore, overweight (BMI 25.0–29.9) was associated with a 55% increased risk of low Apgar scores at 5 minutes; obesity grade I (BMI 30–34.9) and grade II (BMI 35.0–39.9) with an almost 2-fold and a more than 2-fold increased risk, respectively; and obesity grade ΙΙΙ (BMI ≥40.0) with a more than 3-fold increase in risk. Finally, maternal overweight and obesity also increase the risks for seizures and meconium aspiration in the neonate.
What Do These Findings Mean?
These findings suggest that the risk of experiencing an oxygen deficit increases for the babies of women who are overweight or obese. Given the high prevalence of overweight and obesity in many countries worldwide, these findings are important and suggest that preventing women of reproductive age from becoming overweight or obese is therefore important to the health of their children.
A limitation of this study is the lack of data on the effects of clinical interventions and neonatal resuscitation efforts that may have been performed at the time of birth. Also Apgar scoring is based on five variables and a low score is not the most direct way to determine if the infant has experienced an oxygen deficit. However, these findings suggest that early detection of perinatal asphyxia is particularly relevant among infants of overweight and obese women although more studies are necessary to confirm the results in other populations.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Institutes of Health explains and calculates body mass index
The NIH also defines the Apgar scoring system
The United Kingdom's National Health Service has information for pregnant woman who are overweight
The UK-based Overseas Development Institute discusses how changes in diet have led to a worldwide health crisis in its “Future Diets” publication
Information about the Swedish health care system is available
Information in English is available from the National Board of Health and Welfare in Sweden
PMCID: PMC4028185  PMID: 24845218
17.  Partner smoking and maternal cotinine during pregnancy: Implications for negative control methods☆ 
Drug and Alcohol Dependence  2014;139(100):159-163.
Comparison of the associations of maternal and mother's partner smoking with offspring outcomes is, in theory, a useful method for assessing whether there may be an intrauterine effect of tobacco exposure on these outcomes. However, this approach assumes that the effects of passive smoking from exposure to partner smoking during pregnancy are minimal. We evaluated this assumption using a biochemical measure of tobacco exposure in pregnant women.
Cotinine levels taken during the first trimester of pregnancy were measured in a sample of 3928 women from the Avon Longitudinal Study of Parents and Children. Median cotinine values were compared across categories of smoking heaviness (cigarettes per day) of the women during the first trimester and in non-smoking women by the smoking heaviness of their partner.
Cotinine levels were substantially higher in women who smoked compared to non-smokers (range of medians across smoking heaviness categories: 900–5362 ng/ml versus 20 ng/ml, interquartile range (IQR) (0–63) for non-smokers). In contrast, cotinine levels in non-smoking women were only very weakly related to partner smoking status (range of medians in women with smoking partners: 34–69 ng/ml versus 12 ng/ml, IQR (0–48) in women with non-smoking partners).
Levels of tobacco exposure from partner smoking, as assessed by cotinine, were low in non-smoking pregnant women. This suggests that using mother's partner's smoking as a negative control for investigating intrauterine effects is valid.
PMCID: PMC4026952  PMID: 24726428
ALSPAC; Cigarette smoking; Pregnancy; Intrauterine exposure; Negative control
18.  Smoking During Consecutive Pregnancies Among Primiparous Women in the Population-Based Norwegian Mother and Child Cohort Study 
Nicotine & Tobacco Research  2012;15(2):428-434.
This study investigated changes in smoking behavior across pregnancies in a sample of 10,890 primiparous women participating in the prospective population-based Norwegian Mother and Child Cohort Study (MoBa) in order to identify risk factors that may inhibit smoking cessation and promote smoking during a woman’s second pregnancy.
Registry information regarding smoking, age, marital status, parity, and year of birth was applied, in addition to questionnaire assessments of own and partner’s smoking behavior, educational attainment, and symptoms of anxiety and depression at weeks 17 and 30 of gestation from both pregnancies.
The vast majority did not smoke in either of the pregnancies, and more women quit smoking than relapsed to smoking in their second pregnancy. Among smokers in the first pregnancy, 30.9% quit smoking by their second pregnancy. Women living with a nonsmoking partner or a partner who quit between pregnancies were more likely to quit smoking, as were women smoking occasionally in their first pregnancy. Symptoms of psychological distress and increasing number of years between pregnancies were negatively associated with smoking cessation. Among women not smoking in their first pregnancy, 2.3% did smoke during their second. Living with a smoking partner, low educational attainment, symptoms of psychological distress, and increasing number of years between pregnancies were all associated with smoking during the second pregnancy.
These findings, linking smoking behavior to changes taking place between pregnancies, offer new and additional insight into modifiable risk factors that may help facilitate more targeted smoking cessation interventions for women at the highest risk.
PMCID: PMC3611994  PMID: 22855885
19.  Exposure to antiepileptic drugs in utero and child development 
Epilepsia  2013;54(8):1462-1472.
Antiepileptic drugs may cause congenital malformations. Less is known about the effect on development in infancy and childhood. The aim of this study was to examine whether exposure to antiepileptic drugs during pregnancy has an impact on early child development.
From mid-year 1999 through December 2008, children of mothers recruited at 13–17 weeks of pregnancy were studied in the ongoing prospective Norwegian Mother and Child Cohort Study. Information on birth outcomes were obtained from the Medical Birth Registry (108,264 –children), and mothers reported on their child’s motor development, language, social skills, and autistic traits using items from standardized screening tools at 18 months (61,351 children) and 36 months of age (44,147 children). The relative risk of adverse outcomes in children according to maternal or paternal epilepsy with and without prenatal exposure to antiepileptic drugs was estimated as odds ratios (ORs), using logistic regression with adjustment for maternal age, parity, education, smoking, depression/anxiety, folate-supplementation, and child congenital malformation or low birth weight.
Key findings
A total of 333 children were exposed to antiepileptic drugs in utero. At 18 months, the exposed children had increased risk of abnormal scores for gross motor skills (7.1 % vs. 2.9 %; OR, 2.0; 95 % Confidence Interval [CI], 1.1–3.7) and autistic traits (3.5 % vs. 0.9 %; OR, 2.7; CI, 1.1–6.7) compared to children of parents without epilepsy. At 36 months, the exposed children had increased risk of abnormal score for gross motor skills (7.5 % vs. 3.3 %; OR, 2.2; CI, 1.1–4.2), sentence skills (11.2 % vs. 4.8 %; OR, 2.1; CI, 1.2–3.6), and autistic traits (6.0 % vs. 1.5 %; OR, 3.4; CI, 1.6–7.0). The drug-exposed children also had increased risk of congenital malformations (6.1 % vs. 2.9 %; OR, 2.1; CI, 1.4–3.4), but exclusion of congenital malformations did not affect the risk of adverse development. Children born to women with epilepsy who did not use antiepileptic drugs had no increased risks. Children of fathers with epilepsy generally scored within the normal range.
Exposure to antiepileptic drugs during pregnancy is associated with adverse development at 18 and 36 months of age, measured as low scores within key developmental domains rated by mothers. Exposures to valproate, lamotrigine, carbamazepine, or multiple antiepileptic drugs were associated with adverse outcome within different developmental domains.
PMCID: PMC3766256  PMID: 23865818
Epilepsy; Pregnancy; Teratogenicity; MoBa-Study
20.  Is the growth of the child of a smoking mother influenced by the father's prenatal exposure to tobacco? A hypothesis generating longitudinal study 
BMJ Open  2014;4(7):e005030.
Transgenerational effects of different environmental exposures are of major interest, with rodent experiments focusing on epigenetic mechanisms. Previously, we have shown that if the study mother is a non-smoker, there is increased mean birth weight, length and body mass index (BMI) in her sons if she herself had been exposed prenatally to her mother's smoking. The aim of this study was to determine whether the prenatal smoke exposure of either parent influenced the growth of the fetus of a smoking woman, and whether any effects were dependent on the fetal sex.
Population-based prebirth cohort study.
Avon Longitudinal Study of Parents and Children.
Participants were residents of a geographic area with expected date of delivery between April 1991 and December 1992. Among pregnancies of mothers who smoked during pregnancy, data were available concerning maternal and paternal prenatal exposures to their own mother smoking for 3502 and 2354, respectively.
Primary and secondary outcome measures
Birth weight, length, BMI and head circumference.
After controlling for confounders, there were no associations with birth weight, length or BMI. There was a strong adjusted association of birth head circumference among boys whose fathers had been exposed prenatally (mean difference −0.35 cm; 95% CI −0.57 to −0.14; p=0.001). There was no such association with girls (interaction p=0.006). Similar associations were found when primiparae and multiparae were analysed separately. In order to determine whether this was reflected in child development, we examined the relationships with IQ; we found that the boys born to exposed fathers had lower IQ scores on average, and that this was particularly due to the verbal component (mean difference in verbal IQ −3.65 points; 95% CI −6.60 to −0.70).
Head size differences concerning paternal fetal exposure to smoking were unexpected and, as such, should be regarded as hypothesis generating.
PMCID: PMC4120379  PMID: 25015471
21.  Maternal Active and Passive Smoking and Hypertensive Disorders of Pregnancy 
Epidemiology (Cambridge, Mass.)  2013;24(3):379-386.
The inverse association between prenatal smoking and preeclampsia is puzzling, given the increased risks of prematurity and low birthweight associated with both smoking and preeclampsia. We analyzed the Norwegian Mother and Child Birth Cohort (MoBa) to determine whether the associations varied by timing of prenatal smoking.
We conducted an analysis of 74,439 singleton pregnancies with completed second- and third- trimester questionnaires. Active and passive smoke exposure by trimester were determined by maternal self-report, and covered the period of preconception through approximately 30 weeks’ gestation. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.
Rates of active smoking declined dramatically during pregnancy: for trimester 1, 23%; trimester 2, 9%; and trimester 3, 8%. Active smoking in the third trimester was associated with reduced odds of preeclampsia and gestational hypertension, with the strongest association among continuous smokers (for preeclampsia, OR = 0.57 [95% CI = 0.46–0.70]). Women who quit smoking before the third trimester had approximately the same risk of preeclampsia and gestational hypertension as nonsmokers. There was some evidence of dose-response, with the heaviest smokers (more than eight cigarettes per day) having the lowest risks of preeclampsia (0.48 [0.32–0.73]) and gestational hypertension (0.51 [0.28–0.95]). There was little evidence of an association with passive smoking exposure.
The association between smoking and preeclampsia varies substantially according to the timing and intensity of exposure. A better understanding of the biologic pathways that underlie these associations may provide important clues to the etiology of preeclampsia and the development of effective clinical interventions.
PMCID: PMC4137974  PMID: 23429405
22.  Do intrauterine or genetic influences explain the foetal origins of chronic disease? A novel experimental method for disentangling effects 
There is much evidence to suggest that risk for common clinical disorders begins in foetal life. Exposure to environmental risk factors however is often not random. Many commonly used indices of prenatal adversity (e.g. maternal gestational stress, gestational diabetes, smoking in pregnancy) are influenced by maternal genes and genetically influenced maternal behaviour. As mother provides the baby with both genes and prenatal environment, associations between prenatal risk factors and offspring disease maybe attributable to true prenatal risk effects or to the "confounding" effects of genetic liability that are shared by mother and offspring. Cross-fostering designs, including those that involve embryo transfer have proved useful in animal studies. However disentangling these effects in humans poses significant problems for traditional genetic epidemiological research designs.
We present a novel research strategy aimed at disentangling maternally provided pre-natal environmental and inherited genetic effects. Families of children aged 5 to 9 years born by assisted reproductive technologies, specifically homologous IVF, sperm donation, egg donation, embryo donation and gestational surrogacy were contacted through fertility clinics and mailed a package of questionnaires on health and mental health related risk factors and outcomes. Further data were obtained from antenatal records.
To date 741 families from 18 fertility clinics have participated. The degree of association between maternally provided prenatal risk factor and child outcome in the group of families where the woman undergoing pregnancy and offspring are genetically related (homologous IVF, sperm donation) is compared to association in the group where offspring are genetically unrelated to the woman who undergoes the pregnancy (egg donation, embryo donation, surrogacy). These comparisons can be then examined to infer the extent to which prenatal effects are genetically and environmentally mediated.
A study based on children born by IVF treatment and who differ in genetic relatedness to the woman undergoing the pregnancy is feasible. The present report outlines a novel experimental method that permits disaggregation of maternally provided inherited genetic and post-implantation prenatal effects.
PMCID: PMC1913535  PMID: 17587444
23.  Transgenerational consequences of PTSD: risk factors for the mental health of children whose mothers have been exposed to the Rwandan genocide 
Understanding how parental Posttraumatic Stress Disorder (PTSD) may or may not affect the development and mental health in the offspring is particularly important in conflict regions, where trauma-related illness is endemic. In Rwanda, organised atrocities and the genocide against the Tutsi of 1994 have left a significant fraction of the population with chronic PTSD. The aim of the present investigation was to establish whether PTSD in mothers is associated with symptoms of depression, anxiety, and aggressive and antisocial behaviour in their children.
A community sample of 125 Rwandan mothers who experienced the genocide of 1994 and their 12-year-old children were interviewed. Using a structured interview, symptoms of maternal PTSD and children’s depression, anxiety, and aggressive and antisocial behaviour were assessed by trained and on-site supervised local B.A. psychologists. The interview also included a detailed checklist of event types related to family violence.
In showing that a maternal PTSD was not associated with child’s psychopathology, the results contradict the assumption of straight “trans-generational trauma transmission”. Instead, a child’s exposure to maternal family violence posed a significant risk factor for a negative mental health outcome. Furthermore, it was not maternal PTSD-symptoms but mother’s exposure to family violence during her own childhood that was associated with the magnitude of adversities that a child experiences at home.
Contrary to a simple model of a trans-generational transmission of trauma, neither maternal PTSD nor maternal traumatic experiences were directly associated with symptoms of anxiety, depression, or antisocial and aggressive behaviour in the children. Instead, the present results suggest a relationship between parental child rearing practices and children’s mental health. Furthermore, the study details the “cycle of violence”, showing a significant link between maternal violence against a child and its mother’s experience of childhood maltreatment.
PMCID: PMC3978019  PMID: 24690436
24.  Assessment of prenatal exposure to tobacco smoke by cotinine in cord blood for the evaluation of smoking control policies in Spain 
Over the last few years a decreasing trend in smoking has occurred not only in the general population but also during pregnancy. Several countries have implemented laws requiring all enclosed workplace and public places to be free of second hand smoke (SHS). In Spain, legislation to reduce SHS was implemented in 2005. The present study examines the possible effect of this legislation on prenatal SHS exposure.
Mothers and newborns were recruited from 3 independent studies performed in Hospital del Mar (Barcelona) and approved by the local Ethics Committee: 415 participated in a study in 1996-1998, 283 in 2002-2004 and 207 in 2008. A standard questionnaire, including neonatal and sociodemographic variables,tobacco use and exposure during pregnancy, was completed at delivery for all the participants in the three study groups. Fetal exposure to tobacco was studied by measuring cotinine in cord blood by radioimmunoassay (RIA).
32.8% of the pregnant women reported to smoke during pregnancy in 1996-1998, 25.9% in 2002-2004 and 34.1% in 2008. In the most recent group, the percentage of no prenatal SHS exposure (cord blood cotinine 0.2-1 ng/mL) showed an increase compared to the previous groups while the percentages of both: low (1.1-14 ng/mL) and very high (> 100 ng/mL) prenatal SHS exposure showed a decrease.
The results of the three study periods (1996-2008) demonstrated a significant increase in the percentage of newborns free from SHS exposure and a decrease in the percentage of newborns exposed to SHS during pregnancy, especially at the very high levels of exposure. A significant maternal smoking habit was noted in this geographical area with particular emphasis on immigrant pregnant smoking women.
Our study indicates that there is a significant maternal smoking habit in this geographical area. Our recommendation is that campaigns against smoking should be directed more specifically towards pregnant women with particular emphasis on non-native pregnant smokers due to the highest prevalence of tobacco consumption in the immigrant women.
PMCID: PMC3342916  PMID: 22480136
25.  Smoking during teenage pregnancies 
We prospectively examined the relationship between prenatal tobacco exposure (PTE) and child behavior in a birth cohort of 357 offspring of teenage mothers. PTE was defined as any exposure across pregnancy and, in separate analyses, exposure within each trimester. Outcomes included measures of behavior problems, activity, and attention. On average, the children were 6.4 years of age, 48% were females, and 69% were Black. Data on maternal tobacco and other substance use were collected prenatally and postnatally: 46% of the mothers smoked in the first trimester and 58% smoked 6 years later. Child urinary cotinine measured exposure to environmental tobacco smoke (ETS). Stepwise multiple regressions were run. PTE predicted significantly increased offspring activity; impulsivity; and aggression, externalizing, and total behavior problems in step 1. PTE remained a significant predictor of increased activity when maternal psychological characteristics, home environment, and ETS were added. The results were similar when PTE was examined by trimesters, although later pregnancy tobacco exposure predicted the most behavioral outcomes. In the final model, PTE (all three trimesters) and PTE (second trimester) were significant predictors of increased activity and attention problems, respectively. Other predictors of child behavior included maternal anxiety, depression, hostility, and home environment. ETS was not a significant predictor of child behavior when PTE was considered. Smoking during pregnancy among adolescents is a significant predictor of increased activity and attention problems in their offspring after controlling for covariates in the prenatal and current environments. Smoking cessation interventions are recommended for this population to avoid the effects of PTE on the offspring of pregnant adolescents. This is particularly important because these mothers will likely become pregnant again and many will increase their level of tobacco use as they mature.
PMCID: PMC2593871  PMID: 17577803

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