Prenatal smoking and childhood behavior problems: is the association mediated by birth weight?

Maternal smoking during pregnancy is associated with both reduced birth weight and adverse neurobehavioral outcomes. The aim of this study was to investigate longitudinal associations between maternal smoking during pregnancy and childhood behavioral outcomes, and to determine the role of birth weight in mediating such associations. The study included 489 mother-child pairs. Prenatal exposures were assessed via maternal interviews conducted on average 1 year after delivery and child behavior assessments were completed at 5-12 years of age using the Child Behavior Checklist (CBCL) and Teacher Report Form (TRF). Maternal smoking during pregnancy was associated with externalizing and total behavior problems according to both mother and teacher report. Maternal smoking was also associated with the following percentage increases in scores: 41% (CBCL) and 44% (TRF) for aggressive behavior and 65% (CBCL) and 47% (TRF) for attention problems. Associations with behavior problems were attenuated or no longer observed for mothers that quit smoking in early pregnancy. The proportion of the total effect of maternal smoking on behavioral outcomes explained by differences in birth weight was small and ranged from 6.6% for externalizing behavior on the CBCL to 20.1% for rule-breaking behavior on the CBCL. Our results suggest that birth weight differences explain only a small proportion of the magnitude of association between maternal smoking during pregnancy and selected behavioral outcomes.

Intrauterine device use and the risk of pre-eclampsia: a case-control study.

OBJECTIVE: To determine the association between intrauterine device (IUD) use, timing of removal prior to pregnancy, and the risk of pre-eclampsia. DESIGN: A case-control study within the Clinical Practice Research Datalink, UK. SETTING: Medical record database in the UK. SAMPLE: Cases of pre-eclampsia (n = 2744) were identified among pregnancies resulting in singleton deliveries from 1993 to 2010. Four controls, or pregnancies unaffected by pre-eclampsia, were matched to each case on maternal age, general practice, and year of delivery. METHODS: Data on IUD use were obtained from patient records. The odds ratios (ORs) for the association between IUD and pre-eclampsia were adjusted for covariates identified a priori, and analyses were stratified by BMI and number of prior deliveries. MAIN OUTCOME MEASURES: Odds ratios (95% confidence intervals, 95% CIs) of pre-eclampsia in pregnancies among women with a history of IUD use, compared with women without a history of IUD use. RESULTS: Prior IUD use was associated with a reduced risk of pre-eclampsia (OR 0.76; 95% CI 0.58-0.98). The timing of removal in relation to the start of pregnancy showed an inverse association, with shorter intervals associated with a larger decrease in risk of pre-eclampsia. IUD removal within a year prior to pregnancy had an OR of 0.68 (95% CI 0.46-1.00). Among women with a prior delivery, the association between IUD use and pre-eclampsia was null. CONCLUSIONS: Intrauterine device use is associated with a small decreased risk of pre-eclampsia, specifically if removed within the year prior to conception. TWEETABLE ABSTRACT: A case-control study of pregnancies in the UK suggests a reduced risk of pre-eclampsia for former IUD users.

Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study.

OBJECTIVE: To study previously identified associations between specific maternal hypertensive disorders and/or prenatal exposure to antihypertensive medication and birth defects. DESIGN: Case-control study. SETTING: Slone Birth Defects Study, 1998-2010. POPULATION: A total of 5568 cases with birth defects and 7253 liveborn infants without malformations as controls. METHODS: Adjusted odds ratios (aORs) for birth defects associated with prenatal exposure to maternal hypertensive disorders and/or antihypertensive medication were calculated using multivariable logistic regression analyses. MAIN OUTCOME MEASURES: Specific birth defects previously linked to maternal hypertension or antihypertensive medication use during pregnancy. RESULTS: Non-pharmacologically managed chronic hypertension was associated with a three-fold risk of oesophageal atresia (95% CI 1.2-8.3), and pre-eclampsia superimposed on non-pharmacologically managed chronic hypertension was associated with ventricular septal defects (aOR 3.9, 95% CI 1.3-11.7) and atrial septal defects (aOR 6.5, 95% CI 1.8-23.7). For chronic hypertension that was pharmacologically treated early in pregnancy, increased risks were observed for first-degree hypospadias (aOR 2.9, 95% CI 1.1-7.4). Non-pharmacologically managed pre-eclampsia was related to second-/third-degree hypospadias and ventricular septal defects. Pharmacological treatment for gestational hypertension was associated with a number of congenital heart defects. CONCLUSIONS: Our results confirm some, but not all, previously identified associations between pharmacologically treated and non-pharmacologically managed hypertensive disorders and specific birth defects. They support the hypothesis that physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias.

Severe maternal and perinatal outcomes from uterine rupture among women at term with a trial of labor.

OBJECTIVE: To describe maternal and perinatal morbidity and mortality associated with uterine rupture (UR) among women with prior cesarean/s, singleton term pregnancies and a trial of labor after cesarean (TOLAC). STUDY DESIGN: Linked hospital discharge files and birth/fetal death certificates identified potential cases of UR in Massachusetts from 1990 to 1998 with definitive identification by medical record abstraction. RESULT: Among the 347 identified URs, severe outcomes occurred in 86 cases (25%), in 49 (14%) of mothers and 49 (14%) of infants. Of the infants, 25 were discharged with a good prognosis. Maternal age and interdelivery interval <18 months (relative risk (RR)=1.55; 95% confidence interval (CI): 1.05, 2.31) were associated with a severe outcome. The type of hospital and labor were not associated with the increased risk of a severe outcome. CONCLUSION: Assuming a 0.7% UR rate among women at term with a TOLAC, the increased rate of severe outcomes related to UR above the baseline risk of elective cesarean is estimated to be 1.3 per 1000 TOLACs.

Pre-pregnant body mass index, weight gain and the risk of delivering large babies among non-diabetic mothers.

OBJECTIVE: Pre-pregnancy overweight and excess weight gain during pregnancy have each been associated with an increased risk of delivering large babies. However, previous studies have focused on the separate effects of these two indices of weight in diabetic women. METHOD: This study analyzed both separate and combined effects of pre-pregnant body mass index and weight gain in relation to macrosomia (> or =4000 g) in offspring among 815 non-diabetic women, using data collected from a retrospective study. RESULT: Compared to mothers with normal pre-pregnancy BMI and pregnancy weight gain, risk of macrosomia in offspring was significantly elevated only in overweight women with excess weight gain (adjusted OR=2.6, 95% CI [1.2,5.4]) but not among normal weight mothers with excess gain (adjusted OR=1.1, 95% CI [0.5,2.4]) or overweight mothers with normal or low gain (adjusted OR=1.1, 95% CI [0.4,3.1]). CONCLUSION: Given the complications that are associated with delivering large babies, overweight women may benefit from not gaining excess weight in pregnancy.

Neural tube defects in relation to use of folic acid antagonists during pregnancy.

Periconceptional folic acid supplementation reduces the risk of neural tube defects (NTDs). To determine whether periconceptional exposure to folic acid antagonists (FAAs) might therefore increase the risk of NTDs, the authors examined data from an ongoing case-control study of birth defects (1979-1998) in the United States and Canada. They compared data on 1,242 infants with NTDs (spina bifida, anencephaly, and encephalocele) with data from a control group of 6,660 infants with malformations not related to vitamin supplementation. Mothers were interviewed within 6 months of delivery about demographic, reproductive, medical, and behavioral factors and about medication use. The adjusted odds ratios of NTDs related to exposure to FAAs (including carbamazepine, phenobarbital, phenytoin, primidone, sulfasalazine, triamterene, and trimethoprim) during the first or second months after the last menstrual period, compared with no use in either month, were 2.8 (95% confidence interval: 1.7, 4.6) for FAAs as a group, 4.8 (95% confidence interval: 1.5, 16.1) for trimethoprim (based on five exposed cases), and 6.9 (95% confidence interval: 1.9, 25.7) for carbamazepine (six exposed cases). These results are adjusted for region, interview year, periconceptional folic acid supplementation, maternal age, weight, education, and infections early in pregnancy. These findings suggest that a number of FAAs may increase NTD risk, and they provide estimates of risk for selected drugs.

Folic acid antagonists during pregnancy and the risk of birth defects.

BACKGROUND: Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. METHODS: We compared data on exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs for 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects with data for 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use. RESULTS: The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second or third month after the last menstrual period, as compared with infants whose mothers had no such exposure, were 3.4 (95 percent confidence interval, 1.8 to 6.4) and 2.6 (95 percent confidence interval, 1.1 to 6.1), respectively. The relative risks of cardiovascular defects, oral clefts, and urinary tract defects after maternal exposure to antiepileptic drugs were 2.2 (95 percent confidence interval, 1.4 to 3.5), 2.5 (95 percent confidence interval, 1.5 to 4.2), and 2.5 (95 percent confidence interval, 1.2 to 5.0), respectively. Use of multivitamin supplements containing folic acid diminished the adverse effects of dihydrofolate reductase inhibitors, but not that of antiepileptic drugs. CONCLUSIONS: Folic acid antagonists, which include such common drugs as trimethoprim, triamterene, carbamazepine, phenytoin, phenobarbital, and primidone, may increase the risk not only of neural-tube defects, but also of cardiovascular defects, oral clefts, and urinary tract defects. The folic acid component of multivitamins may reduce the risks of these defects.

Use of a job-exposure matrix to assess occupational exposures in relation to birth defects.

Accurate exposure assessment remains a challenge in occupational epidemiology. We evaluated one approach, use of a job-exposure matrix (JEM), by applying the National Institute for Occupational Safety and Health (NIOSH) JEM to a large case-control birth defects study that included parental occupation information. We investigated the JEM exposure predictions in several ways and found that for a substantial proportion of the parents in the birth defects study, the JEM yielded either no exposure data or nonsense predictions. Among exposure predictions that were plausible, most were of low probability. The high probability exposure predictions were statistically unstable, and neither low nor high probability exposure predictions were reliable. There was considerable discrepancy between the JEM predictions and expert assessments for five exposures of interest. Application of the NIOSH JEM to the birth defects study database (and probably other databases as well) does not provide a useful means of assessing occupational exposures.

Comparison of alternative survey methods for sensitive self-reported behaviours in a follow-up study of isotretinoin.

BACKGROUND: Responses to questions on sensitive behaviours can be affected by when and how questions are asked. METHODS: Using data from an ongoing survey of women taking isotretinoin (a teratogenic drug used to treat acne), we compared answers to questions on contraceptive use during therapy among 126966 women who had begun treatment in 1990-93. 20503 were randomly assigned to a group which was surveyed by telephone at the start of treatment, during treatment and 6 months after treatment ended (DAT group). 106463 received a mail survey 6 months after treatment ended (AT group). Women who could not be contacted during treatment, along with the non-respondents in the AT group, received follow-up surveys by US mail, air courier and, if necessary, were called by telephone. RESULTS: The response rate was higher in the DAT group (96.4%) than in the AT group (84.8%). Among respondents, the odds of reported contraceptive use in the AT group compared with the DAT group (asked at 6 months after treatment) was 1.41 [95% confidence interval (CI): 1.36-1.46]. However, rates of oral contraceptive (OC) use were virtually identical in the two groups. In both groups, women surveyed by telephone reported lower rates of contraceptive use than women surveyed by mail. In the AT group, a late response was associated with a significantly lower rate of contraceptive use. CONCLUSIONS: Both mode of data collection (phone versus mail) and time to response affected reported rates of contraceptive use. Reasonable assumptions about the effect of non-response could not account for the difference between the AT and DAT groups. We found that contacting women during their treatment did not increase their reported use of contraceptives.

Achieving a public health recommendation for preventing neural tube defects with folic acid.

OBJECTIVES: This study examined 3 approaches to achieving the public health recommendation that all women of child-bearing age ingest 0.40 mg of folic acid per day to reduce the occurrence of neural tube defects (NTDs). METHODS: A total of 1136 mothers of infants with major malformations from the Boston and Philadelphia areas, whose pregnancies began from 1993 to 1995, were interviewed within 6 months of delivery about vitamin supplementation, dietary intakes, and other factors. RESULTS: Seventy-one percent of the 1136 women in the study did not take folic acid--containing supplements daily before conception, but the proportion decreased over the years of the study. Women not taking supplements consumed an average of 0.25 mg of naturally occurring folates daily. On the basis of dietary intakes reported by women not taking folic acid supplements, a simulation of cereal grain fortification with folic acid at the level required by the US Food and Drug Administration showed that an average of only 0.13 mg of folic acid would be ingested daily. CONCLUSIONS: With consumption of folic acid only through dietary intake, sizeable portions of the childbearing population would receive less than the level of folic acid recommended for preventing NTDs. Even with food fortification, women of childbearing age should be advised to take folic acid--containing supplements on a daily basis.

Maternal cigarette smoking during pregnancy and risk of oral clefts in newborns.

The results of previous epidemiologic research on the possible association between maternal smoking during pregnancy and risk of oral clefts in offspring have been inconsistent. This may be due in part to methodological limitations, including imprecise measurement of tobacco use, failure to consider etiologic heterogeneity among types of oral clefts, and confounding. This analysis, based on a large case-control study, further evaluated the effect of first trimester maternal smoking on oral facial cleft risk by examining the dose-response relationship according to specific cleft type and according to whether or not additional malformations were present. A number of factors, including dietary and supplemental folate intake and family history of clefts, were evaluated as potential confounders and effect modifiers. Data on 3,774 mothers interviewed between 1976 and 1992 by the Slone Epidemiology Unit Birth Defects Study were used. Study subjects were actively ascertained from sites in areas around Boston, Massachusetts and Philadelphia, Pennsylvania; the state of Iowa; and southeastern Ontario, Canada. Cases were infants with isolated defects--cleft lip alone (n = 334), cleft lip and palate (n = 494), or cleft palate alone (n = 244)--and infants with clefts plus (+) additional malformations: cleft lip+ (n = 58), cleft lip and palate+ (n = 140), or cleft palate+ (n = 209). Controls were infants with defects other than clefts, excluding defects possibly associated with maternal cigarette use. There were no associations with maternal smoking for any oral cleft group, except for a positive dose response among infants with cleft lip and palate+ (for light smokers, odds ratio (OR) = 1.09 (95% confidence interval (CI): 0.6, 1.9); for moderate smokers, OR = 1.84 (95% CI: 1.2, 2.9); and for heavy smokers, OR = 1.85 (95% CI: 1.0, 3.5), relative to nonsmokers). This finding may be related to the additional malformations rather than to the cleft itself.

Multivitamin supplementation and risk of birth defects.

It is widely accepted that supplementation with folic acid, a B vitamin, reduces the risk of neural tube defects (NTDs). This case-control study tested the hypothesis that multivitamins reduce risks of selected birth defects other than NTDs. Infants with and without birth defects and aborted fetuses with birth defects were ascertained in the greater metropolitan areas of Boston, Philadelphia, and Toronto during 1993-1996. Mothers were interviewed within 6 months after delivery about a variety of factors, including details on vitamin use. Eight case groups were included: cleft lip with or without cleft palate, cleft palate only, conotruncal defects, ventricular septal defects, urinary tract defects, limb reduction defects, congenital hydrocephaly, and pyloric stenosis (n's ranged from 31 to 186). Controls were 521 infants without birth defects (nonmalformed controls) and 442 infants with defects other than those of the cases (malformed controls). Daily multivitamin supplementation was evaluated according to gestational timing categories, including periconceptional use (28 days before through 28 days after the last menstrual period). Odds ratios (ORs) below 1.0 were observed for all case groups except cardiac defects, regardless of control type. For periconceptional use, ORs with 95% confidence intervals that excluded 1.0 were estimated for limb reduction defects using both nonmalformed controls (OR = 0.3) and malformed controls (OR = 0.2) and for urinary tract defects using both nonmalformed controls (OR = 0.6) and malformed controls (OR = 0.5). Statistically significant ORs for use that began after the periconceptional period were observed for cleft palate only and urinary tract defects. These data support the hypothesis that periconceptional vitamin supplementation may extend benefits beyond a reduction in NTD risk. However, other than folic acid's protecting against NTDs, it is not clear what nutrient or combination of nutrients might affect risk of other specific defects.

Selection bias and the use of controls with malformations in case-control studies of birth defects.

We compared four methods of control selection to assess the effect of using infants with malformations as controls in case-control studies of birth defects. We identified cases and controls using data from the Slone Epidemiology Unit Births Defect Study for the years 1976-1992. Cases were defined as infants with cleft lip and palate and no other malformations (N = 494). Controls (N = 8356) were chosen from infants with other malformations, excluding other oral cleft conditions or syndromes associated with clefts. Maternal smoking during the first 13 weeks of pregnancy was the exposure of interest. We then assessed the measures of association resulting from using controls with varying restrictions. When we excluded all defects potentially associated with maternal smoking (based on reports in the literature), the crude odds ratio for smoking and oral cleft risk was 1.6 (1.3-1.9). When we eliminated all defect groups with a smoking prevalence that was one or more standard deviations above or below the total control group mean, the odds ratio was 1.5 (1.2-1.8); with controls restricted to infants with Mendelian-inherited disorders (with presumably no causal effect of smoking), the odds ratio was 1.6 (1.1-2.7); and when selection was unrestricted, the crude odds ratio was 1.5 (1.2-1.8). When used selectively, infants with malformations other than the anomaly of interest can be a suitable source of controls.

Multivitamin supplementation and multiple births.

It is well established that maternal multivitamin supplementation reduces the risk of neural tube defects and evidence suggests that it may be associated with other reproductive outcomes. The present study was prompted by a report from a randomized trial in Hungary which showed a 40% increase in multiple births among periconceptional vitamin users. Retrospectively collected data on multivitamin supplementation were obtained on multiple and singleton births from three separate studies: Atlanta Birth Defects Case-Control Study (ABDCCS) malformed and nonmalformed infants born 1968-1980, California Birth Defects Monitoring Program (CBDMP) malformed and nonmalformed infants born 1987-1989, and Boston University Slone Epidemiology Unit Birth Defects Study (SEU-BDS) malformed infants born 1987-1994. Supplementation was divided into three mutually exclusive categories based on timing: "periconceptional" use--before through at least the third month after conception; "early" use--beginning in the first month and continuing through at least the third month after conception; and "later" use--beginning in the second or third month after conception. For periconceptional use, four of five datasets showed a 30 to 60% greater prevalence of supplementation among mothers of multiple births. In contrast, this pattern was not evident for "early" and "later" use. Overall, the study findings are tentative, due to a lack of consistency across all five datasets and they should not alter recent recommendations related to folate supplementation for the prevention of neural tube defects.

Case-control study of periconceptional folic acid supplementation and oral clefts.

There is consistent evidence that the risk of neural tube defects is decreased by periconceptional supplementation with folic acid. A similar protective effect has been postulated for oral clefts. A case-control study was conducted in greater metropolitan Boston; Massachusetts; Philadelphia, Pennsylvania; and southeastern Ontario, Canada, from 1988 through 1991 to test the hypothesis that folic acid supplementation during the periconceptional period reduces the risk of oral clefts. Crude and multivariate-adjusted relative risks were calculated for all oral clefts (n = 303), cleft palate (n = 108), and cleft lip with or without cleft palate (n = 195). Controls (n = 1,167) were liveborn or stillborn infants less than age 6 months who had various congenital anomalies other than oral clefts, neural tube defects, or other "midline defects." Adjusted relative risks and 95 percent confidence intervals for daily folic acid supplementation during the periconceptional period were: oral clefts, 1.1 (95% confidence interval (CI) 0.8-1.7), cleft palate, 0.9 (95% CI 0.5-1.6), and cleft lip with or without cleft palate, 1.3 (95% CI 0.8-2.1). These findings do not support a protective association between the periconceptional use of folic acid supplements and the risk of oral clefts.