Katherine A. Ahrens

Use of Antiepileptic Medications in Pregnancy in Relation to Risks of Birth Defects

PURPOSEnTo evaluate use of specific antiepileptic drugs (AEDs) in pregnancy in relation to specific birth defects.nnnMETHODSnUsing data from the National Birth Defects Prevention Study, we assessed use of AEDs and the risk of neural tube defects (NTDs), oral clefts (OCs), heart defects (HDs), hypospadias, and other major birth defects, taking specific agent, timing, and indication into consideration.nnnRESULTSnDrug-specific increased risks were observed for valproic acid in relation to NTDs [adjusted odds ratio (aOR), 9.7;, 95% confidence interval (CI), 3.4-27.5], OCs (aOR, 4.4; 95% CI, 1.6-12.2), HDs (aOR, 2.0; 95% CI, 0.78-5.3), and hypospadias (aOR. 2.4; 95% CI, 0.62-9.0), and for carbamazapine in relation to NTDs (aOR, 5.0; 95% CI, 1.9-12.7). Epilepsy history without AED use did not seem to increase risk.nnnCONCLUSIONSnValproic acid, which current guidelines suggest should be avoided in pregnancy, was most notable in terms of strength and breadth of its associations. Carbamazapine was associated with NTDs, even after controlling for folic acid use. Sample sizes were still too small to adequately assess risks of less commonly used AEDs, but our findings support further study to identify lower risk options for pregnant women.

Folic Acid Intake and Spina Bifida in the Era of Dietary Folic Acid Fortification

Background: The US Food and Drug Administration mandated that enriched grain products be fortified with folic acid by 1998. We evaluated whether intake of folic acid from supplements and diet was associated with a reduction in spina bifida in the setting of folic acid fortification. Methods: Data were collected as part of the Slone Birth Defects Study from 1998 to 2008. Mothers of infants with and without birth defects were interviewed within 6 months of delivery about pregnancy exposures, including details of diet and vitamin intake. Dietary natural folate and synthetic folic acid from fortification were combined into a single, weighted measure—dietary folate equivalent. Periconceptional folic acid supplementation and dietary folate consumption were compared between 205 mothers of spina bifida cases and 6357 mothers of nonmalformed controls. Relative risks of a spina bifida-affected birth were estimated with odds ratios (ORs) and 95% confidence intervals (CIs). Results: Spina bifida was not associated with regular folic acid supplementation (≥4 days per week) either around the time of conception (adjusted OR = 1.1 [95% CI = 0.74–1.7]) or initiated in early pregnancy (0.79 [0.54–1.2]). After adjustment for confounders, a 13% reduced odds of spina bifida was estimated for each 100-&mgr;g increase in daily dietary folate equivalent consumed. Conclusions: In the setting of folic acid fortification of grains, our data suggest that folic acid supplementation does not appear to offer further benefit for reducing risk of spina bifida. Rather, the folate-associated benefit on spina bifida risk was found with increasing amounts of dietary folic acid consumed, regardless of folic acid supplementation level.

Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: exposure prevalence, preterm delivery, and specific birth defects.

UNLABELLEDnWe estimated exposure prevalence and studied potential risks for preterm delivery (PTD) and specific birth defects associated with exposure to the unadjuvanted pH1N1-containing vaccines in the 2009-2010 and 2010-2011 influenza seasons. We used data from 4 regional centers in the United States collected as part of the Slone Epidemiology Centers Birth Defects Study. For PTD, propensity score-adjusted time-varying hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for exposure anytime in pregnancy and for each trimester. For 41 specific major birth defects, propensity score-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated. Among 4191 subjects, there were 3104 mothers of malformed (cases) and 1087 mothers of nonmalformed (controls). Exposure prevalences among controls were 47% for the 2009-2010 season and 38% for the 2010-2011 season; prevalence varied by geographic region. Results for PTD differed between the two seasons, with risks above and below the null for the 2009-2010 and 2010-2011 seasons, respectively. For 41 specific birth defects, most adjusted ORs were close to 1.0. Three defects had adjusted ORs>2.0 and four had risks<0.5; however, 95% CIs for these were wide.nnnCONCLUSIONSnAmong women exposed to pH1N1 vaccine, we found a decreased risk for PTD in the 2010-2011 season; risk was increased in 2009-2010, particularly following exposure in the first trimester, though the decrease in gestational length was less than 2 days. For specific major defects, we found no meaningful evidence of increased risk for specific congenital malformations following pH1N1 influenza vaccinations in the 2009-2010 and 2010-2011 seasons.

Seasonal Influenza Vaccination during Pregnancy and the Risks of Preterm Delivery and Small for Gestational Age Birth

BACKGROUNDnInfluenza vaccination is routinely recommended for pregnant women, yet information on perinatal outcomes is sparse.nnnMETHODSnWe investigated the associations between trivalent (seasonal) influenza vaccination during pregnancy and the risks of preterm delivery (PTD, live birth <37 weeks gestation) and small for gestational age birth (SGA, <10th percentile in weight for sex-specific gestational age) during the influenza seasons 2006-07 through 2009-10. The study population included 1619 mothers of live-born, non-malformed singleton infants interviewed as part of the Slone Epidemiology Centers Birth Defects Study. Associations between influenza vaccination and PTD and SGA were assessed using Cox and logistic regression models, respectively, with propensity scores used to adjust for confounding. Women vaccinated against pandemic H1N1 were excluded from the analysis.nnnRESULTSnInfluenza vaccination during pregnancy showed a near null association with PTD for influenza seasons 2006-07 through 2008-09 compared with unvaccinated women [adjusted hazard ratios (aHR) ranged from 0.79 [95% confidence interval (CI) 0.28, 2.21] in 2007-08 to 1.08 [95% CI: 0.40, 2.95] in 2008-09]. For 2009-10, the risk of PTD was higher in vaccinated women (aHR, 7.81 [95% CI: 2.66, 23.0]). Influenza vaccination was not associated with appreciable risks for SGA for all seasons with sufficient numbers of exposed SGA.nnnCONCLUSIONnThough limited by study size, these findings add support to previous observations of little or no increased risk of PTD or SGA associated with seasonal influenza vaccination for three of the four influenza seasons in our study. The increased risk of PTD observed for the 2009-10 influenza season warrants further investigation.

Antiherpetic medication use and the risk of gastroschisis: findings from the National Birth Defects Prevention Study, 1997-2007.

BACKGROUNDnPrevious studies examining the teratogenic effects of antiherpetic medications have found no associations for birth defects overall but have not examined the risk of specific birth defects.nnnMETHODSnThe National Birth Defects Prevention Study ascertains population-based cases with birth defects and live-born controls without birth defects in 10 states across the United States for the purpose of identifying potential teratogenic risk factors. Mothers of cases and controls are interviewed within 2 years of their estimated date of delivery about demographic, medical and behavioural factors before and during pregnancy. This analysis examined the possible association between use of antiherpetic medications (acyclovir, valacyclovir or famciclovir) during early pregnancy and gastroschisis, a birth defect of the abdominal wall.nnnRESULTSnThe mothers of 1.1% (nu2009=u200910) of 941 gastroschisis cases and 0.3% (nu2009=u200927) of 8339 controls reported antiherpetic medication use during the month before conception through the third month of pregnancy. The adjusted odds ratios for such use in relation to gastroschisis were 4.7 [95% confidence interval 1.7, 13.3] and 4.7 [95% CI 1.2, 19.0] among women with and without self-reported genital herpes, respectively, when compared with women without antiherpetic use or herpes. Among women reporting no antiherpetic medication use, the odds ratio for self-reported genital herpes in relation to gastroschisis was 3.0 [95% CI 1.6, 5.7].nnnCONCLUSIONSnOur study raises the possibility of an increased risk of gastroschisis because of either antiherpetic medication use during early pregnancy or the underlying genital herpes infection for which it was indicated.

Correcting for exposure misclassification using survival analysis with a time-varying exposure.

PURPOSEnSurvival analysis is increasingly being used in perinatal epidemiology to assess time-varying risk factors for various pregnancy outcomes. Here we show how quantitative correction for exposure misclassification can be applied to a Cox regression model with a time-varying dichotomous exposure.nnnMETHODSnWe evaluated influenza vaccination during pregnancy in relation to preterm birth among 2267 non-malformed infants whose mothers were interviewed as part of the Slone Birth Defects Study during 2006 through 2011. The hazard of preterm birth was modeled using a time-varying exposure Cox regression model with gestational age as the time-scale. The effect of exposure misclassification was then modeled using a probabilistic bias analysis that incorporated vaccination date assignment. The parameters for the bias analysis were derived from both internal and external validation data.nnnRESULTSnCorrection for misclassification of prenatal influenza vaccination resulted in an adjusted hazard ratio (AHR) slightly higher and less precise than the conventional analysis: Bias-corrected AHR 1.04 (95% simulation interval, 0.70-1.52); conventional AHR, 1.00 (95% confidence interval, 0.71-1.41).nnnCONCLUSIONSnProbabilistic bias analysis allows epidemiologists to assess quantitatively the possible confounder-adjusted effect of misclassification of a time-varying exposure, in contrast with a speculative approach to understanding information bias.

Collinearity and Causal Diagrams: A Lesson on the Importance of Model Specification.

Background: Correlated data are ubiquitous in epidemiologic research, particularly in nutritional and environmental epidemiology where mixtures of factors are often studied. Our objectives are to demonstrate how highly correlated data arise in epidemiologic research and provide guidance, using a directed acyclic graph approach, on how to proceed analytically when faced with highly correlated data. Methods: We identified three fundamental structural scenarios in which high correlation between a given variable and the exposure can arise: intermediates, confounders, and colliders. For each of these scenarios, we evaluated the consequences of increasing correlation between the given variable and the exposure on the bias and variance for the total effect of the exposure on the outcome using unadjusted and adjusted models. We derived closed-form solutions for continuous outcomes using linear regression and empirically present our findings for binary outcomes using logistic regression. Results: For models properly specified, total effect estimates remained unbiased even when there was almost perfect correlation between the exposure and a given intermediate, confounder, or collider. In general, as the correlation increased, the variance of the parameter estimate for the exposure in the adjusted models increased, while in the unadjusted models, the variance increased to a lesser extent or decreased. Conclusion: Our findings highlight the importance of considering the causal framework under study when specifying regression models. Strategies that do not take into consideration the causal structure may lead to biased effect estimation for the original question of interest, even under high correlation.

Unintended pregnancy and interpregnancy interval by maternal age, National Survey of Family Growth

BACKGROUNDnThe relationship between unintended pregnancy and interpregnancy interval (IPI) across maternal age is not clear.nnnMETHODSnUsing data from the National Survey of Family Growth, we estimated the percentages of pregnancies that were unintended among IPI groups (<6, 6-11, 12-17, 18-23, 24+ months) by maternal age at last live birth (15-19, 20-24, 25-29, 30-44 years).nnnRESULTSnApproximately 40% of pregnancies were unintended and 36% followed an IPI<18 months. Within each maternal age group, the percentage of pregnancies that were unintended decreased as IPI increased.nnnCONCLUSIONnUnintended pregnancies are associated with shorter IPI across the reproductive age spectrum.

Report of the Office of Population Affairs’ expert work group meeting on short birth spacing and adverse pregnancy outcomes: Methodological quality of existing studies and future directions for research

Abstract Background The World Health Organization (WHO) recommends that women wait at least 24 months after a livebirth before attempting a subsequent pregnancy to reduce the risk of adverse maternal, perinatal, and infant health outcomes. However, the applicability of the WHO recommendations for women in the United States is unclear, as breast feeding, nutrition, maternal age at first birth, and total fertility rate differs substantially between the United States and the low‐ and middle‐resource countries upon which most of the evidence is based. Methods To inform guideline development for birth spacing specific to women in the United States, the Office of Population Affairs (OPA) convened an expert work group meeting in Washington, DC, on 14‐15 September 2017 among reproductive, perinatal, paediatric, social, and public health epidemiologists; obstetrician‐gynaecologists; biostatisticians; and experts in evidence synthesis related to womens health. Results Presentations and discussion topics included the methodological quality of existing studies, evaluation of the evidence for causal effects of short interpregnancy intervals on adverse perinatal and maternal health outcomes, good practices for future research, and identification of research gaps and priorities for future work. Conclusions This report provides an overview of the presentations, discussions, and conclusions from the expert work group meeting.

Good practices for the design, analysis, and interpretation of observational studies on birth spacing and perinatal health outcomes

Abstract Background Meta‐analyses of observational studies have shown that women with a shorter interpregnancy interval (the time from delivery to start of a subsequent pregnancy) are more likely to experience adverse pregnancy outcomes, such as preterm delivery or small for gestational age birth, than women who space their births further apart. However, the studies used to inform these estimates have methodological shortcomings. Methods In this commentary, we summarise the discussions of an expert workgroup describing good practices for the design, analysis, and interpretation of observational studies of interpregnancy interval and adverse perinatal health outcomes. Results We argue that inferences drawn from research in this field will be improved by careful attention to elements such as: (a) refining the research question to clarify whether the goal is to estimate a causal effect vs describe patterns of association; (b) using directed acyclic graphs to represent potential causal networks and guide the analytic plan of studies seeking to estimate causal effects; (c) assessing how miscarriages and pregnancy terminations may have influenced interpregnancy interval classifications; (d) specifying how key factors such as previous pregnancy loss, pregnancy intention, and maternal socio‐economic position will be considered; and (e) examining if the association between interpregnancy interval and perinatal outcome differs by factors such as maternal age. Conclusion This commentary outlines the discussions of this recent expert workgroup, and describes several suggested principles for study design and analysis that could mitigate many potential sources of bias.