Samantha E. Parker

Periconceptional Use of Opioids and the Risk of Neural Tube Defects

OBJECTIVE: Opioid medications are among the most effective analgesics. However, the consequences of opioid exposure to the developing human offspring are not known. We assessed whether maternal opioid use in the periconceptional period was associated with the risk of neural tube defects in the offspring. METHODS: We used data from 1998 to 2010 from the Slone Epidemiology Center Birth Defects Study, an ongoing case–control study. Mothers were interviewed by telephone within 6 months of delivery about sociodemographic factors and exposures during pregnancy including detailed questions on type and timing of medication use. Mothers of 305 offsprings with neural tube defect were compared with mothers of 7,125 offsprings in the nonmalformed control group and 13,405 offsprings in the malformed control group. Periconceptional opioid use was defined as any reported use in the 2 months after the last menstrual period. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for study center. RESULTS: A higher percentage of mothers of offsprings with neural tube defects (3.9%) reported using an opioid medication than mothers of offsprings in the nonmalformed control group (1.6%) and offsprings in the malformed control group (2.0%) with adjusted ORs of 2.2 (95% CI 1.2 −4.2) and 1.9 (95% CI 1.0 −3.4), respectively. When offsprings were restricted to those with spina bifida, the adjusted ORs were 2.5 (95% CI 1.3–5.0) and 2.2 (95% CI 1.1–4.1), respectively. CONCLUSION: A 2.2-fold increase in risk would translate to a neural tube defect prevalence of 5.9 per 10,000 live births among women who use opioids. Overall, opioid use in the periconceptional period appeared to be associated with a modest increased risk of neural tube defects. LEVEL OF EVIDENCE: II

The impact of folic acid intake on the association among diabetes mellitus, obesity, and spina bifida

OBJECTIVE The purpose of this study was to investigate the relationship between spina bifida and 2 established risk factors (pregestational diabetes mellitus and obesity) in both the presence and absence of the recommended daily folic acid intake in the periconceptional period. STUDY DESIGN Cases of spina bifida (n = 1154) and control subjects (n = 9439) from the Slone Epidemiology Center Birth Defects Study (1976-2011) were included. Information on preexisting diabetes mellitus (collected 1976-2011) and obesity (collected 1993-2011), defined as a body mass index of ≥30 kg/m(2), was collected through interviews that were conducted within 6 months of delivery. Periconceptional folic acid intake was calculated with both dietary and supplement information. Mothers were classified as consuming more or less than 400 μg/day of folic acid; food folate was included at a 30% discount for its lower bioavailability. Logistic regression models that were adjusted for maternal age, race, education, and study site were used to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for the joint effects of low folic acid intake coupled with diabetes mellitus or obesity. RESULTS Case mothers were more likely to have diabetes mellitus or be obese (0.7% and 19.0%, respectively) than control mothers (0.4% and 10.8%, respectively). The joint effect of diabetes mellitus and lower folic acid intake on spina bifida was larger (aOR, 3.95; 95% CI, 1.56-10.00) than that of diabetes mellitus and higher folic acid intake (aOR, 1.31; 95% CI, 0.17-10.30). Folic acid intake made little difference on the association between obesity and spina bifida. CONCLUSION Our findings suggest that folic acid further attenuates, although does not eliminate, the risk of spina bifida that is associated with diabetes mellitus than the risk with obesity.

Epidemiology of ischemic placental disease: A focus on preterm gestations

Preeclampsia, placental abruption, and intrauterine growth restriction (IUGR) have collectively been termed ischemic placental disease (IPD) due to a suspected common biological pathway involving poor placentation in early pregnancy and subsequent placental insufficiency. Despite decades of research, the etiologies of these conditions remain largely unknown and preventive and therapeutic strategies are lacking. It has been suggested that the underpinnings of IPD lie primarily in preterm gestations and that classification of these conditions based on the gestational age at onset will facilitate etiologic research. The purpose of this review is to describe our current knowledge regarding the risk factors, co-occurrence, and recurrence of the conditions of IPD with a specific focus on the preterm gestational window.

Population-based microcephaly surveillance in the United States, 2009 to 2013: An analysis of potential sources of variation

BACKGROUND Congenital microcephaly has been linked to maternal Zika virus infection. However, ascertaining infants diagnosed with microcephaly can be challenging. METHODS Thirty birth defects surveillance programs provided data on infants diagnosed with microcephaly born 2009 to 2013. The pooled prevalence of microcephaly per 10,000 live births was estimated overall and by maternal/infant characteristics. Variation in prevalence was examined across case finding methods. Nine programs provided data on head circumference and conditions potentially contributing to microcephaly. RESULTS The pooled prevalence of microcephaly was 8.7 per 10,000 live births. Median prevalence (per 10,000 live births) was similar among programs using active (6.7) and passive (6.6) methods; the interdecile range of prevalence estimates was wider among programs using passive methods for all race/ethnicity categories except Hispanic. Prevalence (per 10,000 live births) was lowest among non-Hispanic Whites (6.5) and highest among non-Hispanic Blacks and Hispanics (11.2 and 11.9, respectively); estimates followed a U-shaped distribution by maternal age with the highest prevalence among mothers <20 years (11.5) and ≥40 years (13.2). For gestational age and birth weight, the highest prevalence was among infants <32 weeks gestation and infants <1500 gm. Case definitions varied; 41.8% of cases had an HC ≥ the 10th percentile for sex and gestational age. CONCLUSION Differences in methods, population distribution of maternal/infant characteristics, and case definitions for microcephaly can contribute to the wide range of observed prevalence estimates across individual birth defects surveillance programs. Addressing these factors in the setting of Zika virus infection can improve the quality of prevalence estimates. Birth Defects Research (Part A) 106:972-982, 2016.

Menarche, Menopause, Years of Menstruation, and the Incidence of Osteoporosis: The Influence of Prenatal Exposure to Diethylstilbestrol

CONTEXT Estrogen is critical for bone formation and growth in women. Estrogen exposures occur throughout life, including prenatally, and change with reproductive events, such as menarche and menopause. OBJECTIVE The objective of this study was to investigate the association between age at menarche, age at menopause, and years of menstruation with incidence of osteoporosis and assess the impact of prenatal exposure to diethylstilbestrol (DES), a synthetic estrogen, on such associations. DESIGN, SETTING, AND PARTICIPANTS Participants were 5573 women in the National Cancer Institute Combined Cohort Study of DES (1994-2006). Data on reproductive history and medical conditions were collected through questionnaires at baseline in 1994 and subsequently in 1997, 2001, and 2006. Age-stratified Cox regression models were used to calculate multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs). Effect measure modification by prenatal DES exposure was assessed using cubic restricted spline regression models. MAIN OUTCOME MEASURE Osteoporosis was the main outcome measure. RESULTS The IRRs for osteoporosis incidence with age at menarche less than 11 years and age at menopause of 50 years or younger were 0.82 (CI 0.59, 1.14) and 0.61 (CI 0.40, 0.92), respectively. Fewer than 25 years of menstruation was associated with an increased incidence of osteoporosis (IRR 1.80; CI 1.14, 2.86) compared with 35 years or more of menstruation. Associations were stronger among women who had not been prenatally exposed to DES. CONCLUSIONS Our data support the hypothesis that lifetime cumulative exposure to estrogens is protective against osteoporosis. Furthermore, prenatal exposure to estrogen appears to modify these associations, although the mechanism by which this occurs is unknown.

Maternal Medication and Herbal Use and Risk for Hypospadias: Data from the National Birth Defects Prevention Study, 1997--2007

To investigate associations between maternal use of common medications and herbals during early pregnancy and risk for hypospadias in male infants.

Bias from conditioning on live-births in pregnancy cohorts: an illustration based on neurodevelopment in children after prenatal exposure to organic pollutants (Liew et al. 2015)

Liew et al. ask whether observed inverse associations between prenatal perfluoroalkyl substances (PFAS) exposure and attention deficit hyperactivity disorder (ADHD) could result from including only live-births in a study or a socalled ‘live-birth bias’. They provide a very clear description of a bias structure that could result from prenatal PFAS exposure having an effect on fetal death, when measuring the association between PFAS exposure and ADHD. They conducted simulations of the relationship between PFAS and risk of ADHD in three different scenarios based on reasonable assumptions of the prevalences of exposure, fetal loss and ADHD, and ranges of associations between outcomes and known and unknown covariates. When the authors set the ‘true’ PFAS-ADHD association to 1.0, they indeed show the association is protective when PFAS doubles the risk of fetal death in the presence of strong confounding for the PFAS fetal death association. When the true association was set to 1.2, risk estimates were close to the null under the same conditions, as further evidence of the downward bias. In other words, the answer to the authors’ research question—whether observed inverse associations between prenatal PFAS exposures and ADHD could result from live-birth bias due to the competing risk of fetal death—is yes, in some scenarios. ADHD is an important outcome in terms of its growing incidence, cost of treatments and impact on learning, working and relationships. Thus, identifying causal factors is worthwhile. If environmental pollutants cause ADHD, we ought to know and eliminate the potential for exposure. However, Liew et al.’s research question appears to be misplaced. Adjusting away the competing risk on fetal death to measure the PFAS-ADHD association makes little sense in this situation. On theoretical grounds, competing risks are a concern when they remove individuals from the population at risk. Diagnosis of ADHD is based on child behaviorus and therefore the population at risk is children, not all conceptions. From a practical standpoint, an association between an exposure and ADHD after accounting for the association between that exposure and fetal death is not translatable. The relationship between PFAS exposure and fetal death is irrelevant when interpreting an association between PFAS and risk of ADHD. A pregnant woman may wonder if her fetus will have ADHD, but if she loses that fetus, the question is moot. The question only makes sense among survivors. The translatable question is whether prenatal PFAS exposure affects the risk of ADHD among live-births (who survive into early childhood). The answer to this translatable question could inform public health interventions. As a bonus, the answer would also contribute to the understanding of neurodevelopment. Both types of information are relevant, important and valid, even if the exposure causes fetal death. Knowledge that observed protective associations for an environmental toxin and childhood outcomes could be biased due to live-birth bias might be considered helpful in that it should preempt false health claims that the toxic exposures are beneficial for childhood outcomes. But that same knowledge of a live-birth bias means that the exposure is not beneficial and indeed hazardous due to it causing upstream outcomes. Again, there seems little to be gained from

A Description of Spina Bifida Cases and Co-Occurring Malformations, 1976–2011

Mandatory folic acid fortification in the United States corresponded with a decline in the prevalence of spina bifida (SB). The aim of this study was to describe the epidemiologic characteristics of isolated versus non‐isolated SB cases in both pre‐ and post‐fortification periods. SB cases in the Slone Epidemiology Center Birth Defects Study from 1976 to 2011 without chromosomal anomalies and syndromes were included. A maternal interview, conducted within 6 months of delivery, collected information on demographics, reproductive history, diet, and supplement use. Daily folic acid intake in the periconceptional period was calculated using both dietary and supplement information and categorized as low intake (<400 µg/day) or high intake (≥400 µg/day). SB cases (n = 1170) were classified as isolated (80.4%) or non‐isolated (19.1%). Non‐isolated cases were further divided into subgroups based on accompanying major malformations (midline, renal, genital, heart, laterality). Compared to non‐isolated cases, isolated cases were more likely to be white, non‐Hispanic and have more than 12 years of education. Cases in the renal, genital, and heart subgroups had the lowest proportions of mothers with a high folic acid intake. The change from pre‐ to post‐fortification was associated with a decrease in the proportion of isolated cases from 83% to 72%, though in both periods isolated cases were more likely to be female and their mothers were more likely to have high folic acid intake. These findings highlight the importance of separating isolated and non‐isolated cases in etiologic research of SB.

Induced Abortions and the Risk of Preeclampsia Among Nulliparous Women

Induced abortion (IA) has been associated with a lower risk of preeclampsia among nulliparous women, but it remains unclear whether this association differs by method (either surgical or medical) or timing of IA. We performed a nested case-control study of 12,650 preeclampsia cases and 50,600 matched control deliveries identified in the Medical Birth Register of Finland from 1996 to 2010. Data on number, method, and timing of IAs were obtained through a linkage with the Registry of Induced Abortions. Odds ratios and 95% confidence intervals were calculated. Overall, prior IA was associated with a lower risk of preeclampsia, with odds ratios of 0.9 (95% confidence interval (CI): 0.9, 1.0) for 1 prior IA and 0.7 (95% CI: 0.5, 1.0) for 3 or more IAs. Differences in the associations between IA and preeclampsia by timing and method of IA were small, with odds ratios of 0.8 (95% CI: 0.6, 1.1) for late (≥12 gestation weeks) surgical abortion and 0.9 (95% CI: 0.7, 1.2) for late medical abortion. There was no association between IA in combination with a history of spontaneous abortion and risk of preeclampsia. In conclusion, prior IA only was associated with a slight reduction in the risk of preeclampsia.

Placental Abruption and Subsequent Risk of Pre-eclampsia: A Population-Based Case–Control Study

BACKGROUND Pre-eclampsia and placental abruption may share a common pathophysiologic mechanism, namely, uteroplacental ischaemia. The aim of this study was to investigate the association between placental abruption and risk of pre-eclampsia in a subsequent pregnancy, and to determine whether the association differs by the gestational age at the time of abruption. METHODS A nested case-control study among multiparous women in the Medical Birth Register of Finland from 1996-2010 was conducted. Cases of pre-eclampsia (n = 6487) and frequency matched controls (n = 25,948) were linked to the Hospital Discharge Registry to ascertain data on prior abruption. Abruption was categorised as preterm (<37 weeks) or term (≥37 weeks) based on the gestational age at delivery. We fit logistic regression models to evaluate the associations between abruption and the odds of pre-eclampsia in the subsequent pregnancy before and after adjusting for potential confounders. RESULTS Preterm abruption was associated with over a twofold increase in risk of pre-eclampsia [odds ratio (OR) 2.2, 95% confidence interval (CI) 1.5, 3.3] in a subsequent pregnancy. In contrast, term abruption was not associated with pre-eclampsia (OR 1.1, 95% CI 0.7, 1.7). The association between preterm abruption and pre-eclampsia was further elevated among women with a history of pre-eclampsia. Associations with preterm abruption were also strengthened when the outcome was pre-eclampsia with early delivery (<34 weeks). CONCLUSIONS These findings suggest that placental abruption in a prior pregnancy is associated with a different risk profile of pre-eclampsia based on the gestational age of the abruption-affected pregnancy.