Martha M. Werler

Background: Objective: Research on potentially avoidable caesarean deliveries frequently centres on births to nulliparous birthing people with a singleton, term delivery with vertex presentation (NTSV). However, caesarean deliveries in this population are heterogeneous, and little is known about how the association with caesarean delivery varies across risk indicators. We aimed to estimate absolute associations between caesarean delivery, categorised by risk indicators, and postpartum hospital encounters within 1 year among NTSV birthing people in Massachusetts. Methods: We used data from the Pregnancy and Early Life Longitudinal data system, which captures birth certificate and hospital discharge data for all births in Massachusetts from 2011 to 2019. Risk indicators were categorised into five groups: chronic/acute disease, placental complications, labour complications, fetal concerns and no documented risk. We estimated risk differences for the association of caesarean versus vaginal delivery with hospital encounters within one year postpartum according to risk indication subgroup. Hospital encounters within 30 days, 31 to 180 days and 181 to 365 days were examined. Results: Overall, we estimated 23 (95% confidence interval [CI] 19, 27) excess cases of one‐year postpartum hospital encounters per 1000 live births for caesarean deliveries compared to vaginal deliveries. Among birthing people with no documented risk, caesarean delivery was not associated with higher postpartum hospital encounter rates within one year compared to vaginal deliveries. Caesarean delivery was associated with an increased risk of hospital encounters for all other subgroups. All estimated risk differences were positive for hospital encounters within 30 days; however, across all subgroups, these associations diminished after 180 days postpartum. Conclusions: The association of caesarean delivery with postpartum hospital encounters varies by risk indicator and by the timing of the postpartum hospital encounter. These results suggest that caesarean deliveries among those with no documented risk are not associated with an increased risk of postpartum hospital encounter.

Background: Congenital underdevelopment of one or both ears (microtia/anotia) is the most common component of craniofacial microsomia (CFM). Although the right side is more commonly affected, social determinants of laterality remain understudied. Methods: Using a multicenter North American case–control study of CFM (1996–2002), we evaluated associations between maternal periconceptional cigarette smoking, pregnancy intention, timing of pregnancy recognition, education, and prepregnancy body mass index with microtia/anotia, overall and by laterality. Cases were 137 children < 36 months with microtia/anotia identified at craniofacial centers; up to 4 controls per case ( n = 678) were matched on residence, age at ascertainment, and calendar time. Exposures were ascertained from maternal interviews. We performed conditional logistic regression adjusted for maternal age and education to estimate odds ratios (ORs) and 95% CIs. Results: Among 137 cases, 51 (37%) were left‐sided, 61 (45%) right‐sided, 11 (8%) bilateral, and 14 (10%) unknown. Point estimates for smoking, later pregnancy recognition, lower education, and obesity were elevated overall, though confidence intervals were wide. Left‐sided ORs were smoking 2.16 (95% CI: 0.88–5.30); unplanned pregnancy 1.36 (95% CI: 0.67–2.78); pregnancy recognition > 9 weeks after last menstrual period (vs. < 5 weeks) 3.64 (95% CI: 0.95–14.03); < 12 years of education (vs. ≥ 16 years) 5.24 (95% CI: 1.47–18.68); and obesity (vs. normal weight) 1.65 (95% CI: 0.58–4.63). Corresponding right‐sided ORs were 1.28, 1.00, 1.63, 2.11, and 1.24. Conclusions: Several maternal factors were modestly associated with microtia/anotia, with consistently larger estimates for left‐ than right‐sided anomalies. These findings provide limited evidence that the etiology of microtia/anotia may differ by laterality and warrant confirmation in larger studies.

Background: Clubfoot is a common birth defect that affects one or both feet. Evidence suggests increased risks of clubfoot in offspring associated with maternal medication and cigarette smoking exposure in early pregnancy. We explored whether such associations differed by clubfoot laterality. Methods: This case–control study was conducted in Massachusetts, North Carolina, and New York (2007–2011). State birth defects registries reported clubfoot diagnoses among infants aged < 11 months. Controls without birth defects were random samples of infants from the same catchment areas and born in the same year as cases. Mothers were interviewed within 12 months following delivery. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (CI). Results: Our analysis included 643 isolated cases (bilateral N = 321, left N = 180, right N = 142) and 2037 controls. Estimates for cigarette smoking in early pregnancy were elevated for bilateral, left‐sided, and right‐sided cases, with the greatest effect for > 10 cigarettes per day for bilateral clubfoot (OR 2.42, 95% CI 1.37, 4.28). Acetaminophen, antihistamines, and pseudoephedrine were not associated with increased risk across laterality groups (ORs ranged 0.42 to 1.05). Elevated ORs (1.22 to 1.44) were observed for ibuprofen use for each laterality group. Associations for salicylates and ondansetron use, however, were observed for bilateral cases only (OR 1.82, 95% CI 1.07, 3.09; OR 1.64, 95% CI 0.99, 2.73, respectively). Conclusions: The pattern of associations across laterality varied by risk factor, suggesting a complex pathogenesis of clubfoot laterality. Investigations that can incorporate both genetic and environmental risk factors are needed to understand clubfoot etiologies.

Background: While trial of labor after cesarean delivery (TOLAC) and vaginal birth after cesarean delivery are considered safe options for birthing people with a prior cesarean delivery, current research investigating postpartum outcomes is lacking. Objective: Estimate the absolute association of trial of labor after cesarean and vaginal birth after cesarean delivery, compared to planned repeat cesarean delivery (PRCS) on 90‐day postpartum hospital encounter. Methods: We used data from the pregnancy and early life longitudinal data system, which includes all birth certificate and hospital discharge records for birthing people in Massachusetts, to estimate the effect of TOLAC on postpartum hospital encounter, compared to planned repeat cesarean delivery (PRCS). We then estimated the effect of vaginal birth after cesarean delivery (VBAC) compared to unplanned repeat cesarean deliveries (URCS) on postpartum hospital encounter and examined if hospital volume modified the observed association. Results: We found that TOLAC was associated with a reduced risk of hospital encounter compared to PRCS. Similarly, VBAC was protective against hospital encounter compared to URCS. Discussion: These results affirm VBAC and TOLAC as protective against hospital encounter in the first 90 days postpartum.

Reports of associations between use of specific analgesic medications and specific structural birth defects are inconsistent and difficult to translate for clinical guidelines and informed decision‐making. To overcome this challenge, this study examines associations between use of specific analgesics and severity of structural birth defects, using a novel approach based on survival rates. We recorded average 12‐month survival rates reported in the literature for specific birth defects and applied those rates to birth defects in the National Birth Defects Prevention Study (1997–2011) to create severity groups: < 95% survival ( n = 20,229), < 70% survival ( n = 2936), and ≥ 95% survival (6911). Maternal uses of specific analgesic medications during the month before through the first 3 months of pregnancy (periconception) were compared between non‐malformed controls ( n = 11,614) and severity groups with odds ratios (aOR) and 95% confidence intervals (CI) adjusted for race/ethnicity, maternal education, pre‐pregnancy body mass index, maternal periconceptional alcohol use, exposure to known teratogens, infant sex, and study site. Use of acetaminophen as a single component product or in combination with cough/cold agents was not associated with any of the birth defect severity groups. Elevated aORs in relation to risks of < 70% survival birth defects were observed for use of acetaminophen in combination with aspirin and caffeine, hydrocodone, codeine, or propoxyphene (aOR range: 1.46–2.00) and for hydrocodone alone (OR: 2.45). aORs remained elevated for the < 95% group except for acetaminophen plus codeine (OR 1.07). aORs for each severity group in association with use of acetaminophen combined with oxycodone approximated the null and those for ibuprofen, naproxen, and aspirin ranged between 1.15 and 1.28. In consideration of severity of birth defects, our findings indicate both safer and riskier analgesic medication options are available.

Background: Women with intellectual and developmental disability (IDD), including those with autism and/or intellectual disability, have historically been sterilised and institutionalised to limit their reproductive rights. As sterilisation laws have been repealed and protections against institutionalisation enacted, stigma persists but may be changing over time. Objectives: Our objective was to describe fertility rates among women with identified IDD (defined using ICD codes for intellectual disability or autism) using 11 years of data of all women aged 18–45 and enrolled in Medicaid and/or Medicare. Methods: We identified a cohort of women with IDD enrolled in Medicaid and/or Medicare between January 2011 and December 2022. International Classification of Diseases (ICD) 9 and 10 codes were used to identify pregnancies and IDD diagnoses. We calculated general fertility rate (GFR), age‐specific fertility rate (ASFR) and total fertility rate (TFR) and corresponding 95% confidence intervals (CI) for each year. Results: From 2011 to 2022, we observed 50,562 livebirths among 33,457 women. There were 38,983 births to women with intellectual disability, 9360 with autism, and 2219 with autism and co‐occurring intellectual disability. There were 1403 pregnancies to women with cerebral palsy and autism or intellectual disability. GFR in women with IDD was relatively stable over the years, from 9.3 per 1000 (95% CI 9.0, 9.6) in 2011 to 9.9 per 1000 (95% CI 9.6, 10.2) in 2022. ASFR for both women with autism—only and women with an intellectual disability—only was highest at 21–25 years. Total fertility rates were slightly higher for those with autism‐only (ranging from 0.22 to 0.40 across years) than for women with intellectual disability‐only (ranging from 0.25 to 0.27). Data also reveal that fertility rates for women with IDD have increased in most states. Conclusion: Trends in fertility rates among women with IDD were consistent over time. Incremental increase in fertility rates were observed among women with autism. Results warrant the need to further examine factors related to access, quality and continuity of care among women with IDD.

Background: Empirically evaluating the potential impact of recall bias on observed associations of prenatal medication exposure is crucial. Objective: We sought to assess the effects of exposure misclassification on previous studies of the use of nonsteroidal anti‐inflammatory drugs (NSAIDs) in early pregnancy and increased risk of amniotic band syndrome (ABS). Methods: Using data from the National Birth Defects Prevention Study (NBDPS) on births from 1997 to 2011, we included 189 mothers of infants with ABS and 11,829 mothers of infants without congenital anomalies. We identified external studies of medication use during pregnancy to obtain validity parameters for a probabilistic bias analysis to adjust for exposure misclassification. Due to uncertainty about the transportability of these parameters, we conducted multidimensional bias analyses to explore combinations of values on the results. Results: When we assumed higher specificity in cases or higher sensitivity in controls, misclassification‐adjusted estimates suggested confounding‐adjusted estimates were attenuated. However, in a few instances, when we assumed greater sensitivity in the cases than the controls (and Sp ≥ 0.9), the misclassification‐adjusted estimates suggested upward bias in the confounding‐adjusted estimates. Conclusions: Results from our bias analysis highlighted that the magnitude of bias depended on the mechanism and the extent of misclassification. However, the parameters available from the validation studies were not directly applicable to our study. In the absence of reliable validation studies, considering mechanisms of bias and simulation studies to outline combinations of plausible scenarios to better inform conclusions on the effects of these medications on pregnancy outcomes remains important.

Many examples of the use of real-world data in the area of pharmacoepidemiology include “big data,” such as insurance claims, medical records, or hospital discharge databases. However, “big” is not always better, particularly when studying outcomes with narrow windows of etiologic relevance. Birth defects are such an outcome, for which specificity of exposure timing is critical. Studies with primary data collection can be designed to query details about the timing of medication use, as well as type, dose, frequency, duration, and indication, that can better characterize the “real world.” Because birth defects are rare, etiologic studies are typically case‑control in design, like the National Birth Defects Prevention Study, Birth Defects Study to Evaluate Pregnancy Exposures, and Slone Birth Defects Study. Recall bias can be a concern, but the ability to collect detailed information about both prescription and over-the-counter medication use and other exposures such as diet, family history, and sociodemographic factors is a distinct advantage over claims and medical record data sources. Case‑control studies with primary data collection are essential to advancing the pharmacoepidemiology of birth defects. This article is part of a Special Collection on Pharmacoepidemiology.