Stephen M. Kerr

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.

Sofosbuvir/Velpatasvir (SOF/VEL) is a combination drug used for chronic hepatitis C (HCV) infection. However, limited information exists regarding the pharmacokinetics of SOF/VEL and its metabolites in hemodialysis patients. We conducted a prospective investigation of the pharmacokinetic parameters of SOF/VEL after a single dose of SOF/VEL (400/100 mg) on days with and without dialysis in 12 Thai hemodialysis patients with chronic HCV infection, who had been undergoing hemodialysis for a duration of 0.5–20 years. Blood samples were collected before dose (0) and 0.5, 1.0, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, 8.0, and 12.0 h after dose. Dialysate samples were also collected before dose (0) and 1.0, 2.0, 3.0, and 4.0 h after dose. Plasma and dialysate samples were quantified for SOF and its metabolite, GS‐331007, and VEL concentrations using a fully validated LCMS technique. In addition, a preliminary efficacy study was conducted using the proposed SOF/VEL dose reduction regimen in all patients. No differences in SOF/VEL PK parameters between on‐ and off‐dialysis studies. On the contrary, GS‐331007 exhibited a 30% reduction in the area under the plasma concentration–time curve from time 0 to 24 h (AUC_0‐24h) on dialysis days compared with non‐dialysis days (AUC_0‐24h ratio 0.68 vs. 1.04, respectively). The dialysis clearance of SOF and GS‐331007 was 9.35 (8.72–15.11) and 8.89 (8.52–14.07) mL/min, respectively. Subsequently, an alternate‐day regimen of SOF/VEL (400/100 mg) was administered for 12 weeks, resulting in an undetectable plasma HCV viral load without side effects. Further clinical studies are warranted to validate the efficacy and safety of our proposed dose reduction regimen.

Background: Although results from studies of first‐trimester influenza vaccination and congenital heart defects (CHDs) have been reassuring, data are limited for specific CHDs.Methods: We assessed associations between reported maternal influenza vaccination, 1 month before pregnancy (B1) through end of third pregnancy month (P3), and specific CHDs using data from a multisite, population‐based case–control study. Analysis included 2,982 case children diagnosed with a simple CHD (no other cardiac involvement with or without extracardiac defects) and 4,937 control children without a birth defect with estimated delivery dates during 2006–2011. For defects with ≥5 exposed case children, we used logistic regression to estimate propensity score‐adjusted odds ratios (aORs) and 95% confidence intervals (CIs), adjusting for estimated delivery year and season; plurality; and maternal age at delivery, race/ethnicity, low folate intake, and smoking and alcohol use during B1P3.Results: Overall, 124 (4.2%) simple CHD case mothers and 197 (4.0%) control mothers reported influenza vaccination from 1 month before through the third pregnancy month. The aOR for any simple CHD was 0.97 (95% CI: 0.76–1.23). Adjusted ORs for specific simple CHDs ranged from 0.62 for hypoplastic left heart syndrome to 2.34 for total anomalous pulmonary venous return (TAPVR). All adjusted CIs included the null except for TAPVR.Conclusions: Although we cannot fully exclude that exposure misclassification may have masked risks for some CHDs, findings add to existing evidence supporting the safety of inactivated influenza vaccination during pregnancy. The TAPVR result may be due to chance, but it may help inform future studies.

Background: Many previous studies have identified risk factors for stillbirth, but few examine stillbirth among pregnancies affected with birth defects. Because many hypothesized etiologies of stillbirth work through vascular pathologies of the placenta, we examined maternal use of vasoactive medications in relation to stillbirth among pregnancies affected with birth defects.Methods: Data were analyzed from the National Birth Defects Prevention Study (1997–2011). We examined use of nonsteroidal anti‐inflammatory drugs (NSAIDs), decongestants, short‐ or long‐acting beta‐agonists (SABA/LABA), and antihypertensive medications in relation to pregnancies affected by birth defects ending in stillbirth compared to live birth. Associations were measured with odds ratios (ORs) for early pregnancy use and hazard ratios (HRs) for time‐varying late pregnancy use.Results: Among all birth defects (n = 12,394), the risk of stillbirth was associated with use of antihypertensive medications in early (odds ratio [OR]: 1.8; 95% confidence interval [CI]: 1.0, 3.1) and late pregnancy (HR: 2.0; 95% CI: 1.1, 3.6). Other vasoactive medications were not associated with increased risk of stillbirth. Of 27 specific defect groups, increased risks were observed for only one medication/defect pair: early decongestant use was more common among mothers of stillbirth versus live birth cases with spina bifida (OR: 2.4; 95% CI: 0.9, 6.5).Conclusion: This exploratory analysis of vasoactive medication use suggests that use of NSAIDs, decongestants, and SABA/LABA is not associated with increased risk of stillbirth among pregnancies affected with birth defects. Our finding of increased risks associated with antihypertensive medication use raises questions of confounding by indication, which we were not able to fully address.

Background Maternal folic acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study. Methods We assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of >= 400 mcg as a potential effect modifier. Results We analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake >= 400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null. Conclusions Similar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake >= 400 mcg, with some associations somewhat stronger in this group.

Background: The tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine is recommended during pregnancy to protect newborns against pertussis infection in the months prior to their primary pertussis vaccination. Although research on the safety of the vaccine has been reassuring, most previous studies have considered major malformations as a single outcome, and have not examined potential risks for specific malformations.Methods: Using data from the Slone Epidemiology Center Birth Defects Study collected between 2006 and 2015, we identified exposures to Tdap vaccine in both early and late pregnancy and examined potential risks for specific malformations. We used logistic regression models to calculate propensity score‐adjusted odds ratios (aORs) and 95% confidence intervals (CIs).Results: We identified 2,357 women exposed to Tdap during pregnancy. For first trimester exposures, the risk estimate for malformations overall was 1.0 (0.7, 1.5). We had power to examine nine specific malformations and found adjusted odds ratios ranging from 0.7 to 1.3, none of which had confidence intervals that excluded 1.0. For second or third trimester exposures, we examined 15 malformations with potential late pregnancy etiology, and calculated adjusted risk estimates for nine of these. Risk estimates ranged from 0.5 to 1.9, with no lower confidence bounds that excluded 1.0.Conclusions: We observed no evidence of appreciable risks for selected specific major malformations associated with Tdap vaccine exposure during early or late pregnancy. As pertussis remains a public health concern and Tdap vaccination levels in pregnancy remain below desired levels, these data provide further reassurance regarding the current recommendations for Tdap vaccination in pregnancy.

Background: Influenza during pregnancy contributes to maternal morbidity and mortality. Neuraminidase inhibitors, including oseltamivir, are recommended for treating women with influenza during pregnancy.Methods: Data from the Slone Birth Defects Study from 2009 to 2015 were used to investigate associations between oseltamivir and specific birth defects. We classified exposures according to timing in pregnancy and examined 52 and 16 defects with early and potential late pregnancy etiology, respectively; we calculated crude odds ratios (ORs) and 95% confidence intervals (CIs) for defects with three or more exposures.Results: Among 8,379 cases and 4,190 nonmalformed controls, we identified 79 and 42 oseltamivir exposures, respectively. The majority of defects had no exposures. ORs were elevated for several defects, but the CI excluded the null only for intestinal malrotation (OR: 10.7 [1.8, 45.2]; three exposures).Conclusions: Largely null findings for specific defects are reassuring. The association with intestinal malrotation, while unstable, warrants further investigation.

Background: The Zika epidemic has brought increased attention to congenital microcephaly as a birth outcome. However, little is known about risks for microcephaly unrelated to Zika.Methods: Using data from the Slone Epidemiology Center Birth Defects Study from 1993 to 2015, we identified 57 cases of microcephaly alone (“isolated”) and 109 cases of microcephaly that included other major birth defects (“non‐isolated”), and considered a large number of potential risk factors including demographic characteristics, illnesses, and medications used during pregnancy. Where numbers permitted, we used logistic regression models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs).Results: Substantial differences in risk factors were observed for isolated versus non‐isolated microcephaly. For isolated microcephaly, risk estimates were elevated for mothers of non‐Hispanic, non‐White race/ethnicity, and underweight pre‐pregnancy body mass index (BMI). The risk for exposure anytime in pregnancy to acetaminophen was null; in contrast, the aOR for NSAIDs was 2.4 (95% CI: 1.3–4.2). This association was weakened (but not eliminated) after excluding those exposed to opioids or illicit drugs, and risk was not present among those reporting less frequent exposures. For non‐isolated microcephaly, elevated risk estimates were found for urinary tract infection.Conclusions: Risk factors differed for isolated and non‐isolated microcephaly. While some findings support previously reported associations, (e.g., smoking, alcohol, underweight BMI), we also identified risk factors not previously described, notably NSAID use for isolated microcephaly and urinary tract infection for non‐isolated microcephaly; however, these results should be viewed as hypothesis generating.