Background

Previous studies of prenatal acetaminophen use have not addressed what indications and maternal co-factors describe acetaminophen use.

Objective

The objective of this study was to describe these parameters in a well-characterised, prospective birth cohort.

Methods

Data were drawn from the MotherToBaby study of pregnant women enrolled from 2004 to 2018. Daily acetaminophen diaries were calculated for all exposed women with complete dose and duration information. Descriptive statistics were used to assess maternal characteristics associated with acetaminophen use. Prevalence by 2-year interval was described, and linear regression was used to test for trend. Indication of use and dose per indication were summarised.

Results

Of 2441 subjects, 1515 (62%) reported use of acetaminophen. Over the 15-year period, there was a decline in use of 2.5% for each 2-year period (test for trend = 0.001) with 58% reporting acetaminophen use in 2017-2018. Among women with acetaminophen use in pregnancy (n = 1515), 58% reported <10 days of use, 13% reported 10-19 days of use, 9% reported 20-44 days of use, and 9% reported 45 or more days of use. Twelve per cent had undefined duration of use. Increasing duration of exposure was associated with tobacco use, obesity, self-reported depression or anxiety, and antidepressant use. The most frequently reported indication was headache, however, indication varied by duration of use, with more women reporting use for sleep or pain/injury in the categories with the longest duration of use. Median dose per exposed day was highest among those reporting use for sleep, and higher doses were more frequently reported for arthritis, injury, and pain.

Conclusion

Acetaminophen is used by the majority of pregnant women, and some continue to use for many weeks in pregnancy. Given the heterogeneity in duration of use, indication, and dose, studies that estimate the risk of adverse outcomes associated with acetaminophen must carefully consider these factors.

Background

Antidepressant use later in pregnancy has been associated with preeclampsia and postpartum haemorrhage (PPH) in some studies.

Objectives

To evaluate the association between patterns of prenatal antidepressant dose across gestationand risk of precclampsia and PPH.

Methods

We utilised OptumLabs® Data Warehouse (2012-2016) administrative health care claims, identifying 226 932 singleton liveborn deliveries for this retrospective cohort study. Antidepressant dispensing doses were converted to fluoxetine equivalents. Using k-means longitudinal, we identified women with similar patterns of antidepressant exposure, that is, trajectory groups, during the first 20 and 35 gestational weeks. We estimated risk ratios (RR) and 95% confidence intervals (CI) for the association between trajectory groups and preeclampisa (20-week groups) and PPH (35-week groups), adjusting for demographics, co-morbidities, and other psychotropic medications. Linear trend tests assessing increasing risk of the outcomes across groups were performed.

Results

Among 15 041 (6.6%) pregnancies exposed to an antidepressant, the following trajectory groups were identified: A-low exposure, starting pregnancy at ~10 mg/d, with 1st trimester reduction/discontinuation, B-low sustained exposure of ~20 mg/d, C-moderate exposure (~40 mg/d) with 1st trimester reduction/discontinuation, D-moderate sustained exposure of ~40 mg/d, and E-high sustained exposure of ~75 mg/d. In the low exposure with reduction/discontinuation trajectory, risks were 8.2% for preeclampsia and 2.7% for PPH. Compared with this group, low, moderate, and high sustained trajectories were associated with preeclampsia (adjusted RR 1.17, 95% CI 1.01, 1.34; RR 1.31, 95% CI 1.12, 1.54; and RR 1.41, 95% CI 1.05, 1.90, respectively) and PPH (RR 1.32, 95% CI 1.05, 1.66; RR 1.35, 95% CI 1.03, 1.78; RR 2.51, 95% CI 1.69, 3.71, respectively); P < .01 for linear trend tests for both outcomes. There was no increased risk for either outcome for moderate exposure with reduction/discontinuation (trajectory C).

Conclusions

Women with sustained antidepressant exposure, especially at higher doses, were at increased risk for preeclampsia and PPH, but underlying depression and anxiety may contribute to the increased risk.

OBJECTIVE: To investigate causes of discrepancies in the association between early pregnancy oral glucocorticoid (OGC) use and preterm birth risk among women with rheumatoid arthritis (RA) in health care utilization data from California Medicaid (Medi-Cal) and the prospective cohort MotherToBaby Pregnancy Studies. METHODS: Separately, we estimated risk ratios (RRs) between OGC exposure before gestational day 140 and preterm birth risk in data from Medi-Cal (2007-2013; n = 844) and MotherToBaby (2003-2014; n = 528). We explored differences in socioeconomic status, OGC dose distribution, exposure misclassification, and confounding by RA severity across the data sources. RESULTS: Preterm birth risk in women without OGC was 17.3% in Medi-Cal and was 9.7% in MotherToBaby. There was no association between OGC and preterm birth in Medi-Cal (adjusted RR 1.00 [95% confidence interval (95% CI) 0.71, 1.42]), and a 1.85-fold (95% CI 1.20, 2.84) increased preterm birth risk in MotherToBaby. When restricting each sample to women with a high-school diploma or less, preterm birth risk following no OGC exposure was 15.9% in Medi-Cal and 16.7% in MotherToBaby; adjusted RRs were 1.16 (95% CI 0.74, 1.80) in Medi-Cal and 0.81 (95% CI 0.25, 2.64) in MotherToBaby. Cumulative OGC dose was higher in MotherToBaby (median 684 mg) than in Medi-Cal (median 300 mg). An OGC dose of ≤300 mg was not associated with increased preterm birth risk. Exposure misclassification and confounding by RA severity were unlikely explanations of differences. CONCLUSION: Higher baseline preterm birth risk and lower OGC dose distribution in Medi-Cal may explain the discrepancies. Studies are needed to understand the effects of autoimmune disease severity and undertreatment on preterm birth risk in low-income populations.

To estimate the risk of neonatal outcomes from patterns of prenatal antidepressant use. From the OptumLabs Data Warehouse, 226 932 singleton deliveries were identified. Antidepressant claims with coverage between the last menstrual period and 35 weeks' gestation were converted to fluoxetine equivalents, and a longitudinal cluster analysis was performed. Outcomes included major cardiac malformations (11.7 of 1000 births), preterm birth (75.7 of 1000 births), and newborn respiratory distress (54.2 of 1000 births). The lowest trajectory was the primary reference group, and depression and anxiety with no antidepressant claims served as secondary reference groups. From 15 041 (6.6%) pregnancies exposed to an antidepressant, use patterns were best described as (1) low use (∼10 mg/day) with first-trimester reduction, (2) low sustained use (∼20 mg/day), (3) moderate use (∼40 mg/day) with first-trimester reduction, (4) moderate sustained use (∼40 mg/day), and (5) high sustained use (∼75 mg/day). Moderate sustained use increased the risk of major cardiac malformations, although results included the null when compared with depression or anxiety reference groups. Moderate sustained (adjusted risk ratio [RR] 1.31; 95% confidence interval [CI] 1.16-1.49) and high sustained (adjusted RR 1.78; 95% CI 1.48-2.14) trajectories were associated with an increased risk of preterm birth. All 4 trajectories increased the risk of neonatal respiratory distress in a dose-response fashion (adjusted RRs 1.36 [95% CI 1.20-1.50] to 2.23 [95% CI 1.83-2.77]). Although findings support continuation of the lowest effective dose to treat depression or anxiety, which benefits the mother, they also highlight an increased risk for newborn respiratory distress in all groups and preterm birth at moderate to high sustained doses.

Background

Covariate selection to reduce bias in observational data analysis has primarily relied upon statistical criteria to guide researchers. This approach may lead researchers to condition on variables that ultimately increase bias in the effect estimates. The use of directed acyclic graphs (DAGs) aids researchers in constructing thoughtful models based on hypothesised biologic mechanisms to produce the least biased effect estimates possible.

Methods

After providing an overview of different relations in DAGs and the prevailing mechanisms by which conditioning on variables increases or reduces bias in a model, we illustrate examples of DAGs for maternal antidepressants in pregnancy and four separate perinatal outcomes.

Results

By comparing and contrasting the diagrams for maternal antidepressant use in pregnancy and spontaneous abortion, major malformations, preterm birth, and postnatal growth, we illustrate the different conditioning sets required for each model. Moreover, we illustrate why it is not appropriate to condition on the same set of covariates for the same exposure and different perinatal outcomes. We further discuss potential selection biases, overadjustment of mediators on the causal path, and sufficient sets of conditioning variables.

Conclusion

In our efforts to construct parsimonious models that minimise confounding and selection biases, we must rely upon our scientific knowledge of the causal mechanism. By structuring data collection and analysis around hypothesised DAGs, we ultimately aim to validly estimate the causal effect of interest.

Studies of antidepressant safety in pregnancy typically do not address complex patterns of use throughout pregnancy. We performed longitudinal trajectory modeling to describe patterns of antidepressant use in the first 32 weeks of pregnancy, and test whether these trajectories are associated with a reduction in birth weight or gestational age at delivery. Our study included 166 pregnant women with deliveries between 2011 and 2015 who were prescribed an antidepressant between 91 days prior to last menstrual period and 32 weeks of gestation. From electronic medical records, we estimated average daily dose and cumulative dose per week for the first 32 weeks of gestation and for the first 13 weeks postnatal. We clustered women with similar utilization patterns using k-means longitudinal modeling and assessed the associations between trajectory group and birth weight and gestational age at delivery. We identified four cumulative dose trajectory groups and three average daily dose trajectory groups in each period. Relative to the lowest trajectory group, the highest trajectory group during pregnancy was associated with reduced birth weight in multivariable analysis (average daily highest trajectory vs. lowest trajectory β - 314.1 g, 95% CI - 613.7, - 15.5) adjusted for depression severity score, maternal age, race, and pregnancy smoking. Trajectory groups were not associated with gestational age at delivery. The highest trajectory group of antidepressant use in pregnancy was associated with a modest reduction in birth weight but not with gestational age at delivery. Longitudinal trajectories allow for a dynamic visualization and quantification of medication use among pregnant women.

Objective

To identify frequently reported prescription medications and supplements among couples planning pregnancy because there is a lack of descriptive information on these agents in women and men who are trying to conceive.

Methods

Five hundred one couples enrolled in the Longitudinal Study of Infertility and the Environment, which took place between 2005 and 2009. Participants reported prescription medications as well as prescription and over-the-counter supplements used through interviews at study enrollment and through daily dairies during the 12-month follow-up. We identified prescription medications and supplements prospectively reported by ≥1% of women and men at baseline and from daily journal information grouped into 3-month preconception follow-up intervals while couples tried for pregnancy.

Results

The 5 most reported prescription medications among women were levothyroxine (5.8%), cetirizine (2.6%), fluticasone (2.4%), escitalopram (1.8%), and fluoxetine (1.8%) and for men were lisinopril (2.0%), mometasone (2.0%), fexofenadine (1.8%), atorvastatin (1.6%), and montelukast (1.6%). The most reported supplements were multivitamins (63.3%, 43.5%) and fish oil (13.2%, 9.4%) for women and men, respectively, and prenatal vitamins (22.0%) for women. For women during the first 3 months of follow-up, prenatal vitamins (6.0%) and antibiotics (1.2%-2.6%) were among the most frequently started medications. During the next 3 months, clomiphene (4.5%) was the most frequently initiated medication.

Conclusions

Couples trying for pregnancy reported a variety of prescription medications and supplements, and they differed by gender. Preconception guidance should address medication and supplement use to avoid potential exposures associated with adverse reproductive and perinatal outcomes.

Objective

The aim was to characterize SLE medication trends before, during and after pregnancy and to compare other commonly used medications during SLE pregnancies with non-SLE pregnancies.

Methods

Women with pregnancies ending in live birth or stillbirth were identified from the Swedish Medical Birth Register (2006-12). National registers were used to identify women with prevalent SLE during pregnancy and a sample without SLE and to identify prescription medications dispensed from 3 months pre-pregnancy until 6 months postpartum. We reported the prevalence of DMARDs, systemic CSs and NSAIDs (aspirin reported separately) in SLE pregnancies. We calculated prevalence estimates of other medications that were dispensed during pregnancy to ⩾ 5% of SLE pregnancies and for the same medications among non-SLE pregnancies.

Results

There were 483 pregnancies among women with SLE and 5723 pregnancies among women without SLE. In SLE pregnancies, 49.3% had one or more dispensing for DMARDs during pregnancy; the prevalence was 48.0% for CSs, 40.8% for aspirin and 6.0% for other NSAIDs and varied by pregnancy period. The prevalence of common medications among SLE pregnancies was 1.2- to 20-fold higher than among non-SLE pregnancies; for example, dalteparin (20.9 vs 1.0%), paracetamol (18.2 vs 2.9%) and levothyroxine (15.9 vs 4.9%).

Conclusion

In nearly half of SLE pregnancies, women were dispensed DMARDs and CSs. Commonly used medications in SLE pregnancies had far higher prevalence estimates compared with non-SLE pregnancies. Research regarding benefits and risks of commonly used medications on SLE pregnancies, breast milk and long-term outcomes for offspring is needed.

Background

There is limited information regarding the impact of dose and gestational timing of oral corticosteroid (OCS) use on preterm birth (PTB), especially among women with asthma.

Objectives

To evaluate OCS dose and timing on PTB for asthma and, as a comparison, systemic lupus erythematosus (SLE).

Methods

We used health care data from California Medicaid enrollees linked to birth certificates (2007-2013), identifying women with asthma (n = 22,084) and SLE (n = 1174). We estimated risk ratios (RR) for OCS cumulative dose trajectories and other disease-related medications before gestational day 140 and hazard ratios (HR) for time-varying exposures after day 139.

Results

For asthma, PTB risk was 14.0% for no OCS exposure and 14.3%, 16.8%, 20.5%, and 32.7% in low, medium, medium-high, and high cumulative dose trajectory groups, respectively, during the first 139 days. The high-dose group remained associated with PTB after adjustment (adjusted RR [aRR]: 1.46; 95% confidence interval [CI]: 1.00, 2.15). OCS dose after day 139 was not clearly associated with PTB, nor were controller medications. For SLE, PTB risk for no OCS exposure was 24.9%, and it was 39.1% in low- and 61.2% in high-dose trajectory groups. aRR were 1.80 (95% CI: 1.34, 2.40) for high and 1.24 (95% CI: 0.97, 1.58) for low groups. Only prednisone equivalent dose >20 mg/day after day 139 was associated with increased PTB (adjusted HR: 2.54; 95% CI: 1.60, 4.03).

Conclusions

For asthma, higher OCS doses early in pregnancy, but not later, were associated with increased PTB. For SLE, higher doses early and later in pregnancy were associated with PTB.

Objective

To evaluate the association between subclinical and clinical chorioamnionitis and risk of preterm birth (PTB).

Methods

Demographic and clinical characteristics were abstracted from medical records and placental examinations performed (N = 1371 pregnancies including spontaneous and medically-indicated PTBs). Pregnancies were classified as having clinical chorioamnionitis (with or without histologic chorioamnionitis), subclinical chorioamnionitis (histologic, but not clinical, chorioamnionitis), or no chorioamnionitis; pregnancies with histologic chorioamnionitis were further evaluated for fetal vasculitis. Relative risks for PTB, early and late PTB, and PTB ± premature rupture of membranes (PROM) were adjusted for maternal characteristics.

Results

Clinical (4.3%) and subclinical (24.5%) chorioamnionitis were not associated with PTB overall. In pregnancies without clinical or subclinical chorioamnionitis, the risk of PTB with PROM and early PTB was 2.2% and 8.6%, respectively. In comparison, clinical chorioamnionitis was associated with an increased risk of PTB with PROM (aRR: 3.42 (95%CI: 1.07, 10.98), whereas subclinical chorioamnionitis was associated with increased risk of PTB with PROM (aRR: 3.92 (95% CI: 2.15, 7.12)) and early PTB (aRR: 1.77 (95% CI: 1.18, 2.64)). Histologic chorioamnionitis with fetal vasculitis was associated with increased risk of PTB with PROM (aRR: 7.44 (95% CI: 3.68, 15.05)) and early PTB (aRR: 2.94 (95% CI: 1.78, 4.87)), whereas histologic chorioamnionitis without fetal vasculitis was associated with increased risk of PTB with PROM only (aRR: 2.64, 95% CI: 1.27, 5.50).

Conclusions

Subclinical chorioamnionitis and histologic chorioamnionitis with fetal vasculitis were associated with early PTB and PTB with PROM but not with PTB overall, likely due to inclusion of indicated PTBs.