Metformin Use in the First Trimester of Pregnancy and Risk for Nonlive Birth and Congenital Malformations: Emulating a Target Trial Using Real-World Data.

BACKGROUND: Metformin is a first-line pharmacotherapy for type 2 diabetes, but there is limited evidence about its safety in early pregnancy. OBJECTIVE: To evaluate the teratogenicity of metformin use in the first trimester of pregnancy. DESIGN: In an observational cohort of pregnant women with pregestational type 2 diabetes receiving metformin monotherapy before the last menstrual period (LMP), a target trial with 2 treatment strategies was emulated: insulin monotherapy (discontinue metformin treatment and initiate insulin within 90 days of LMP) or insulin plus metformin (continue metformin and initiate insulin within 90 days of LMP). SETTING: U.S. Medicaid health care administration database (2000 to 2018). PARTICIPANTS: 12 489 pregnant women who met the eligibility criteria. MEASUREMENTS: The risk and risk ratio of nonlive births, live births with congenital malformations, and congenital malformations among live births were estimated using standardization to adjust for covariates. RESULTS: A total of 850 women were in the insulin monotherapy group and 1557 in the insulin plus metformin group. The estimated risk for nonlive birth was 32.7% under insulin monotherapy (reference) and 34.3% under insulin plus metformin (risk ratio, 1.02 [95% CI, 1.01 to 1.04]). The estimated risk for live birth with congenital malformations was 8.0% (CI, 5.7% to 10.2%) under insulin monotherapy and 5.7% (CI, 4.5% to 7.3%) under insulin plus metformin (risk ratio, 0.72 [CI, 0.51 to 1.09]). LIMITATION: Possible residual confounding by glycemic control and body mass index. CONCLUSION: Compared with switching to insulin monotherapy, continuing metformin and adding insulin in early pregnancy resulted in little to no increased risk for nonlive birth among women receiving metformin before pregnancy. Under conventional statistical criteria, anything between a 49% decrease and a 9% increase in risk for congenital malformations was highly compatible with our data. PRIMARY FUNDING SOURCE: National Institutes of Health.

Emulating a Target Trial of Interventions Initiated During Pregnancy with Healthcare Databases: The Example of COVID-19 Vaccination.

BACKGROUND: Observational studies are often the only option to estimate effects of interventions during pregnancy. Causal inference from observational data can be conceptualized as an attempt to emulate a hypothetical pragmatic randomized trial: the target trial. OBJECTIVE: To provide a step-by-step description of how to use healthcare databases to estimate the effects of interventions initiated during pregnancy. As an example, we describe how to specify and emulate a target trial of COVID-19 vaccination during pregnancy, but the framework can be generally applied to point and sustained strategies involving both pharmacologic and non-pharmacologic interventions. METHODS: First, we specify the protocol of a target trial to evaluate the safety and effectiveness of vaccination during pregnancy. Second, we describe how to use observational data to emulate each component of the protocol of the target trial. We propose different target trials for different gestational periods because the outcomes of interest vary by gestational age at exposure. We identify challenges that affect (i) the target trial and thus its observational emulation (censoring and competing events), and (ii) mostly the observational emulation (confounding, immortal time, and measurement biases). CONCLUSION: Some biases may be unavoidable in observational emulations, but others are avoidable. For instance, immortal time bias can be avoided by aligning the start of follow-up with the gestational age at the time of the intervention, as we would do in the target trial. Explicitly emulating target trials at different gestational ages can help reduce bias and improve the interpretability of effect estimates for interventions during pregnancy.

A prospective cohort study of preconception COVID-19 vaccination and miscarriage.

STUDY QUESTION: To what extent is preconception maternal or paternal coronavirus disease 2019 (COVID-19) vaccination associated with miscarriage incidence? SUMMARY ANSWER: COVID-19 vaccination in either partner at any time before conception is not associated with an increased rate of miscarriage. WHAT IS KNOWN ALREADY: Several observational studies have evaluated the safety of COVID-19 vaccination during pregnancy and found no association with miscarriage, though no study prospectively evaluated the risk of early miscarriage (gestational weeks [GW] <8) in relation to COVID-19 vaccination. Moreover, no study has evaluated the role of preconception vaccination in both male and female partners. STUDY DESIGN, SIZE, DURATION: An Internet-based, prospective preconception cohort study of couples residing in the USA and Canada. We analyzed data from 1815 female participants who conceived during December 2020-November 2022, including 1570 couples with data on male partner vaccination. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eligible female participants were aged 21-45 years and were trying to conceive without use of fertility treatment at enrollment. Female participants completed questionnaires at baseline, every 8 weeks until pregnancy, and during early and late pregnancy; they could also invite their male partners to complete a baseline questionnaire. We collected data on COVID-19 vaccination (brand and date of doses), history of SARS-CoV-2 infection (yes/no and date of positive test), potential confounders (demographic, reproductive, and lifestyle characteristics), and pregnancy status on all questionnaires. Vaccination status was categorized as never (0 doses before conception), ever (≥1 dose before conception), having a full primary sequence before conception, and completing the full primary sequence ≤3 months before conception. These categories were not mutually exclusive. Participants were followed up from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss to follow-up, 20 weeks' gestation), whichever occurred first. We estimated incidence rate ratios (IRRs) for miscarriage and corresponding 95% CIs using Cox proportional hazards models with GW as the time scale. We used propensity score fine stratification weights to adjust for confounding. MAIN RESULTS AND THE ROLE OF CHANCE: Among 1815 eligible female participants, 75% had received at least one dose of a COVID-19 vaccine by the time of conception. Almost one-quarter of pregnancies resulted in miscarriage, and 75% of miscarriages occurred <8 weeks' gestation. The propensity score-weighted IRR comparing female participants who received at least one dose any time before conception versus those who had not been vaccinated was 0.85 (95% CI: 0.63, 1.14). COVID-19 vaccination was not associated with increased risk of either early miscarriage (GW: <8) or late miscarriage (GW: 8-19). There was no indication of an increased risk of miscarriage associated with male partner vaccination (IRR = 0.90; 95% CI: 0.56, 1.44). LIMITATIONS, REASONS FOR CAUTION: The present study relied on self-reported vaccination status and infection history. Thus, there may be some non-differential misclassification of exposure status. While misclassification of miscarriage is also possible, the preconception cohort design and high prevalence of home pregnancy testing in this cohort reduced the potential for under-ascertainment of miscarriage. As in all observational studies, residual or unmeasured confounding is possible. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study to evaluate prospectively the relation between preconception COVID-19 vaccination in both partners and miscarriage, with more complete ascertainment of early miscarriages than earlier studies of vaccination. The findings are informative for individuals planning a pregnancy and their healthcare providers. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Health [R01-HD086742 (PI: L.A.W.); R01-HD105863S1 (PI: L.A.W. and M.L.E.)], the National Institute of Allergy and Infectious Diseases (R03-AI154544; PI: A.K.R.), and the National Science Foundation (NSF-1914792; PI: L.A.W.). The funders had no role in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. L.A.W. is a fibroid consultant for AbbVie, Inc. She also receives in-kind donations from Swiss Precision Diagnostics (Clearblue home pregnancy tests) and Kindara.com (fertility apps). M.L.E. received consulting fees from Ro, Hannah, Dadi, VSeat, and Underdog, holds stock in Ro, Hannah, Dadi, and Underdog, is a past president of SSMR, and is a board member of SMRU. K.F.H. reports being an investigator on grants to her institution from UCB and Takeda, unrelated to this study. S.H.-D. reports being an investigator on grants to her institution from Takeda, unrelated to this study, and a methods consultant for UCB and Roche for unrelated drugs. The authors report no other relationships or activities that could appear to have influenced the submitted work. TRIAL REGISTRATION NUMBER: N/A.

Misconceptions About the Direction of Bias From Nondifferential Misclassification.

Measurement error is pervasive in epidemiologic research. Epidemiologists often assume that mismeasurement of study variables is nondifferential with respect to other analytical variables and then rely on the heuristic that "nondifferential misclassification will bias estimates towards the null." However, there are many exceptions to the heuristic for which bias towards the null cannot be assumed. In this paper, we compile and characterize 7 exceptions to this rule and encourage analysts to take a more critical and nuanced approach to evaluating and discussing bias from nondifferential mismeasurement.

Emulating a target trial of the comparative effectiveness of clomiphene citrate and letrozole for ovulation induction.

STUDY QUESTION: What are the comparative pregnancy outcomes in women who receive up to six consecutive cycles of ovulation induction with letrozole versus clomiphene citrate? SUMMARY ANSWER: The risks of pregnancy, livebirth, multiple gestation, preterm birth, neonatal intensive care unit (NICU) admission and congenital malformations were higher for letrozole compared with clomiphene in participants with polycystic ovarian syndrome (PCOS), though no treatment differences were observed in those with unexplained infertility. WHAT IS KNOWN ALREADY: Randomized trials have reported higher pregnancy and livebirth rates for letrozole versus clomiphene among individuals with PCOS, but no differences among those with unexplained infertility. None of these trials were designed to study maternal or neonatal complications. STUDY DESIGN, SIZE, DURATION: We emulated a hypothetical trial of the comparative effectiveness of letrozole versus clomiphene citrate for ovulation induction among all women, then stratified by PCOS and unexplained infertility status. We used real-world data from a large healthcare claims database in the USA (2011-2015). PARTICIPANTS/MATERIALS, SETTING, METHODS: We analyzed data from 18 120 women who initiated letrozole and 49 647 women who initiated clomiphene during 2011-2014, and who were aged 18-45 years with no history of diabetes, thyroid disease, liver disease or breast cancer and had no fertility treatments for 3 months before trial initiation. The treatment strategies were clomiphene citrate or letrozole for six consecutive cycles. The outcomes were pregnancy, livebirth, multiple gestation, preterm birth, small for gestational age (SGA), NICU admission and major congenital malformations. We estimated the probability of each outcome under each strategy via pooled logistic regression and used standardization to adjust for confounding and selection bias due to loss to follow-up. MAIN RESULTS AND THE ROLE OF CHANCE: The estimated probabilities of pregnancy, livebirth and neonatal outcomes were similar under each strategy, both overall and among individuals with unexplained infertility. Among women with PCOS, the probability of pregnancy was 43% for letrozole vs 37% for clomiphene (risk difference [RD] = 6.0%; 95% CI: 4.4, 7.7) in the intention-to-treat analyses. The corresponding probability of livebirth was 32% vs 29% (RD = 3.1%; 95% CI: 1.5, 4.8). In per protocol analyses, the risk of multiple gestation was 19% vs 9%, the risk of preterm birth was 20% vs 15%, the risk of SGA was 5% vs 3%, the risk of NICU admission was 22% vs 16% and the risk of congenital malformation was 8% vs 2% among those with a livebirth. LIMITATIONS, REASONS FOR CAUTION: We cannot completely rule out the possibility of residual confounding by body mass index or duration of infertility. However, we adjusted for proxies identified in administrative data and results did not change. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that for women with unexplained infertility, the two treatments result in comparable probabilities of a livebirth. For women with PCOS, letrozole appears slightly more effective for attaining a livebirth. Neonatal outcomes were similar for the two treatments among women with unexplained infertility; we did not confirm the hypothesized higher risk of adverse neonatal outcomes for clomiphene versus letrozole. The risks of adverse neonatal outcomes were slightly greater among women with PCOS who were treated with letrozole versus clomiphene. It is likely that these effects are partially mediated through an increased risk of multiple gestation among women who received letrozole. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institute of Child Health and Human Development (R01HD088393). Y.-H.C. reports grants from the American Heart Association (834106) and NIH (R01HD097778). P.R. reports grants from the National Institutes of Health. J.H. reports grants from the National Institutes of Health, the Agency for Healthcare Research and Quality, and the California Health Care Foundation during the conduct of the study; and consulting for several health care delivery organizations including Cambridge Health Alliance, Columbia University, University of Southern California, Community Servings, and the Delta Health Alliance. S.H.-D. reports grants from the National Institutes of Health and the US Food and Drug Administration during the conduct of the study; grants to her institution from Takeda outside the submitted work; consulting for UCB (biopharmaceutical company) and Roche; and being an adviser for the Antipsychotics Pregnancy Registry and epidemiologist for the North American Antiepileptics Pregnancy Registry, both at Massachusetts General Hospital. M.A.H. reports grants from the National Institutes of Health and the U.S. Veterans Administration during the conduct of the study; being a consultant for Cytel; and being an adviser for ProPublica. TRIAL REGISTRATION NUMBER: N/A.

Predictive models of pregnancy based on data from a preconception cohort study.

STUDY QUESTION: Can we derive adequate models to predict the probability of conception among couples actively trying to conceive? SUMMARY ANSWER: Leveraging data collected from female participants in a North American preconception cohort study, we developed models to predict pregnancy with performance of ∼70% in the area under the receiver operating characteristic curve (AUC). WHAT IS KNOWN ALREADY: Earlier work has focused primarily on identifying individual risk factors for infertility. Several predictive models have been developed in subfertile populations, with relatively low discrimination (AUC: 59-64%). STUDY DESIGN, SIZE, DURATION: Study participants were female, aged 21-45 years, residents of the USA or Canada, not using fertility treatment, and actively trying to conceive at enrollment (2013-2019). Participants completed a baseline questionnaire at enrollment and follow-up questionnaires every 2 months for up to 12 months or until conception. We used data from 4133 participants with no more than one menstrual cycle of pregnancy attempt at study entry. PARTICIPANTS/MATERIALS, SETTING, METHODS: On the baseline questionnaire, participants reported data on sociodemographic factors, lifestyle and behavioral factors, diet quality, medical history and selected male partner characteristics. A total of 163 predictors were considered in this study. We implemented regularized logistic regression, support vector machines, neural networks and gradient boosted decision trees to derive models predicting the probability of pregnancy: (i) within fewer than 12 menstrual cycles of pregnancy attempt time (Model I), and (ii) within 6 menstrual cycles of pregnancy attempt time (Model II). Cox models were used to predict the probability of pregnancy within each menstrual cycle for up to 12 cycles of follow-up (Model III). We assessed model performance using the AUC and the weighted-F1 score for Models I and II, and the concordance index for Model III. MAIN RESULTS AND THE ROLE OF CHANCE: Model I and II AUCs were 70% and 66%, respectively, in parsimonious models, and the concordance index for Model III was 63%. The predictors that were positively associated with pregnancy in all models were: having previously breastfed an infant and using multivitamins or folic acid supplements. The predictors that were inversely associated with pregnancy in all models were: female age, female BMI and history of infertility. Among nulligravid women with no history of infertility, the most important predictors were: female age, female BMI, male BMI, use of a fertility app, attempt time at study entry and perceived stress. LIMITATIONS, REASONS FOR CAUTION: Reliance on self-reported predictor data could have introduced misclassification, which would likely be non-differential with respect to the pregnancy outcome given the prospective design. In addition, we cannot be certain that all relevant predictor variables were considered. Finally, though we validated the models using split-sample replication techniques, we did not conduct an external validation study. WIDER IMPLICATIONS OF THE FINDINGS: Given a wide range of predictor data, machine learning algorithms can be leveraged to analyze epidemiologic data and predict the probability of conception with discrimination that exceeds earlier work. STUDY FUNDING/COMPETING INTEREST(S): The research was partially supported by the U.S. National Science Foundation (under grants DMS-1664644, CNS-1645681 and IIS-1914792) and the National Institutes for Health (under grants R01 GM135930 and UL54 TR004130). In the last 3 years, L.A.W. has received in-kind donations for primary data collection in PRESTO from FertilityFriend.com, Kindara.com, Sandstone Diagnostics and Swiss Precision Diagnostics. L.A.W. also serves as a fibroid consultant to AbbVie, Inc. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Predictive models of miscarriage on the basis of data from a preconception cohort study.

OBJECTIVE: To use self-reported preconception data to derive models that predict the risk of miscarriage. DESIGN: Prospective preconception cohort study. SETTING: Not applicable. PATIENTS: Study participants were female, aged 21-45 years, residents of the United States or Canada, and attempting spontaneous pregnancy at enrollment during 2013-2022. Participants were followed for up to 12 months of pregnancy attempts; those who conceived were followed through pregnancy and postpartum. We restricted analyses to participants who conceived during the study period. EXPOSURE: On baseline and follow-up questionnaires completed every 8 weeks until pregnancy, we collected self-reported data on sociodemographic factors, reproductive history, lifestyle, anthropometrics, diet, medical history, and male partner characteristics. We included 160 potential predictor variables in our models. MAIN OUTCOME MEASURES: The primary outcome was a miscarriage, defined as pregnancy loss before 20 weeks of gestation. We followed participants from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss of follow-up, or 20 weeks of gestation), whichever occurred first. We fit both survival and static models using Cox proportional hazards models, logistic regression, support vector machines, gradient-boosted trees, and random forest algorithms. We evaluated model performance using the concordance index (survival models) and the weighted F1 score (static models). RESULTS: Among the 8,720 participants who conceived, 20.4% reported miscarriage. In multivariable models, the strongest predictors of miscarriage were female age, history of miscarriage, and male partner age. The weighted F1 score ranged from 73%-89% for static models and the concordance index ranged from 53%-56% for survival models, indicating better discrimination for the static models compared with the survival models (i.e., the ability of the model to discriminate between individuals with and without miscarriage). No appreciable differences were observed across strata of miscarriage history or among models restricted to ≥8 weeks of gestation. CONCLUSION: Our findings suggest that miscarriage is not easily predicted on the basis of preconception lifestyle characteristics and that advancing age and a history of miscarriage are the most important predictors of incident miscarriage.

Perinatal Outcomes Associated With Metformin Use During Pregnancy in Women With Pregestational Type 2 Diabetes Mellitus.

OBJECTIVE: We emulated a modified randomized trial (Metformin in Women With Type 2 Diabetes in Pregnancy [MiTy]) to compare the perinatal outcomes in women continuing versus discontinuing metformin during pregnancy among those with type 2 diabetes treated with metformin plus insulin before pregnancy. RESEARCH DESIGN AND METHODS: This study used two health care claims databases (U.S., 2000-2020). Pregnant women age 18-45 years with type 2 diabetes who were treated with metformin plus insulin at conception were eligible. The primary outcome was a composite of preterm birth, birth injury, neonatal respiratory distress, neonatal hypoglycemia, and neonatal intensive care unit admission. Secondary outcomes included the components of the primary composite outcome, gestational hypertension, preeclampsia, maternal hypoglycemia, cesarean delivery, infants large for gestational age, infants small for gestational age (SGA), sepsis, and hyperbilirubinemia. We adjusted for potential baseline confounders, including demographic characteristics, comorbidities, and proxies for diabetes progression. RESULTS: Of 2,983 eligible patients, 72% discontinued use of metformin during pregnancy. The average age at conception was 32 years, and the prevalence of several comorbidities was higher among continuers. The risk of the composite outcome was 46% for continuers and 48% for discontinuers. The adjusted risk ratio was 0.92 (95% CI 0.81, 1.03). Risks were similar between treatments and consistent between databases for most secondary outcomes, except for SGA, which was elevated in continuers only in the commercially insured population. CONCLUSIONS: Our findings were consistent with those reported in the MiTy randomized trial. Continuing metformin during pregnancy was not associated with increased risk of a neonatal composite adverse outcome. However, a possible metformin-associated risk of SGA warrants further consideration.

Risk of Miscarriage in Relation to Seasonal Influenza Vaccination Before or During Pregnancy.

OBJECTIVE: To evaluate the association between seasonal influenza vaccination and miscarriage using data from an ongoing, prospective cohort study. METHODS: We analyzed 2013-2022 data from PRESTO (Pregnancy Study Online), a prospective prepregnancy cohort study of female pregnancy planners and their male partners in the United States and Canada. Female participants completed a baseline questionnaire and then follow-up questionnaires every 8 weeks until pregnancy, during early and late pregnancy, and during the postpartum period. Vaccine information was self-reported on all questionnaires. Miscarriage was identified from self-reported information during follow-up. Male partners were invited to complete a baseline questionnaire only. We used Cox proportional hazard models to estimate the hazard ratio (HR) and 95% CI for the association between vaccination less than 3 months before pregnancy detection through the 19th week of pregnancy and miscarriage, with gestational weeks as the time scale. We modeled vaccination as a time-varying exposure and used propensity-score fine stratification to control for confounding from seasonal and female partner factors. RESULTS: Of 6,946 pregnancies, 23.3% of female partners reported exposure to influenza vaccine before or during pregnancy: 3.2% during pregnancy (gestational age 4-19 weeks) and 20.1% during the 3 months before pregnancy detection. The miscarriage rate was 16.2% in unvaccinated and 17.0% among vaccinated participants. Compared with no vaccine exposure, influenza vaccination was not associated with increased rate of miscarriage when administered before (HR 0.99, 95% CI 0.81-1.20) or during (HR 0.83, 95% CI 0.47-1.47) pregnancy. Of the 1,135 couples with male partner vaccination data available, 10.8% reported vaccination less than 3 months before pregnancy. The HR for the association between male partner vaccination and miscarriage was 1.17 (95% CI 0.73-1.90). CONCLUSION: Influenza vaccination before or during pregnancy was not associated with miscarriage.

Preconception contraceptive use and miscarriage: prospective cohort study.

Objectives: To evaluate the association between preconception contraceptive use and miscarriage. Design: Prospective cohort study. Setting: Residents of the United States of America or Canada, recruited from 2013 until the end of 2022. Participants: 13 460 female identified participants aged 21-45 years who were planning a pregnancy were included, of whom 8899 conceived. Participants reported data for contraceptive history, early pregnancy, miscarriage, and potential confounders during preconception and pregnancy. Main outcome measure: Miscarriage, defined as pregnancy loss before 20 weeks of gestation. Results: Preconception use of combined and progestin-only oral contraceptives, hormonal intrauterine devices, copper intrauterine devices, rings, implants, or natural methods was not associated with miscarriage compared with use of barrier methods. Participants who most recently used patch (incidence rate ratios 1.34 (95% confidence interval 0.81 to 2.21)) or injectable contraceptives (1.44 (0.99 to 2.12)) had higher rates of miscarriage compared with recent users of barrier methods, although results were imprecise due to the small numbers of participants who used patch and injectable contraceptives. Conclusions: Use of most contraceptives before conception was not appreciably associated with miscarriage rate. Individuals who used patch and injectable contraceptives had higher rates of miscarriage relative to users of barrier methods, although these results were imprecise and residual confounding was possible.

COVID-19 vaccination and menstrual cycle characteristics: A prospective cohort study.

We prospectively examined the association between COVID-19 vaccination and menstrual cycle characteristics in an internet-based prospective cohort study. We included a sample of 1,137 participants who enrolled in Pregnancy Study Online (PRESTO), a preconception cohort study of couples trying to conceive, during January 2021-August 2022. Eligible participants were aged 21-45 years, United States or Canadian residents, and trying to conceive without fertility treatment. At baseline and every 8 weeks for up to 12 months, participants completed questionnaires on which they provided information on COVID-19 vaccination and menstrual cycle characteristics, including cycle regularity, cycle length, bleed length, heaviness of bleed, and menstrual pain. We fit generalized estimating equation (GEE) models with a log link function and Poisson distribution to estimate the adjusted risk ratio (RR) for irregular cycles associated with COVID-19 vaccination. We used linear regression with GEE to estimate adjusted mean differences in menstrual cycle length associated with COVID-19 vaccination. We adjusted for sociodemographic, lifestyle, medical and reproductive factors. Participants had 1.1 day longer menstrual cycles after receiving the first dose of COVID-19 vaccine (95 % CI: 0.4, 1.9) and 1.3 day longer cycles after receiving the second dose (95 % CI: 0.2, 2.5). Associations were attenuated at the second cycle post-vaccination. We did not observe strong associations between COVID-19 vaccination and cycle regularity, bleed length, heaviness of bleed, or menstrual pain. In conclusion, COVID-19 vaccination was associated with a ∼1 day temporary increase in menstrual cycle length, but was not appreciably associated with other menstrual cycle characteristics.

The association between time-to-pregnancy and postpartum depressive symptoms in a North American prospective cohort study.

PURPOSE: To prospectively examine the association between time-to-pregnancy (TTP) and postpartum depression (PPD) and determine whether perceived stress during early pregnancy mediated this association. METHODS: In Pregnancy Study Online, an internet-based preconception cohort study of pregnancy planners, participants completed questionnaires every 8 weeks for up to 12 months or conception, during pregnancy, and at postpartum. A total of 2643 women provided information on sociodemographic factors, reproductive history, and stress (i.e., Perceived Stress Scale [PSS]) during preconception and early pregnancy (completed at ∼4-12 weeks' gestation) and on postpartum depressive symptoms (i.e., Edinburgh Postnatal Depression Scale [EPDS]) at ∼6 months postpartum. We used multivariable modified Poisson regression models to estimate risk ratios and 95% confidence intervals (CIs) for the association between TTP (<3, 3-5, 6-11, ≥12 menstrual cycles) and PPD (EPDS score ≥13). Causal mediation analyses assessed the mediating role of early pregnancy PSS scores. RESULTS: 10.6% of women had EPDS scores indicating possible PPD (≥13). Compared with women who took less than 3 cycles to conceive, risk ratios for those who took 3-5, 6-11, and greater than or equal to 12 were 1.06 (95% CI: 0.77, 1.45), 1.24 (95% CI: 0.90, 1.70), and 1.31 (95% CI: 0.87, 1.99), respectively. Approximately 30% of the association between infertility (TTP ≥ 12) and PPD was mediated by early pregnancy PSS. CONCLUSIONS: There was a modest positive dose-response association between delayed conception and PPD. Perceived stress in early pregnancy explained a small proportion of this association. However, given the width of the CIs, chance cannot be ruled out as an explanation for the observed association.

A Prospective Study of Male Depression, Psychotropic Medication Use, and Fecundability.

We examined the associations of male depression and psychotropic medication use with fecundability in a North American preconception cohort study (2013-2020). Men aged ≥21 years completed a baseline questionnaire with questions on history of diagnosed depression, the Major Depression Inventory (MDI), and psychotropic medication use. Pregnancy status was updated via bimonthly female follow-up questionnaires until pregnancy or 12 menstrual cycles, whichever occurred first. Analyses were restricted to 2,398 couples attempting conception for ≤6 menstrual cycles at entry. We fit proportional probabilities models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs), adjusting for age (male and female), education, (male and female), race/ethnicity, physical activity, alcohol intake, body mass index, smoking, and having previously impregnated a partner. Nearly 12% of participants reported a depression diagnosis; 90.6% had low depressive symptoms (MDI <20), 3.5% had mild symptoms (MDI: 20-24), 2.7% had moderate symptoms (MDI: 25-29), and 3.3% had severe symptoms (MDI: ≥30). A total of 8.8% of participants reported current use of psychotropic medications. History of depression was associated with slightly reduced fecundability, although this result was also reasonably compatible with chance (FR = 0.89; 95% CI: [0.76, 1.04]). FRs for mild, moderate, and severe compared with low depressive symptoms were 0.89 (95% CI: [0.66, 1.21]), 0.90 (95% CI: [0.62, 1.31]), and 0.88 (95% CI: [0.65, 1.20]), respectively. This indicates little evidence of a dose-response relationship for depressive symptoms with fecundability, although estimates were imprecise. Current psychotropic medication use mediated 44% of the association between depressive symptoms and fecundability.

Phthalate and DINCH urinary concentrations across pregnancy and risk of preterm birth.

Preconception and prenatal exposure to phthalates has been associated with an increased risk of preterm birth. However, it is unclear whether there are periods of heightened susceptibility during pregnancy. This prospective cohort study included 386 women undergoing fertility treatment who gave birth to a singleton infant during 2005 through 2018. Eleven phthalate metabolites were measured in spot urine samples collected at each trimester. In approximately 50% of participants, two metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), a phthalate substitute, were also measured. The molar sum of four di(2-ethylhexyl) phthalate metabolites (∑DEHP) was calculated. We evaluated the associations of mean maternal biomarker concentrations with risk of preterm birth using modified log-binomial models and utilized multiple informant models to compare trimester-specific associations. We examined the relative biomarker concentration across gestation comparing women with preterm birth to women with term delivery using quadratic mixed model. The risk ratio for preterm birth associated with a one-unit increase in the natural log-transformed urinary concentrations of ∑DEHP (mean during pregnancy) was 1.21 (95% confidence interval (CI): 0.84, 1.72). In multiple informant models, these associations were strongest in the third trimester (RR = 1.51; 95% CI: 1.17, 1.95). Estimated mean ∑DEHP concentrations were higher among women with preterm than term delivery, especially late in gestation. Associations with preterm birth were also observed for each of the four individual DEHP metabolites. Detection of cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), a metabolite of DINCH, appeared to be positively related to preterm birth. In this prospective cohort of subfertile couples, maternal ∑DEHP metabolite concentrations during pregnancy were associated with an increased risk of preterm birth, particularly during late gestation.

Effectiveness and safety of intrauterine insemination vs. assisted reproductive technology: emulating a target trial using an observational database of administrative claims.

OBJECTIVE: To compare the effectiveness and safety of 1 cycle of assisted reproductive technology (ART) vs. 3 cycles of intrauterine insemination (IUI). DESIGN: Target trial emulation using observational data. SETTING: A healthcare claims database (2011-2015). PATIENT(S): The patients were 29,021 women aged 18-45 years with an infertility diagnosis and no history of IUI or ART within the past 12 months. INTERVENTION(S): One ART cycle immediately, with no more cycles of ART or IUI within the next 4 months; or 1 IUI cycle immediately, with 2 additional consecutive cycles of IUI within the next 4 months unless pregnancy occurred. MAIN OUTCOME MEASURE(S): Live births, multiple births, congenital malformations, preterm births, small-for-gestational-age newborns, large-for-gestational-age newborns, admission to neonatal intensive care unit (NICU), gestational diabetes, preeclampsia, and gestational hypertension. RESULT(S): The probability of live birth was 27.3% for ART and 26.3% for IUI. The observational analogue of per-protocol risk difference (95% confidence interval) for ART compared with IUI was 1.0% (-0.1%, 2.2%) for live births, 4.3% (3.7%, 4.9%) for multiple births, 3.4% (2.8%, 4.0%) for preterm births, 1.5% (0.9%, 2.1%) for NICU admissions, and 0.6% (0.2%, 1.0%) for gestational diabetes. The risk differences for the other outcomes were <0.5%. The results of the 2 strategies were similar in women ≤40 years, but in women >40 years the probability of live birth was greater for ART (14.4%) than for IUI (7.4%). CONCLUSION(S): Compared with 3 cycles of IUI, 1 cycle of ART was estimated to have a similar probability of live birth but slightly higher risks of multiple gestations, preterm births, and NICU admissions.

A prospective study of preconception asthma and spontaneous abortion.

PURPOSE: To evaluate the relationships among history of asthma, asthma severity, and spontaneous abortion (SAB). METHODS: Pregnancy Study Online is a preconception cohort study of North American couples. During the preconception period, female participants reported their history of physician-diagnosed asthma, age at first diagnosis, and use of asthma medications in the previous 4 weeks. Asthma severity was classified by medication use proximal to conception, from level 0 to 3 in increasing severity. Pregnancy and SAB were identified using data from follow-up questionnaires. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 6325 participants who conceived, 19% experienced SAB and 17% reported a history of asthma. There was no appreciable association between asthma history and SAB incidence (HR = 0.98; 95% CI: 0.84, 1.14). HRs comparing severity levels 0, 1, and 2-3 with no asthma were 0.82 (95% CI: 0.67, 1.01), 1.20 (95% CI: 0.91, 1.60), and 1.31 (95% CI: 0.97, 1.78), respectively. Among women who conceived without the use of fertility treatment, level 2-3 severity was associated with SAB (HR = 1.39; 95% CI: 1.02, 1.89). CONCLUSIONS: While history of asthma diagnosis was not materially associated with SAB, having severe asthma (based on medication use) was associated with greater SAB risk.

A North American prospective study of depression, psychotropic medication use, and semen quality.

OBJECTIVE: To evaluate the associations of a history of diagnosed depression, current depressive symptoms, and recent use of psychotropic medications with semen quality and to consider mediation of the association between depression and semen quality by medication use. DESIGN: Prospective cohort study. SETTING: United States. PATIENT(S): The patients were 329 men aged ≥21 years (566 semen samples) who participated in a semen-testing substudy of Pregnancy Study Online. Pregnancy Study Online is an ongoing, web-based preconception cohort study of couples attempting to conceive. At baseline, participants reported information about depression diagnosis, depressive symptoms using the Major Depression Inventory, medication use in the last 4 weeks, and selected covariates. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The men used an at-home semen-testing kit (Trak; Sandstone Diagnostics, Inc., Pleasanton, California) to measure semen volume, sperm concentration, and motile sperm concentration. We calculated percent motility, total sperm count in the ejaculate, and total motile sperm count. RESULT(S): Forty-nine men (15%) reported a history of depression diagnosis, and 41 (12%) reported recent use of psychotropic medications. A history of depression diagnosis was associated with a 4.3-fold increase in the risk of low semen volume (<1.5 mL) (95% CI 1.16, 16). A 5-unit increase in Major Depression Inventory score was associated with a 1.38-fold increase in the risk of low semen volume (95% CI 0.92, 2.1). The results for other semen parameters were inconsistent. Recent use of psychotropic medications was associated with worse semen quality, and this association was confounded by a history of depression diagnosis. The observed association between depression and semen volume showed little mediation by psychotropic medication use. CONCLUSION: A history of diagnosed depression and severe depressive symptoms at enrollment were associated with low semen volume.

Perinatal Outcomes Associated with Maternal Asthma and Its Severity and Control During Pregnancy.

BACKGROUND: Estimates of the effects of maternal asthma on pregnancy outcomes are inconsistent across studies, possibly because of differences in exposure definition. OBJECTIVE: To evaluate the risk of adverse perinatal outcomes associated with maternal asthma diagnosis, severity, and control in a large, nationally representative cohort. METHODS: This study was conducted within the IBM Health MarketScan Commercial Claims and Encounters Database (2011-2015) and the Medicaid Analytic eXtract database (2000-2014). Asthma was identified by diagnosis and treatment codes, severity was based on medications dispensed, and control was based on short-acting ß-agonist dispensations and exacerbations. We estimated the relative risks (RRs) of stillbirth, spontaneous abortion, preterm birth, small for gestational age (SGA), neonatal intensive care unit (NICU) admission, and congenital malformations, comparing pregnancies with differing asthma disease status. RESULTS: We identified 29,882 pregnancies complicated by asthma in the MarketScan database and 160,638 in the Medicaid Analytic eXtract database. We observed no consistent associations between asthma diagnosis, severity, or control, and stillbirth, abortions, or malformations. However, we observed increased risks of prematurity, SGA, and NICU admission among women with asthma compared with those without asthma. Compared with women with well-controlled asthma, women with poor control late in pregnancy had an increased risk of preterm birth (relative risk, 1.39; 95% CI, 1.32-1.46) and NICU admission (relative risk, 1.26; 95% CI, 1.17-1.35). More severe asthma was associated with SGA (relative risk, 1.18; 95% CI, 1.07-1.30). CONCLUSIONS: We did not observe an increased risk of pregnancy losses or malformations among women with asthma. However, we found an association between asthma severity and SGA, and between exacerbations late in pregnancy and preterm delivery and NICU admission.