Faculty Bibliography

OBJECTIVE::This study aimed to evaluate the trends in cardiovascular disease (CVD)-related pregnancy-associated mortality in the United States and assess the impact of ascertainment by death certificate type using national- and state-level data. STUDY DESIGN::We conducted a cross-sectional analysis of all live births and CVD-related pregnancy-associated deaths in the United States (1999–2018) based on the National Vital Statistics System data. The primary outcome was CVD-related pregnancy-associated deaths identified using the International Classification of Diseases, Tenth Revision, codes. To account for the effect of the implementation of the 2003 revised US standard death certificate on reported pregnancy-associated mortality ratios (PMRs), we used state-level indicators at the individual level to determine how many deaths were recorded each year according to the standard US death certificate (1989 revision) vs the 2003 revised version. We examined changes in 42-day PMRs (expressed per 100,000 live births) between 1999 and 2018 by death certificate type. The trends in PMRs were quantified based on rate ratios (RRs) with 95% confidence intervals (CIs), derived from log-linear regression models with a Poisson distribution (using a “log” link function with robust variance estimation). RESULTS::Throughout the study period (1999–2018), there were 80,802,690 live births and 238 CVD-related deaths in the United States. The overall CVD-related PMR increased from 0.24 to 0.91 per 100,000 live births (adjusted RR, 3.32; 95% CI, 1.99–5.54). The overall CVD-related PMRs were 0.20 per 100,000 live births using the 1989 version and 0.38 per 100,000 live births using the 2003 version (Table). However, when we adjusted for death certificate type, there was a reduction in the overall risk between 1999 to 2000 and 2017 to 2018 (RR, 0.55; 95% CI, 0.12–2.48). Analyses stratified by CVD subtype, including pulmonary heart disease and hypertensive heart disease, are shown in the Table. CONCLUSION::In this large population-based cross-sectional analysis, we identified an increase in the CVD-related PMR in the United States from 1999 to 2018 using national data. However, in the analyses that adjusted for death certificate type, we found that the use of the 2003 revised US standard death certificate resulted in RRs that showed no difference in mortality rates throughout the study period. Despite the wide 95% CIs (highlighting imprecision in the estimates), this analysis suggests that the certificate version may be an effect modifier. We believe that the increased number of deaths captured by the 2003 revised US standard death certificate reflects a true increase in mortality rather than an artifact from misclassification. Although the study has some limitations, including its retrospective design based on data that lack specific clinical details regarding each death, this analysis suggests that the observed time trend of an increasing CVD-related PMR is not an artifact of the 2003 checkbox revision but a real trend that warrants attention.

OBJECTIVES/OBJECTIVE:To estimate the association between chronic hypertension and perinatal mortality and to evaluate the extent to which risks are impacted by preterm delivery. DESIGN/METHODS:Cross-sectional analysis. SETTING/METHODS:United States, 2015-18. POPULATION/METHODS:Singleton births (20-44 weeks of gestation). EXPOSURE/METHODS:Chronic hypertension, defined as elevated blood pressure diagnosed before pregnancy or recognised before 20 weeks of gestation. MAIN OUTCOMES AND MEASURES/METHODS:We derived the risk of perinatal mortality in relation to chronic hypertension from Poisson models, adjusted for confounders. The impacts of misclassification and unmeasured confounding were assessed. Causal mediation analysis was performed to quantify the impact of preterm delivery on the association. RESULTS: weeks may optimally balance risk in these pregnancies. Additionally, 87% (95% CI 84-90%) of perinatal deaths could be eliminated if preterm deliveries, as a result of chronic hypertension, were preventable. CONCLUSIONS:Chronic hypertension is associated with increased risk for perinatal mortality. Planned early term delivery and targeting modifiable risk factors for chronic hypertension may reduce perinatal mortality rates. TWEETABLE ABSTRACT/CONCLUSIONS:Maternal chronic hypertension is associated with increased risk for perinatal mortality, largely driven by preterm birth.

For many research questions in perinatal epidemiology, gestational age is a mediator that features the causal pathway between exposure and outcome. A mediator is an intermediate variable between an exposure and outcome, which is influenced by the exposure on the causal pathway to the outcome. Therefore, conventional analyses that adjust, stratify, or match for gestational age or its proxy (eg, preterm vs term deliveries) are problematic. This practice, which is entrenched in perinatal research, induces an overadjustment bias. Depending on the causal question, it may be inappropriate to adjust (or condition) for a mediator, such as gestational age, by either design or statistical analysis, but its effect can be quantified through causal mediation analysis. In an exposition of such methods, we demonstrated the relationship between the exposure and outcome and provided a formal analytical framework to quantify the extent to which a causal effect is influenced by a mediator. We reviewed concepts of confounding and causal inference, introduced the concept of a mediator and illustrated the perils of adjusting for a mediator in an exposure-outcome paradigm for a given causal question, adopted causal methods that call for an evaluation of a mediator in a causal exposure effect on the outcome, and discussed unmeasured confounding assumptions in mediation analysis. Furthermore, we reviewed other developments in the causal mediation analysis literature, including decomposition of a total effect when the mediator interacts with the exposure (4-way decomposition), methods for multiple mediators, mediation methods for case-control studies, mediation methods for time-to-event outcomes, sample size and power analysis for mediation analysis, and available software to apply these methods. To illustrate these methods, we provided a clinical example to estimate the risk of perinatal mortality (outcome) concerning placental abruption (exposure) and to determine the extent to which preterm delivery (mediator; a proxy for gestational age) plays a role in this causal effect. We hoped that the adoption of mediation methods described in this review will move research in perinatal epidemiology away from biased adjustments of mediators toward a more nuanced quantification of effects that pose unique challenges and provide unique insights in our field.

We urgently need answers to basic epidemiological questions regarding SARS-CoV-2 infection in pregnant and postpartum women and its effect on their newborns. While many national registries, health facilities, and research groups are collecting relevant data, we need a collaborative and methodologically rigorous approach to better combine these data and address knowledge gaps, especially those related to rare outcomes. We propose that using a sequential, prospective meta-analysis (PMA) is the best approach to generate data for policy- and practice-oriented guidelines. As the pandemic evolves, additional studies identified retrospectively by the steering committee or through living systematic reviews will be invited to participate in this PMA. Investigators can contribute to the PMA by either submitting individual patient data or running standardized code to generate aggregate data estimates. For the primary analysis, we will pool data using two-stage meta-analysis methods. The meta-analyses will be updated as additional data accrue in each contributing study and as additional studies meet study-specific time or data accrual thresholds for sharing. At the time of publication, investigators of 25 studies, including more than 76,000 pregnancies, in 41 countries had agreed to share data for this analysis. Among the included studies, 12 have a contemporaneous comparison group of pregnancies without COVID-19, and four studies include a comparison group of non-pregnant women of reproductive age with COVID-19. Protocols and updates will be maintained publicly. Results will be shared with key stakeholders, including the World Health Organization (WHO) Maternal, Newborn, Child, and Adolescent Health (MNCAH) Research Working Group. Data contributors will share results with local stakeholders. Scientific publications will be published in open-access journals on an ongoing basis.

OBJECTIVES:To examine the risks of neonatal and infant mortality in relation to infertility treatment and to quantify the extent to which preterm delivery mediates this relationship. DESIGN:Cross-sectional study. SETTING:United States, 2015-2018. PATIENT(S):A total of 14,961,207 pregnancies resulting in a singleton live birth. INTERVENTION(S):Any infertility treatment, including assisted reproductive technology and fertility-enhancing drugs. MAIN OUTCOME MEASURE(S):Neonatal (<28 days) mortality. The effect measure, risk ratio (RR), and 95% confidence interval (CI) were derived from log-linear Poisson models. A causal mediation analysis of the relationship between infertility treatment and mortality associated with preterm delivery (<37 weeks) was performed. The effects of exposure misclassification and unmeasured confounding biases were assessed. RESULT(S):Any infertility treatment was documented in 1.3% (n = 198,986) of pregnancies. Infertility treatment was associated with a 51% increased risk of neonatal mortality (RR 1.51, 95% CI 1.39-1.64), with a slightly higher risk for early neonatal mortality (RR 1.57, 95% CI 1.43-1.73) than late neonatal mortality (RR 1.33, 95% CI 1.11-1.58). These risks were similar for pregnancies conceived through assisted reproductive technology and fertility-enhancing drugs. The mediation analysis showed that 72% (95% CI 59-85) of the total effect of infertility treatment on neonatal mortality was mediated through preterm delivery. In a sensitivity analysis, following corrections for exposure misclassification and unmeasured confounding biases, these risks were higher for early, but not for late, neonatal mortality. CONCLUSION(S):Pregnancies conceived with infertility treatment are associated with increased neonatal mortality, and this association is largely mediated through preterm delivery. However, given the substantial underreporting of infertility treatment, these associations must be cautiously interpreted.

OBJECTIVE:To evaluate the association between infertility treatments and small for gestational age (SGA) births. DESIGN/METHODS:Cross-sectional study. SETTING/METHODS:United States, 2015-2019. PATIENTS/METHODS:Women (n = 16,836,228) who delivered nonmalformed, singleton live births (24-44 weeks' gestation). INTERVENTIONS/METHODS:Any infertility treatment, including assisted reproductive technology (ART) and prescribed fertility-enhancing medications. MAIN OUTCOME MEASURES/METHODS:Small for gestational age birth, defined as sex-specific birth weight <10% for gestational age. Associations between SGA and infertility treatment were derived from Poisson regression with robust variance. Risk ratios (RR) and 95% confidence intervals (CI) were derived after adjusting for confounders. In a sensitivity analysis, we corrected for nondifferential exposure misclassification and unmeasured confounding biases. RESULTS:Subsequently, 1.4% (n = 231,177) of pregnancies resulted from infertility treatments (0.8% ART and 0.6% fertility-enhancing medications). Of these, SGA births occurred in 9.4% (n = 21,771) and 11.9% (n = 1,755,925) of pregnancies conceived with infertility treatment and naturally conceived pregnancies, respectively (adjusted RR, 1.07; 95% CI, 1.06, 1.08). However, after correction for misclassification bias and unmeasured confounding, infertility treatment was associated with a 27% reduced risk of SGA (bias-corrected RR, 0.73; 95% CI, 0.53, 0.85). Similar trends were seen for analyses stratified by exposure to ART and fertility-enhancing medications, as well as for SGA <5th and <3rd percentiles. CONCLUSIONS:Exposure to infertility treatment is associated with a reduced risk of SGA births. These findings, which are contrary to some published reports, may reflect changes in the modern practice of infertility care, maternal lifestyle, and compliance with prenatal care within the infertile population. Until these findings are corroborated, the associations must be cautiously interpreted.