Infertility treatment is associated with increased risk of postpartum hospitalization due to heart disease.

BACKGROUND: Cardiovascular disease is a major cause of maternal mortality, but the extent to which infertility treatment is implicated in heart disease remains unclear. OBJECTIVE: To evaluate the association between infertility treatment and postpartum heart disease. METHODS: We designed a retrospective cohort study of patients who delivered in the United States between 2010 and 2018. The primary outcome was hospitalization within 12-month post-delivery due to heart disease (including ischemic heart disease, atherosclerotic heart disease, cardiomyopathy, hypertensive disease, heart failure, and cardiac dysrhythmias). We estimated the rate difference (RD) of hospitalizations among patients who conceived with infertility treatment and those who conceived spontaneously. Associations were expressed as hazard ratios (HRs) and 95% confidence intervals (CIs), derived from Cox proportional hazards regression after adjustment for potential confounders. RESULTS: Infertility treatment was recorded in 0.9% (n = 287,813) of 31,339,991 deliveries. Rates of heart disease hospitalizations with infertility treatment and with spontaneous conception were 550 and 355 per 100,000, respectively (RD 195, 95% CI: 143-247; adjusted HR 1.99, 95% CI: 1.80-2.20). The most important increase in risk was observed for hypertensive disease (adjusted HR 2.16, 95% CI: 1.92-2.42). This increased risk was apparent as early as 30-day post-delivery (HR 1.61, 95% CI: 1.39-1.86), with progressively increasing risk up to a year. CONCLUSIONS: Although the absolute risk of postpartum heart disease hospitalization is low, infertility treatment is associated with an increased risk, especially for hypertensive disease. These findings highlight the importance of timely postpartum follow-ups in patients who received infertility treatment.

Maternal mortality in the United States: are the high and rising rates due to changes in obstetrical factors, maternal medical conditions, or maternal mortality surveillance?

BACKGROUND: National Vital Statistics System reports show that maternal mortality rates in the United States have nearly doubled, from 17.4 in 2018 to 32.9 per 100,000 live births in 2021. However, these high and rising rates could reflect issues unrelated to obstetrical factors, such as changes in maternal medical conditions or maternal mortality surveillance (eg, due to introduction of the pregnancy checkbox). OBJECTIVE: This study aimed to assess if the high and rising rates of maternal mortality in the United States reflect changes in obstetrical factors, maternal medical conditions, or maternal mortality surveillance. STUDY DESIGN: The study was based on all deaths in the United States from 1999 to 2021. Maternal deaths were identified using the following 2 approaches: (1) per National Vital Statistics System methodology, as deaths in pregnancy or in the postpartum period, including deaths identified solely because of a positive pregnancy checkbox, and (2) under an alternative formulation, as deaths in pregnancy or in the postpartum period, with at least 1 mention of pregnancy among the multiple causes of death on the death certificate. The frequencies of major cause-of-death categories among deaths of female patients aged 15 to 44 years, maternal deaths, deaths due to obstetrical causes (ie, direct obstetrical deaths), and deaths due to maternal medical conditions aggravated by pregnancy or its management (ie, indirect obstetrical deaths) were quantified. RESULTS: Maternal deaths, per National Vital Statistics System methodology, increased by 144% (95% confidence interval, 130-159) from 9.65 in 1999-2002 (n=1550) to 23.6 per 100,000 live births in 2018-2021 (n=3489), with increases occurring among all race and ethnicity groups. Direct obstetrical deaths increased from 8.41 in 1999-2002 to 14.1 per 100,000 live births in 2018-2021, whereas indirect obstetrical deaths increased from 1.24 to 9.41 per 100,000 live births: 38% of direct obstetrical deaths and 87% of indirect obstetrical deaths in 2018-2021 were identified because of a positive pregnancy checkbox. The pregnancy checkbox was associated with increases in less specific and incidental causes of death. For example, maternal deaths with malignant neoplasms listed as a multiple cause of death increased 46-fold from 0.03 in 1999-2002 to 1.42 per 100,000 live births in 2018-2021. Under the alternative formulation, the maternal mortality rate was 10.2 in 1999-2002 and 10.4 per 100,000 live births in 2018-2021; deaths from direct obstetrical causes decreased from 7.05 to 5.82 per 100,000 live births. Deaths due to preeclampsia, eclampsia, postpartum hemorrhage, puerperal sepsis, venous complications, and embolism decreased, whereas deaths due to adherent placenta, renal and unspecified causes, cardiomyopathy, and preexisting hypertension increased. Maternal mortality increased among non-Hispanic White women and decreased among non-Hispanic Black and Hispanic women. However, rates were disproportionately higher among non-Hispanic Black women, with large disparities evident in several causes of death (eg, cardiomyopathy). CONCLUSION: The high and rising rates of maternal mortality in the United States are a consequence of changes in maternal mortality surveillance, with reliance on the pregnancy checkbox leading to an increase in misclassified maternal deaths. Identifying maternal deaths by requiring mention of pregnancy among the multiple causes of death shows lower, stable maternal mortality rates and declines in maternal deaths from direct obstetrical causes.

Pregnancy-associated mortality due to cardiovascular disease: Impact of hypertensive disorders of pregnancy.

BACKGROUND: Reported rates of maternal mortality in the United States have been staggeringly high and increasing, and cardiovascular disease (CVD) is a chief contributor to such deaths. However, the impact of hypertensive disorders of pregnancy (HDP) on the short-term risk of cardiovascular death is not well understood. OBJECTIVES: To evaluate the association between HDP (chronic hypertension, gestational hypertension, preeclampsia, eclampsia, and superimposed preeclampsia) and pregnancy-associated mortality rates (PMR) from all causes, CVD-related causes both at delivery and within 1 year following delivery. METHODS: We used the Nationwide Readmissions Database (2010-2018) to examine PMRs for females 15-54 years old. International Classification of Disease 9 and 10 diagnosis codes were used to identify pregnancy-associated deaths due to HDP and CVD. Discrete-time Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for mortality at delivery (0 days) and at <30, <60, <90, <180, and <365 days after delivery in relation to HDP. RESULTS: Of 33,417,736 hospital deliveries, the rate of HDP was 11.0% (n = 3,688,967), and the PMR from CVD was 6.4 per 100,000 delivery hospitalisations (n = 2141). Compared with normotensive patients, HRs for CVD-related PMRs increased with HDP severity, reaching over 58-fold for eclampsia patients. HRs were higher for stroke-related (1.2 to 170.9) than heart disease (HD)-related (0.99 to 39.8) mortality across all HDPs. Except for gestational hypertension, the increased risks of CVD mortality were evident at delivery and persisted 1 year postpartum for all HDPs. CONCLUSIONS: HDPs are strong risk factors for pregnancy-associated mortality due to CVD at delivery and within 1 year postpartum; the risks are stronger for stroke than HD-related PMR. While absolute PMRs are low, this study supports the importance of extending postpartum care beyond the traditional 42-day postpartum visit for people whose pregnancies are complicated by hypertension.

Temporal changes in pre-existing health conditions five years prior to pregnancy in British Columbia, Canada, 2000-2019.

BACKGROUND: Pre-existing health conditions increase the risk of obstetric complications during pregnancy and birth. However, the prevalence and recent changes in the frequency of pre-existing health conditions in the childbearing population remain unknown. OBJECTIVES: To estimate the temporal changes in the prevalence of pre-existing health conditions among pregnant women in British Columbia, Canada. METHODS: We carried out a population-based cross-sectional study of 825,203 deliveries in BC between 2000 and 2019 and examined 17 categories of physical and psychiatric health conditions recorded within 5 years before childbirth. We also undertook age-period-cohort analyses to evaluate temporal changes in pre-existing health conditions. RESULTS: The prevalence of any pre-existing health condition was 26.2% (n = 216,214) with overall trends remaining stable during the study period. Between 2000 and 2019, the prevalence rates of anxiety (5.6%-9.6%), bipolar (1.6%-3.4%), psychosis (0.7%-0.8%), and eating disorders (0.2%-0.3%) increased. The prevalence of hypertension increased sharply from 0.06% in 2000 to 0.3% in 2019. Diabetes mellitus and stroke rates increased, as did the prevalence of systemic lupus, multiple sclerosis, and chronic kidney disease. Advanced maternal age was strongly associated with both psychiatric and circulatory/metabolic conditions. A strong birth cohort effect was evident, with rates of psychiatric conditions increasing among women born after 1985. CONCLUSIONS: In British Columbia, Canada, 1 in 4 mothers had a pre-existing health condition 5 years prior to pregnancy. These findings underscore the need for multi-disciplinary care for women with pre-existing health conditions to improve maternal, foetal, and infant health.

Placental Abruption and Cardiovascular Event Risk (PACER): Design, data linkage, and preliminary findings.

BACKGROUND: Obstetrical complications impact the health of mothers and offspring along the life course, resulting in an increased burden of chronic diseases. One specific complication is abruption, a life-threatening condition with consequences for cardiovascular health that remains poorly studied. OBJECTIVES: To describe the design and data linkage algorithms for the Placental Abruption and Cardiovascular Event Risk (PACER) cohort. POPULATION: All subjects who delivered in New Jersey, USA, between 1993 and 2020. DESIGN: Retrospective, population-based, birth cohort study. METHODS: We linked the vital records data of foetal deaths and live births to delivery and all subsequent hospitalisations along the life course for birthing persons and newborns. The linkage was based on a probabilistic record-matching algorithm. PRELIMINARY RESULTS: Over the 28 years of follow-up, we identified 1,877,824 birthing persons with 3,093,241 deliveries (1.1%, n = 33,058 abruption prevalence). The linkage rates for live births-hospitalisations and foetal deaths-hospitalisations were 92.4% (n = 2,842,012) and 70.7% (n = 13,796), respectively, for the maternal cohort. The corresponding linkage rate for the live births-hospitalisations for the offspring cohort was 70.3% (n = 2,160,736). The median (interquartile range) follow-up for the maternal and offspring cohorts was 15.4 (8.1, 22.4) and 14.4 (7.4, 21.0) years, respectively. We will undertake multiple imputations for missing data and develop inverse probability weights to account for selection bias owing to unlinked records. CONCLUSIONS: Pregnancy offers a unique window to study chronic diseases along the life course and efforts to identify the aetiology of abruption may provide important insights into the causes of future CVD. This project presents an unprecedented opportunity to understand how abruption may predispose women and their offspring to develop CVD complications and chronic conditions later in life.

Changes in the prevalence of maternal chronic conditions during pregnancy: A nationwide age-period-cohort analysis.

OBJECTIVE: To estimate temporal changes in the prevalence of pre-existing chronic conditions among pregnant women in Sweden and evaluate the extent to which secular changes in maternal age, birth cohorts and obesity are associated with these trends. DESIGN: Population-based cross-sectional study. SETTING: Sweden, 2002-2019. POPULATION: All women (aged 15-49 years) who delivered in Sweden (2002-2019). METHODS: An age-period-cohort analysis was used to evaluate the effects of age, calendar periods, and birth cohorts on the observed temporal trends. MAIN OUTCOME MEASURES: Pre-existing chronic conditions, including 17 disease categories of physical and psychiatric health conditions recorded within 5 years before childbirth, presented as prevalence rates and rate ratios (RRs) with 95% confidence intervals (CIs). Temporal trends were also adjusted for pre-pregnancy body mass index (BMI) and the mother's country of birth. RESULTS: The overall prevalence of at least one pre-existing chronic condition was 8.7% (147 458 of 1 703 731 women). The rates of pre-existing chronic conditions in pregnancy increased threefold between 2002-2006 and 2016-2019 (RR 2.82, 95% CI 2.77-2.87). Rates of psychiatric (RR 3.80, 95% CI 3.71-3.89), circulatory/metabolic (RR 1.62, 95% CI 1.55-1.71), autoimmune/neurological (RR 1.69, 95% CI 1.61-1.78) and other (RR 2.10, 95% CI 1.99-2.22) conditions increased substantially from 2002-2006 to 2016-2019. However, these increasing rates were less pronounced between 2012-2015 and 2016-2019. No birth cohort effect was evident for any of the pre-existing chronic conditions. Adjusting for secular changes in obesity and the mother's country of birth did not affect these associations. CONCLUSIONS: The burden of pre-existing chronic conditions in pregnancy in Sweden increased from 2002 to 2019. This increase may be associated with the improved reporting of diagnoses and advancements in chronic condition treatment among women, potentially enhancing their fecundity.

Effect of the COVID-19 Pandemic on Stillbirths in Canada and the United States.

OBJECTIVE: There is uncertainty regarding the effect of the COVID-19 pandemic on population rates of stillbirth. We quantified pandemic-associated changes in stillbirth rates in Canada and the United States. METHODS: We carried out a retrospective study that included all live births and stillbirths in Canada and the United States from 2015 to 2020. The primary analysis was based on all stillbirths and live births at ≥20 weeks gestation. Stillbirth rates were analyzed by month, with March 2020 considered to be the month of pandemic onset. Interrupted time series analyses were used to determine pandemic effects. RESULTS: The study population included 18 475 stillbirths and 2 244 240 live births in Canada and 134 883 stillbirths and 22 963 356 live births in the United States (8.2 and 5.8 stillbirths per 1000 total births, respectively). In Canada, pandemic onset was associated with an increase in stillbirths at ≥20 weeks gestation of 1.01 (95% confidence interval [CI] 0.56-1.46) per 1000 total births and an increase in stillbirths at ≥28 weeks gestation of 0.35 (95% CI 0.16-0.54) per 1000 total births. In the United States, pandemic onset was associated with an increase in stillbirths at ≥20 weeks gestation of 0.48 (95% CI 0.22-0.75) per 1000 total births and an increase in stillbirths at ≥28 weeks gestation of 0.22 (95% CI 0.12-0.32) per 1000 total births. The increase in stillbirths at pandemic onset returned to pre-pandemic levels in subsequent months. CONCLUSION: The COVID-19 pandemic's onset was associated with a transitory increase in stillbirth rates in Canada and the United States.

Epidemiologic trends and risk factors associated with the decline in mortality from coronary heart disease in the United States, 1990-2019.

BACKGROUND: Despite the decline in the rate of coronary heart disease (CHD) mortality, it is unknown how the 3 strong and modifiable risk factors - alcohol, smoking, and obesity -have impacted these trends. We examine changes in CHD mortality rates in the United States and estimate the preventable fraction of CHD deaths by eliminating CHD risk factors. METHODS: We performed a sequential time-series analysis to examine mortality trends among females and males aged 25 to 84 years in the United States, 1990-2019, with CHD recorded as the underlying cause of death. We also examined mortality rates from chronic ischemic heart disease (IHD), acute myocardial infarction (AMI), and atherosclerotic heart disease (AHD). All underlying causes of CHD deaths were classified based on the International Classification of Disease 9th and 10th revisions. We estimated the preventable fraction of CHD deaths attributable to alcohol, smoking, and high body-mass index (BMI) through the Global Burden of Disease. RESULTS: Among females (3,452,043 CHD deaths; mean [standard deviation, SD] age 49.3 [15.7] years), the age-standardized CHD mortality rate declined from 210.5 in 1990 to 66.8 per 100,000 in 2019 (annual change -4.04%, 95% CI -4.05, -4.03; incidence rate ratio [IRR] 0.32, 95% CI, 0.41, 0.43). Among males (5,572,629 CHD deaths; mean [SD] age 47.9 [15.1] years), the age-standardized CHD mortality rate declined from 442.4 to 156.7 per 100,000 (annual change -3.74%, 95% CI, -3.75, -3.74; IRR 0.36, 95% CI, 0.35, 0.37). A slowing of the decline in CHD mortality rates among younger cohorts was evident. Correction for unmeasured confounders through a quantitative bias analysis slightly attenuated the decline. Half of all CHD deaths could have been prevented with the elimination of smoking, alcohol, and obesity, including 1,726,022 female and 2,897,767 male CHD deaths between 1990 and 2019. CONCLUSIONS: The decline in CHD mortality is slowing among younger cohorts. The complex dynamics of risk factors appear to shape mortality rates, underscoring the importance of targeted strategies to reduce modifiable risk factors that contribute to CHD mortality.

Placental abruption at near-term and term gestations: pathophysiology, epidemiology, diagnosis, and management.

Placental abruption is the premature separation of the placenta from its uterine attachment before the delivery of a fetus. The clinical manifestations of abruption typically include vaginal bleeding and abdominal pain with a wide variety of abnormal fetal heart rate patterns. Clinical challenges arise when pregnant people with this condition present with profound vaginal bleeding, necessitating urgent delivery, especially when there is a concern for maternal and fetal compromise and coagulopathy. Abruption occurs in 0.6% to 1.2% of all pregnancies, with nearly half of abruption occurring at term gestations. An exposition of abruption at near-term (defined as the late preterm period from 34 0/7 to 36 6/7 weeks of gestation) and term (defined as ≥37 weeks of gestation) provides unique insights into its direct effects, as risks associated with preterm birth do not impact outcomes. Here, we explore the pathophysiology, epidemiology, and diagnosis of abruption. We discuss the interaction of chronic processes (decidual and uteroplacental vasculopathy) and acute processes (shearing forces applied to the abdomen) that underlie the pathophysiology. Risk factors for abruption and strengths of association are summarized. Sonographic findings of abruption and fetal heart rate tracings are presented. In addition, we propose a management algorithm for acute abruption that incorporates blood loss, vital signs, and urine output, among other factors. Lastly, we discuss blood component therapy, viscoelastic point-of-care testing, disseminated intravascular coagulopathy, and management of abruption complicated by fetal death. The review seeks to provide comprehensive, clinically focused guidance during a gestational age range when neonatal outcomes can often be favorable if rapid and evidence-based care is optimized.

Optimal timing of labor induction after prelabor rupture of membranes at term: a secondary analysis of the TERMPROM study.

BACKGROUND: In the case of prelabor rupture of membranes at term, the risk for neonatal and maternal infectious morbidity increases progressively with time from prelabor rupture of membranes. Although most studies identified a benefit associated with early induction within the first 24 hours following term prelabor rupture of membranes, there is currently no precise data regarding how early should induction be scheduled. OBJECTIVE: This study aimed to identify the optimal timing of labor induction among women with term prelabor rupture of membranes by comparing the maternal and neonatal outcomes associated with labor induction with those of expectant management at any given 1-hour interval following prelabor rupture of membranes. STUDY DESIGN: This was a secondary analysis of data from the TERMPROM trial, an international, multicenter, randomized clinical trial on immediate delivery vs expectant management of women with prelaor rupture of membranes at term (≥37+0/7 weeks' gestation). We considered all participants as a single cohort of women with term prelabor rupture of membranes, irrespective of the original randomized study group allocation. For each given 1-hour time interval within the first 36 hours following prelabor rupture of membranes, we compared the outcomes of subjects for whom labor induction was initiated during this interval with those of subjects managed expectantly at the same time interval. The primary neonatal outcome was a composite of neonatal infection and admission to the neonatal intensive care unit. The primary maternal outcomes included maternal infection (clinical chorioamnionitis or postpartum fever) and cesarean delivery. RESULTS: Of the 4742 subjects who met the study criteria, 2622 underwent labor induction, and 2120 experienced a spontaneous onset of labor. The rates of the neonatal composite outcome, neonatal admission to intensive care unit, and maternal infection increased progressively with time after prelabor rupture of membranes. The risk for these outcomes was lower among women who underwent induction when compared with those managed expectantly within the first 15 to 20 hours after prelabor rupture of membranes without affecting the risk for cesarean delivery. In addition, women who underwent labor induction within the first 30 to 36 hours had a shorter prelabor rupture of membranes to delivery time and a shorter total maternal hospital stay when compared with those managed expectantly at the same time interval. Among women managed expectantly, less than two-thirds (64%; 1365/2120) experienced a spontaneous onset of labor within the first 24 hours following prelabor rupture of membranes. CONCLUSION: These findings suggest that immediate labor induction seems to be the optimal management strategy to minimize neonatal and maternal morbidity in the setting of prelabor rupture of membranes at term gestations. In cases for which immediate induction is not feasible, labor induction remains the preferred option over expectant management if performed within the first 15 to 20 hours after prelabor rupture of membranes.

Early coronavirus disease 2019 restrictive measures and changes in maternal characteristics, use of assisted reproductive technology, and stillbirth.

BACKGROUND: The initial COVID-19 pandemic response-related effects on conceptions following the use of assisted reproductive technologies (ART), and on changes in the maternal characteristics of women who conceived during the early vs. pre-pandemic period, have been understudied. OBJECTIVES: To examine the effects of ART clinic closures in the United States (US) in March 2020 on the frequency of ART-conceived live births, multiple births and stillbirths; and to describe changes in the characteristics of women who conceived in the early pandemic period. METHODS: Population-based cohort study including all births in the US from January 2015 to December 2020 (22,907,688 live births; 134,537 stillbirths). Interrupted time series (ITS) methodology was used to estimate rate ratios (RR) of expected versus observed rates in December 2020 (i.e., among births conceived mainly in March 2020). Demographic and clinical characteristics were compared between mothers who conceived in March 2020 versus March 2015-2019. RESULTS: Overall, 1.1% of live births and 1.7% of stillbirths were conceived by ART. ART-conceived live births decreased by 57.0% in December 2020 (observed vs. expected RR 0.43, 95% confidence interval [CI] 0.40, 0.45), and these declines occurred in all subgroups of women. Multiple births also declined in December 2020. Stillbirth rates increased in December 2020 in ART-conceived births (RR 2.55, 95% CI 1.63, 3.92) but remained unchanged in the non-ART group. Maternal characteristics of women who conceived in the early pandemic versus pre-pandemic period differed and included an increased prevalence of pre-pregnancy obesity class 3 and chronic hypertension. CONCLUSIONS: The early pandemic closure of ART clinics resulted in a substantial decline in ART-conceived live births and multiple births in December 2020 and an increase in the proportion of stillbirths among ART-conceived births. Women who conceived in the early pandemic period also had an increased prevalence of obesity and chronic hypertension.

Familial aggregation of stillbirth: A pedigree analysis of a matched case-control study.

OBJECTIVE: To determine whether stillbirth aggregates in families and quantify its familial risk using extended pedigrees. DESIGN: State-wide matched case-control study. SETTING: Utah, United States. POPULATION: Stillbirth cases (n = 9404) and live birth controls (18 808) between 1978 and 2019. METHODS: Using the Utah Population Database, a population-based genealogical resource linked with state fetal death and birth records, we identified high-risk pedigrees with excess familial aggregation of stillbirth using the Familial Standardised Incidence Ratio (FSIR). Stillbirth odds ratio (OR) for first-degree relatives (FDR), second-degree relatives (SDR) and third-degree relatives (TDR) of parents with a stillbirth (affected) and live birth (unaffected) were estimated using logistic regression models. MAIN OUTCOME MEASURES: Familial aggregation estimated using FSIR, and stillbirth OR estimated for FDR, SDR and TDR of affected and unaffected parents using logistic regression models. RESULTS: We identified 390 high-risk pedigrees with evidence for excess familial aggregation (FSIR ≥2.00; P-value <0.05). FDRs, SDRs and TDRs of affected parents had 1.14-fold (95% confidence interval [CI]: 1.04-1.26), 1.22-fold (95% CI 1.11-1.33) and 1.15-fold (95% CI 1.08-1.21) higher stillbirth odds compared with FDRs, SDRs and TDRs of unaffected parents, respectively. Parental sex-specific analyses showed male FDRs, SDRs and TDRs of affected fathers had 1.22-fold (95% CI 1.02-1.47), 1.38-fold (95% CI 1.17-1.62) and 1.17-fold (95% CI 1.05-1.30) higher stillbirth odds compared with those of unaffected fathers, respectively. FDRs, SDRs and TDRs of affected mothers had 1.12-fold (95% CI 0.98-1.28), 1.09-fold (95% CI 0.96-1.24) and 1.15-fold (95% CI 1.06-1.24) higher stillbirth odds compared with those of unaffected mothers, respectively. CONCLUSIONS: We provide evidence for familial aggregation of stillbirth. Our findings warrant investigation into genes associated with stillbirth and underscore the need to design large-scale studies to determine the genetic architecture of stillbirth.

Invited Commentary: Intermittent Opioid Use and Ischemic Placental Disease-Clarifying Associations With Adverse Pregnancy Outcomes.

Discomfort and, to a lesser extent, pain are common complaints during pregnancy, and some patients may turn to opioids for pain relief. Esposito et al. (Am J Epidemiol. 2022;191(5):759-768) report associations between intermittent exposure to opioids during pregnancy and the risk of ischemic placental disease-a syndrome that includes preeclampsia, placental abruption, births that are small for gestational age, and preterm delivery. They found that early opioid exposure in pregnancy was associated with a modestly increased risk for abruption, births that are small for gestational age, and preterm delivery, and both early and late exposures were associated with the greatest risk for these outcomes. Surprisingly, preeclampsia was not associated with opioid use. Through quantitative bias analysis, the authors cleverly tackle a number of biases to assess their roles in explaining the associations, including unmeasured confounding, outcome misclassification, and residual confounding; none exerted strong influences on the associations. Although the findings appear fairly robust on the surface, the lack of association between intermittent opioid use and preeclampsia, and important differences in characteristics of patients in the opioid-exposed group compared with the unexposed group, suggest that further study is needed to clarify the relationship between intermittent opioid use, lifestyle factors, and ischemic placental disease risk.

Understanding Etiologic Pathways Through Multiple Sequential Mediators: An Application in Perinatal Epidemiology.

BACKGROUND: Causal mediation analysis facilitates decomposing the total effect into a direct effect and an indirect effect that operates through an intermediate variable. Recent developments in causal mediation analysis have clarified the process of evaluating how-and to what extent-different pathways via multiple causally ordered mediators link the exposure to the outcome. METHODS: Through an application of natural effect models for multiple mediators, we show how placental abruption might affect perinatal mortality using small for gestational age (SGA) birth and preterm delivery as two sequential mediators. We describe methods to disentangle the total effect into the proportions mediated via each of the sequential mediators, when evaluating natural direct and natural indirect effects. RESULTS: Under the assumption that SGA births causally precedes preterm delivery, an analysis of 16.7 million singleton pregnancies is consistent with the hypothesis that abruption exerts powerful effects on perinatal mortality (adjusted risk ratio = 11.9; 95% confidence interval = 11.6, 12.1). The proportions of the estimated total effect mediated through SGA birth and preterm delivery were 2% and 58%, respectively. The proportion unmediated via either SGA or preterm delivery was 41%. CONCLUSIONS: Through an application of causal mediation analysis with sequential mediators, we uncovered new insights into the pathways along which abruption impacts perinatal mortality.

Pathologic characteristics, patterns of care, and outcomes of Asian-Americans and Pacific islanders with uterine cancer.

OBJECTIVES: To compare the patterns of care and outcomes of Asian-Americans/Pacific Islanders (AAPI) to non-Hispanic White (NHW) women with uterine cancer, and examine differences across Asian country of origin. METHODS: National Cancer Database was used to identify AAPI and NHW women with uterine cancer diagnosed from 2004 to 2017. Marginal multivariable log-linear regression models and Cox proportional-hazards models were developed to estimate differences in quality-of-care and all-cause mortality between AAPI and NHW women and across AAPI ethnic groups. RESULTS: We identified 13,454 AAPI and 354,693 NHW women. Compared to NHW women, AAPI patients were younger at diagnosis (median age 57 vs. 62 years), had fewer comorbidities, more often had serous or sarcoma histologic subtypes and stage III/IV cancer. AAPI women had a slightly higher rate of receiving pelvic lymphadenectomy for deeply invasive or high-grade tumors (77.6% vs. 74.3%), and a lower rate of undergoing minimally invasive surgery (70.4% vs. 74.8%) for stage I-IIIC tumors. Among patients undergoing hysterectomy, AAPI women had a lower mortality compared with NHW women for cancer stage I/II/III, and a 28% reduction for type I (grade 1 or 2 endometrioid cancers) disease (aHR = 0.72; 95% CI, 0.64-0.81). Among AAPI subgroups, Pacific Islanders had the worst survival across different cancer stage and disease type. CONCLUSION: AAPI women are diagnosed with uterine cancer at a younger age and have more aggressive histologic subtypes and advanced stage than their White counterparts. They have a similar level of quality-of-care as NHW women, and an improved survival for early stage and type I disease.

A principled approach to mediation analysis in perinatal epidemiology.

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.

A new index for obstetrics safety and quality of care: integrating cesarean delivery rates with maternal and neonatal outcomes.

BACKGROUND: Cesarean delivery rates have been used as obstetrical quality indicators. However, these approaches do not consider the accompanying maternal and neonatal morbidities. A challenge in the field of obstetrics has been to establish a valid outcomes quality measure that encompasses preexisting high-risk maternal factors and associated maternal and neonatal morbidities and is universally acceptable to all stakeholders, including patients, healthcare providers, payers, and governmental agencies. OBJECTIVE: This study aimed to (1) establish a new single metric for obstetrical quality improvement among nulliparous patients with term singleton vertex-presenting fetus, integrating cesarean delivery rates adjusted for preexisting high-risk maternal factors with associated maternal and neonatal morbidities, and (2) determine whether obstetrician quality ranking by this new metric is different compared with the rating based on individual crude and/or risk-adjusted cesarean delivery rates. The single metric has been termed obstetrical safety and quality index. STUDY DESIGN: This was a cross-sectional study of all nulliparous patients with term singleton vertex-presenting fetuses delivered by 12 randomly chosen obstetricians in a single institution. A review of all records was performed, including a review of maternal high-risk factors and maternal and neonatal outcomes. Maternal and neonatal medical records were reviewed to determine crude and adjusted cesarean delivery rates by obstetricians and quantify maternal and neonatal complications. We estimated the obstetrician-specific crude cesarean delivery rates and rates adjusted for obstetrician-specific maternal and neonatal complications from logistic regression models. From this model, we derived the obstetrical safety and quality index for each obstetrician. The final ranking based on the obstetrical safety and quality index was compared with the initial ranking by crude cesarean delivery rates. Maternal and neonatal morbidities were analyzed as ≥1 and ≥2 maternal and/or neonatal complications. RESULTS: These 12 obstetricians delivered a total of 535 women; thus, 1070 (535 maternal and 535 neonatal) medical records were reviewed to determine crude and adjusted cesarean delivery rates by obstetricians and quantify maternal and neonatal complications. The ranking of crude cesarean delivery rates was not correlated (rho=0.05; 95% confidence interval, -0.54 to 0.60) to the final ranking based on the obstetrical safety and quality index. Of note, 8 of 12 obstetricians shifted their rank quartiles after adjustments for high-risk maternal conditions and maternal and neonatal outcomes. There was a strong correlation between the ranking based on ≥1 maternal and/or neonatal complication and ranking based on ≥2 maternal and/or neonatal complications (rho=0.63; 95% confidence interval, 0.08-0.88). CONCLUSION: Ranking based on crude cesarean delivery rates varied significantly after considering high-risk maternal conditions and associated maternal and neonatal outcomes. Therefore, the obstetrical safety and quality index, a single metric, was developed to identify ways to improve clinician practice standards within an institution. Use of this novel quality measure may help to change initiatives geared toward patient safety, balancing cesarean delivery rates with optimal maternal and neonatal outcomes. This metric could be used to compare obstetrical quality not only among individual obstetricians but also among hospitals that practice obstetrics.

Altmetric and bibliometric analysis of obstetrics and gynecology research: influence of public engagement on citation potential.

BACKGROUND: Whether research engagement on social media and other public platforms results in increased citations in obstetrics and gynecology remains uncertain. The Altmetric Attention Score is a metric of research influence based on mentions on social media and public platforms, such as newsfeeds and Wikipedia. The correlation between Altmetric Attention Scores, absolute citation rates, and the Relative Citation Ratio (a novel metric of research engagement also based on citation rates) in obstetrics and gynecology research is uncertain. OBJECTIVE: To evaluate the correlation between Altmetric Attention Score, absolute citation rate, and Relative Citation Ratio for articles published in obstetrics and gynecology journals from 2004 to 2019. Our second objective was to identify, characterize, and compare the 100 articles with highest Altmetric Attention Scores, the 100 most-cited articles, and the 100 articles with highest Relative Citation Ratios. STUDY DESIGN: We performed a cross-sectional altmetric and bibliometric study of all obstetrics and gynecology articles indexed in the National Institutes of Health Open Citation Collection from 2004 to 2019. Articles were included if they were published in obstetrics and gynecology journals according to InCites Journal Citation Reports indexing. Citation data, including citation numbers and Relative Citation Ratios, were downloaded on March 20, 2021 and merged with altmetric data from the Altmetric Explorer on the basis of each article's unique PubMed identification number. We assessed correlation between Altmetric Attention Scores and number of citations and Altmetric Attention Scores and Relative Citation Ratios by calculating the Pearson correlation coefficient. The 100 articles with highest Altmetric Attention Scores, the 100 most-cited articles, and the 100 articles with highest Relative Citation Ratios were characterized and compared using means (standard deviations) and mean differences (95% confidence intervals). RESULTS: There were 156,592 articles published in 82 obstetrics and gynecology journals and indexed in the National Institutes of Health Open Citation Collection between 2004 and 2019. The correlation coefficient was 0.18 (95% confidence interval, 0.17-0.19) for Altmetric Attention Scores vs number of citations and 0.10 (95% confidence interval, 0.09-0.11) for Altmetric Attention Scores vs Relative Citation Ratios. There was no overlap among the 100 articles on the highest Altmetric Attention Score list and the 100 most-cited list, and there was minimal overlap among the 100 articles on the highest Altmetric Attention Score list and the 100 highest Relative Citation Ratio list (98 unique articles on each list). Articles with highest Altmetric Attention Scores generated substantially more engagement on social media and other public platforms than most-cited articles (mean Altmetric Attention Score, 763.1 [standard deviation, 520.8] vs 49.9 [standard deviation, 81.6]; mean difference, -713.2 [95% confidence interval, -819.9 to -606.6]) and highest Relative Citation Ratio articles (mean, 116.2 [standard deviation, 415.9]; mean difference, -661.5 [95% confidence interval, -746.2 to -576.9]). In contrast, the articles with highest Altmetric Attention Scores generated far fewer citations than most-cited articles (mean, 39.7 [standard deviation, 47.6] vs 541.8 [standard deviation, 312.8]; mean difference, 502.0 [95% confidence interval, 439.0-565.0]) and highest Relative Citation Ratio articles (mean, 458.9 [standard deviation, 363.5]; mean difference, 427.7 [95% confidence interval, 353.8-501.6]). Nearly half of articles with highest Altmetric Attention Scores were basic/translational studies, often about menopause and environmental factors impacting fertility, whereas most-cited articles and articles with highest Relative Citation Ratios were more likely to be reviews and consensus statements, respectively, often about placentation and polycystic ovary syndrome, respectively. Articles with highest Altmetric Attention Scores were more likely to be published as open-access. CONCLUSION: There seems to be weak short-term correlation between Altmetric Attention Scores and citation rates. Further study is warranted to ascertain whether there may be long-term correlation between alternative metrics and citation rates in obstetrics and gynecology.

Super-Utilizers of Inpatient Care in an Obstetrical Population: A Cross-Sectional Study.

OBJECTIVES: The aim of the study is to estimate hospital charges (HC) and length of stay (LOS) for pregnancy and 6 weeks postpartum and to characterize the outliers who utilize a disproportionate share of health care resources. STUDY DESIGN: We performed a cross-sectional study of 500 subjects at a tertiary center between 2012 and 2014. Subjects were included who had inpatient status and an ICD-9 code for pregnancy; those with an ICD-9 code for ectopic pregnancy were excluded. Data were collected 266 days prior to the estimated date of delivery (EDD) and up to 42 days post-delivery. Medical diagnoses, obstetrical details, demographics, HC, and LOS were collected. Super-utilizers (SUs) were selected as patients with total HC exceeding $75,000, those who incurred $75,000 or less were assigned to the typical utilizer (TU) group. RESULTS: HC was positively skewed, with median's (interquartile range) of $151,143 (97,707-198,732) and $28,186 (19,292-38,943) among SUs and TUs, respectively. Despite the low proportion of SU patients (7%, n = 36), they accounted for 30% of charges. Similarly, SUs had longer LOS (16 vs. 3 days, p <0.05). They had earlier deliveries (34.5 vs. 38.5 weeks, p <0.05), higher cesarean section rates (69 vs. 35%, p <0.05), and more hysterectomies (8.3 vs. 0%, p <0.05). The most common complications in SUs were preterm labor (33.3 vs. 5.4%, p <0.05) and preterm premature rupture of membranes (25 vs. 3.9%, p< 0.05). The most common pre-existing condition in SUs was chronic hypertension (11.1 vs. 3%, p< 0.05). CONCLUSION: Although SUs comprise only 7% of the obstetrical population, they account for almost a third of the total HCs; in turn, SUs are at risk of adverse outcomes. Targeting this population can guide efforts to improve maternal health through prevention, research, and personalized care. SUs may have clustering at hospitals with higher levels of care and this topic warrants further investigation with state and national level data. KEY POINTS: · Just 7% of pregnant patients accounted for 30% of hospital charges.. · Super-utilizers had higher rates of preterm delivery, cesarean section, and hysterectomy.. · The most common pre-existing medical condition in super-utilizers was chronic hypertension..

Maternal Cardiovascular and Cerebrovascular Health After Placental Abruption: A Systematic Review and Meta-Analysis (CHAP-SR).

Placental abruption and cardiovascular disease (CVD) have common etiological underpinnings, and there is accumulating evidence that abruption may be associated with future CVD. We estimated associations between abruption and coronary heart disease (CHD) and stroke. The meta-analysis was based on the random-effects risk ratio (RR) and 95% confidence interval (CI) as the effect measure. We conducted a bias analysis to account for abruption misclassification, selection bias, and unmeasured confounding. We included 11 cohort studies comprising 6,325,152 pregnancies, 69,759 abruptions, and 49,265 CHD and stroke cases (1967-2016). Risks of combined CVD morbidity-mortality among abruption and nonabruption groups were 16.7 and 9.3 per 1,000 births, respectively (RR = 1.76, 95% CI: 1.24, 2.50; I2 = 94%; τ2 = 0.22). Women who suffered abruption were at 2.65-fold (95% CI: 1.55, 4.54; I2 = 85%; τ2 = 0.36) higher risk of death related to CHD/stroke than nonfatal CHD/stroke complications (RR = 1.32, 95% CI: 0.91, 1.92; I2 = 93%; τ2 = 0.15). Abruption was associated with higher mortality from CHD (RR = 2.64, 95% CI: 1.57, 4.44; I2 = 76%; τ2 = 0.31) than stroke (RR = 1.70, 95% CI: 1.19, 2.42; I2 = 40%; τ2 = 0.05). Corrections for the aforementioned biases increased these estimates. Women with pregnancies complicated by placental abruption may benefit from postpartum screening or therapeutic interventions to help mitigate CVD risks.