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Opioids affect placental development and function in animal models, but human data on their association with ischemic placental disease are limited. Using a cohort of pregnant women in the US nationwide Medicaid Analytic eXtract (2000–2014), we compared women with ≥2 opioid dispensings in pregnancy with unexposed women. Given an uncertain etiologically relevant window, we assessed exposure occurring in early pregnancy, late and not early pregnancy, and both early and late pregnancy. For placental abruption, preterm delivery, small for gestational age (SGA), and preeclampsia, we estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) using Cox proportional hazard models adjusting for demographic factors, indications/comorbidities, and medications. Among 1,833,871 eligible pregnancies, ≥2 opioid dispensings were filled in 6.5%. We observed an early exposure aHR of 1.34 (95% CI: 1.26, 1.43) for placental abruption, 1.21 (95% CI: 1.18, 1.23) for preterm delivery, 1.13 (95% CI: 1.09, 1.17) for SGA, and 0.95 (0.91, 0.98) for preeclampsia. Estimates for late exposure were attenuated. Early and late exposure was associated with higher aHRs for placental abruption, 1.62 (95% CI: 1.47, 1.78); preterm delivery, 1.37 (95% CI: 1.33, 1.42); and SGA, 1.26 (95% CI: 1.19, 1.33); but not preeclampsia, 0.99 (95% CI: 0.93, 1.05). Prescription opioids may modestly increase risk of placental abruption, preterm birth and SGA, but they do not appear to be associated with preeclampsia. [ABSTRACT FROM AUTHOR]

Objectives: Primary: Analyze the Adverse Events (AEs) reported to the Food and Drug Administration (FDA) after use of mifepristone as an abortifacient. Secondary: Analyze maternal intent after ongoing pregnancy and investigate hemorrhage after mifepristone alone. Methods: Adverse Event Reports (AERs) for mifepristone used as an abortifacient, submitted to the FDA from September 2000 to February 2019, were analyzed using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAEv3). Results: The FDA provided 6158 pages of AERs. Duplicates, non-US, or AERs previously published (Gary, 2006) were excluded. Of the remaining, there were 3197 unique, US-only AERs of which there were 537 (16.80%) with insufficient information to determine clinical sever-ity, leaving 2660 (83.20%) Codable US AERs. (Figure 1). Of these, 20 were Deaths, 529 were Life-threatening, 1957 were Severe, 151 were Moderate, and 3 were Mild. The deaths included: 9 (45.00%) sepsis, 4 (20.00%) drug toxicity/overdose, 1 (5.00%) ruptured ectopic pregnancy, 1 (5.00%) hemorrhage, 3 (15.00%) possible homicides, 1 (5.00%) suicide, 1 (5.00%) unknown. (Table 1) Retained products of conception and hemorrhage caused most morbidity. There were 75 ectopic pregnancies, including 26 ruptured ectopics (includes one death). There were 2243 surgeries including 2146 (95.68%) D&Cs of which only 853 (39.75%) were performed by abortion providers. Of 452 patients with ongoing pregnancies, 102 (22.57%) chose to keep their baby, 148 (32.74%) had terminations, 1 (0.22%) miscarried, and 201 (44.47%) had unknown outcomes. Hemorrhage occurred more often in those who took mifepristone and misoprostol (51.44%) than in those who took mifepristone alone (22.41%). Conclusions: Significant morbidity and mortality have occurred following the use of mifepristone as an abortifacient. A pre-abortion ultrasound should be required to rule out ectopic pregnancy and confirm gestational age. The FDA AER system is inadequate and significantly underestimates the adverse events from mifepristone. A mandatory registry of ongoing pregnancies is essential considering the number of ongoing pregnancies especially considering the known teratogenicity of misoprostol. The decision to prevent the FDA from enforcing REMS during the COVID-19 pandemic needs to be reversed and REMS must be strengthened. Conflict of Interest Statement: The authors did not report any potential conflicts of interest. Authors note that although Dr. Harrison is an associate editor for Issues in Law and Medicine, she recused herself from any involvement in the peer review process for this manuscript. [ABSTRACT FROM AUTHOR]

Background: Rural hospitals are closing obstetric units, and limited information is available about local emergency obstetric preparedness and capacity in rural communities where hospitals do not routinely provide this care. Objective: To describe emergency obstetric capacity at rural US hospitals that do not routinely offer childbirth services. Methods: Data from the 2018 American Hospital Association Annual Survey were used to identify a random sample of rural hospitals that did not offer obstetric services. A survey was developed based on World Health Organization criteria for obstetric emergencies. With data collected from 69 rural hospital emergency departments (48% response rate), we analyzed local capacity to support childbirth. Results: Most responding hospitals (65%) were located 30 or more miles away from a hospital with obstetric services. Some reported having emergency room births in the past year (28%), an unanticipated adverse birth outcome (32%), and/or a delay in urgent transport for a pregnant patient (22%). More than 90% of responding hospitals had capacity for blood transfusion, intravenous antibiotics or anticonvulsants, and basic neonatal resuscitation. However, less than one‐fifth had capacity to perform surgery (16%), remove retained products of delivery (17%), or had a policy for emergency cesarean (18%). Almost all respondents (80%) reported the need for additional training or resources to handle emergency obstetric situations. Conclusion: Many rural hospitals do not have basic capacity to provide emergency obstetric services. Programs and policies to improve this may focus on surgical care, clinician and staff training, transportation, and coordination with nearby hospitals that provide obstetric services. [ABSTRACT FROM AUTHOR]

Objective  Placental disease is a leading cause of stillbirth. Our purpose was to characterize stillbirths associated with placental disease. Study Design  The Stillbirth Collaborative Research Network conducted a prospective, case–control study of stillbirths and live births from 2006 to 2008. This analysis includes 512 stillbirths with cause of death assignment and a comparison group of live births. We compared exposures between women with stillbirth due to placental disease and those due to other causes as well as between women with term (≥ 37 weeks) stillbirth due to placental disease and term live births. Results  A total of 121 (23.6%) out of 512 stillbirths had a probable or possible cause of death due to placental disease by Initial Causes of Fetal Death. Characteristics were similar between stillbirths due to placental disease and other stillbirths. When comparing term live births to stillbirths due to placental disease, women with non-Hispanic black race, Hispanic ethnicity, lack of insurance, or who were born outside of the United States had higher odds of stillbirth due to placental disease. Nulliparity and antenatal bleeding also increased risk of stillbirth due to placental disease. Conclusion  Multiple discrete exposures were associated with stillbirth caused by placental disease. The relationship between these factors and utility of surveillance warrants further study. [ABSTRACT FROM AUTHOR]

Objective: The aims of this study were to ascertain the frequency of disorders of villous maturation in fetal death and to also delineate other placental histopathologic lesions in fetal death. Methods: This was a retrospective observational cohort study of fetal deaths occurring among women between January 2004 and January 2016 at Hutzel Women's Hospital, Detroit, MI, USA. Cases comprised fetuses with death beyond 20 weeks' gestation. Fetal deaths with congenital anomalies and multiple gestations were excluded. Controls included pregnant women without medical/obstetrical complications and delivered singleton, term (37–42 weeks) neonate with 5-min Apgar score ≥7 and birthweight between the 10th and 90th percentiles. Results: Ninety-two percent (132/143) of placentas with fetal death showed placental histologic lesions. Fetal deaths were associated with (1) higher frequency of disorders of villous maturation [44.0% (64/143) vs. 1.0% (4/405), P < 0.0001, prevalence ratio, 44.6; delayed villous maturation, 22% (31/143); accelerated villous maturation, 20% (28/143); and maturation arrest, 4% (5/143)]; (2) higher frequency of maternal vascular malperfusion lesions [75.5% (108/143) vs. 35.7% (337/944), P < 0.0001, prevalence ratio, 2.1] and fetal vascular malperfusion lesions [88.1% (126/143) vs. 19.7% (186/944), P < 0.0001, prevalence ratio, 4.5]; (3) higher frequency of placental histologic patterns suggestive of hypoxia [59.0% (85/143) vs. 9.3% (82/942), P < 0.0001, prevalence ratio, 6.8]; and (4) higher frequency of chronic inflammatory lesions [53.1% (76/143) vs. 29.9% (282/944), P < 0.001, prevalence ratio 1.8]. Conclusion: This study demonstrates that placentas of women with fetal death were 44 times more likely to present disorders of villous maturation compared to placentas of those with normal pregnancy. This suggests that the burden of placental disorders of villous maturation lesions is substantial. [ABSTRACT FROM AUTHOR]

Introduction: The presence of a previous uterine scar is a strong risk factor for developing abnormally invasive placentation (AIP). We sought to determine whether a short interpregnancy interval predisposes to AIP. We hypothesized that a short interpregnancy interval after a previous cesarean delivery increases the risk of AIP in comparison with a longer interpregnancy interval.Material and Methods: We performed a retrospective cohort study of women with a histological diagnosis of AIP and a history of a previous cesarean section. Women were included in the control group if they had a previous cesarean section with a placenta underlying the previous uterine scar or an anterior previa. The time interval between pregnancy and AIP data was analyzed using the chi-square test and two-tailed Fisher's exact test.Results: There was no statistical difference in the interpregnancy interval between women who had AIP vs the control group. Gravidity and parity were found to be significantly higher in the women with AIP vs the controls.Conclusions: These results suggest that a short interpregnancy interval may not increase the risk of developing AIP. [ABSTRACT FROM AUTHOR]

Objective: Antenatal diagnosis of morbidly adherent placenta has been shown to improve outcomes, but existing predictors lack sensitivity. Our objective was to determine whether the presence of myometrial fibres attached to the placental basal plate (BPMYO) in an antecedent pregnancy is associated with subsequent morbidly adherent placenta.Design: A case-control study.Setting: Departments of Obstetrics and Gynecology and Pathology, Northwestern University, Chicago, IL, USA.Sample: Women who had at least two pregnancies with placental pathological evaluation.Methods: Cases were defined as women with evidence of morbidly adherent placenta (both clinically and pathologically) in their most recent pregnancy whereas women without evidence of morbidly adherent placenta served as controls. Pathological specimens of placentas from previous pregnancies were evaluated for BPMYO. The presence of BPMYO on a previous placenta was evaluated to determine whether it could be used to improve the antenatal diagnosis of morbidly adherent placenta.Results: Of the 25 cases of morbidly adherent placenta, 19 (76%) had BPMYO present on their previous placenta compared with 41 (41%) of controls (odds ratio 4.8, 95% CI 1.8-13.0). Adding BPMYO to a regression including other risk factors for morbidly adherent placenta (i.e. maternal age, number of previous caesarean sections, placenta praevia, previous multiple gestation, any previous curettage, and ultrasonographic suspicion of placenta accreta) significantly improved the sensitivity of antenatal diagnosis of morbidly adherent placenta (61% versus 39%, P < 0.001) without a change in specificity (97% versus 97%, P = 1.00).Conclusion: BPMYO on previous placental pathology is associated with an increased risk of morbidly adherent placenta in a subsequent pregnancy. These findings may shed light on the pathophysiology of accreta and inform future research on predictors of accreta.Tweetable Abstract: Previous basal plate myometrium improves the ability to detect subsequent morbidly adherent placenta. [ABSTRACT FROM AUTHOR]

Objective: To describe the prevalence, trends, adverse maternal-fetal morbidities and healthcare costs associated with placenta accreta (PA) in the United States (US) between 1998 and 2011.Methods: A retrospective, cross-sectional analysis of inpatient hospital discharges was conducted using the National Inpatient Sample (NIS). We used International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) codes to identify both cases of PA and of selected comorbidities. Survey logistic regression was used to assess the association between PA and various maternal-fetal outcomes. Joinpoint regression modeling was used to estimate annual percent changes (APCs) in PA prevalence during the study period.Results: The prevalence of PA from 1998 to 2011 was 3.7 per 1000 delivery-related discharges. After adjusting for known or suspected confounders, PA conferred between a 20% to over a 19-fold increased odds of experiencing an adverse outcome. This resulted in a higher mean, per-hospitalization, cost of inpatient care after adjustment for inflation ($5561 versus $4989), translating into over $115 million dollars in additional inpatient expenditures relative to non-PA affected deliveries from 2001 to 2011.Conclusions: This study updates recent trends in the prevalence of PA, which is valuable to clinicians and policymakers as they formulate targeted strategies to address factors related to PA. [ABSTRACT FROM AUTHOR]

Background: Maternal vitamin D deficiency has been linked to fetal growth restriction, but the underlying mechanisms are unclear. Objective: We tested the hypothesis that poor maternal 25-hydroxyvitamin D [25(OH)D] is associated with increased risk of placental vascular pathology. Design: Maternal serum 25(OH)D was measured at ≤26 wk of gestation in a random subcohort of term, singleton infants in the Collaborative Perinatal Project (1959-1966; n = 2048). A dichotomous vascular construct was created from the presence of any of 12 pathologies identified on placental examinations, including evidence of placental abruption, infarction, hypoxia, decidual vasculopathy, or thrombosis of fetal vessels (n = 240 cases). Results: The relation between 25(OH)D and vascular pathology was modified by infant sex (P = 0.003). A maternal 25(OH)D concentration ≥80 compared with <50 nmol/L was associated with 49% lower risk of pathology in boys [adjusted OR (95% CI): 0.27, 0.95] after conditioning on study site. No associations were observed between maternal 25(OH)D and pathology in mothers with female offspring. Subsequent analyses showed that, in pregnancies with a female fetus, vascular pathology was associated with a reduced birth-weight z score when the mother's 25(OH)D concentration was <30 nmol/L (β: -0.73; 95% CI: -1.17, -0.30). No association was observed between pathology and birth weight in mothers of female offspring with 25(OH)D concentrations ≥30 nmol/L or in boys, regardless of maternal 25(OH)D status. Conclusions: Our findings suggest complex relations between vitamin D, placental vascular pathology, and birth weight that differ by infant sex. Maternal vitamin D status may be beneficial for male and female offspring through different mechanisms. [ABSTRACT FROM AUTHOR]

Women seropositive for human immunodeficiency virus type 1 (HIV-1) are at an increased risk for a number of adverse perinatal outcomes. Although efforts to reduce mother-to-child transmission of HIV (MTCT) remain a priority in resource-limited countries, HIV testing and treatment have led to steep declines in MTCT in well-resourced countries. Even so, HIV seropositive pregnant women in the United States continue to deliver a disproportionately high number of preterm and low birth weight infants. In this mini-review, we address the role of the placenta in such HIV-related perinatal sequelae. We posit that adverse perinatal outcomes may result from two mutually non-exclusive routes: (1) HIV infection of the placenta proper, potentially leading to impaired maternal-fetal exchange; and (2) infection of the maternal decidual microenvironment, possibly disrupting normal placental implantation and development. Further research into the relationship between HIV-1 infection and placental pathology may lead to the development of novel strategies to improve birth outcomes among HIV-1 seropositive parturients. [ABSTRACT FROM AUTHOR]

The authors use recent methodology in causal inference to disentangle the direct and indirect effects that operate through a mediator in an exposure-response association paradigm. They demonstrate how total effects can be partitioned into direct and indirect effects even when the exposure and mediator interact. The impact of bias due to unmeasured confounding on the exposure-response association is assessed through a series of sensitivity analyses. These methods are applied to a problem in perinatal epidemiology to examine the extent to which the effect of abruption on perinatal mortality is mediated through preterm delivery. Data on over 26 million US singleton births (1995–2002) were utilized. Risks of mortality among abruption and nonabruption births were 102.7 and 6.2 per 1,000 births, respectively. Risk ratios of the natural direct and indirect (preterm delivery-mediated) effects of abruption on mortality were 10.18 (95% confidence interval: 9.80, 10.58) and 1.35 (95% confidence interval: 1.33, 1.38), respectively. The proportion of increased mortality risk mediated through preterm delivery was 28.1%, with even higher proportions associated with deliveries at earlier gestational ages. Sensitivity analyses underscore that the qualitative conclusions of some mediated effects and substantial direct effects are reasonably robust to unmeasured confounding of a fairly considerable magnitude. [ABSTRACT FROM AUTHOR]

Abstract: In a large prospective study (1959-1966), the perinatal mortality rate for U.S. Whites was 34 deaths per 1000 total births, for Blacks 51/1000, for Puerto Ricans 41/1000, and for Orientals 23/1000. A number of disorders were responsible for these differences. Premature rupture of the fetal membranes occurred 92 per cent more often in Blacks than in Whites, marked placental growth retardation 56 per cent more often, amniotic fluid infections 45 per cent more often, and major congenital malformations 15 percent more often. Most other disorders were less common in Blacks than in Whites. Stratifying the data by selected factors, such as prepregnancy body weight and antenatal medical care, eliminated or greatly reduced almost all of these interracial differences. The only major unexplained differences remaining were an excess of amniotic fluid infections and major congenital malformations in Blacks, and an excess of abruptio placentae and large placental infarcts in Whites. (Am J Public Health 69:857-861, 1979.) [ABSTRACT FROM AUTHOR]

Although much progress is being made in understanding the molecular pathways in the placenta that are involved in the pathophysiology of pregnancy-related disorders, a significant gap exists in the utilization of this information for the development of new drug therapies to improve pregnancy outcome. On March 5-6, 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled Placental Origins of Adverse Pregnancy Outcomes: Potential Molecular Targets to begin to address this gap. Particular emphasis was given to the identification of important molecular pathways that could serve as drug targets and the advantages and disadvantages of targeting these particular pathways. This article is a summary of the proceedings of that workshop. A broad number of topics were covered that ranged from basic placental biology to clinical trials. This included research in the basic biology of placentation, such as trophoblast migration and spiral artery remodeling, and trophoblast sensing and response to infectious and noninfectious agents. Research findings in these areas will be critical for the formulation of the development of future treatments and the development of therapies for the prevention of a number of pregnancy disorders of placental origin that include preeclampsia, fetal growth restriction, and uterine inflammation. Research was also presented that summarized ongoing clinical efforts in the United States and in Europe that has tested novel interventions for preeclampsia and fetal growth restriction, including agents such as oral arginine supplementation, sildenafil, pravastatin, gene therapy with virally delivered vascular endothelial growth factor, and oxygen supplementation therapy. Strategies were also proposed to improve fetal growth by the enhancement of nutrient transport to the fetus by modulation of their placental transporters and the targeting of placental mitochondrial dysfunction and oxidative stress to improve placental health. The roles of microRNAs and placental-derived exosomes, as well as messenger RNAs, were also discussed in the context of their use for diagnostics and as drug targets. The workshop discussed the aspect of safety and pharmacokinetic profiles of potential existing and new therapeutics that will need to be determined, especially in the context of the unique pharmacokinetic properties of pregnancy and the hurdles and pitfalls of the translation of research findings into practice. The workshop also discussed novel methods of drug delivery and targeting during pregnancy with the use of macromolecular carriers, such as nanoparticles and biopolymers, to minimize placental drug transfer and hence fetal drug exposure. In closing, a major theme that developed from the workshop was that the scientific community must change their thinking of the pregnant woman and her fetus as a vulnerable patient population for which drug development should be avoided, but rather be thought of as a deprived population in need of more effective therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objective: Retained placenta complicates 2-3% of vaginal deliveries and is a known cause of postpartum hemorrhage. Treatment includes manual or operative placental extraction, potentially increasing risks of hemorrhage, infections, and prolonged hospital stays. We sought to evaluate risk factors for retained placenta, defined as more than 30 minutes between the delivery of the fetus and placenta, in a large US obstetrical cohort.Study Design: We included singleton, vaginal deliveries ≥24 weeks (n = 91,291) from the Consortium of Safe Labor from 12 US institutions (2002-2008). Multivariable logistic regression analyses estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) for potential risk factors for retained placenta stratified by parity, adjusting for relevant confounding factors. Characteristics such as stillbirth, maternal age, race, and admission body mass index were examined.Results: Retained placenta complicated 1047 vaginal deliveries (1.12%). Regardless of parity, significant predictors of retained placenta included stillbirth (nulliparous adjusted OR, 5.67; 95% CI, 3.10-10.37; multiparous adjusted OR, 4.56; 95% CI, 2.08-9.94), maternal age ≥30 years, delivery at 24 0/7 to 27 6/7 compared with 34 weeks or later and delivery in a teaching hospital. In nulliparous women, additional risk factors were identified: longer first- or second-stage labor duration, whereas non-Hispanic black compared with non-Hispanic white race was found to be protective. Body mass index was not associated with an increased risk.Conclusion: Multiple risk factors for retained placenta were identified, particularly the strong association with stillbirth. It is plausible that there could be something intrinsic about stillbirth that causes a retained placenta, or perhaps there are shared pathways of certain etiologies of stillbirth and a risk of retained placenta. [ABSTRACT FROM AUTHOR]

Inadequate placental development results in a number of untoward pregnancy outcomes, including pre-eclampsia, placental abruption and infarction, and fetal growth restriction and stillbirth. Although it was once assumed that these pregnancy-related complications caused only upfront maternal and fetal morbidity and mortality, poor placental development and function is now a well-recognized female-specific risk factor for future vascular morbidity and mortality. The epidemiological, genetic, and physiological research linking placental development and cardiovascular disease is growing, and this knowledge will undoubtedly not only translate into improved pregnancy outcomes for at-risk women, but also help to identify which women who had a complicated pregnancy could benefit from long-term follow-up and risk modification for cardiovascular disease. This article reviews the literature and provides suggestions for future follow-up of this vulnerable population of women., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Many previous reports on perinatal mortality mix primary and secondary causes of death, exclude such important causes as necrotizing enterocolitis and intrauterine growth retardation, and do not break down causes of extrinsic perinatal hypoxia. To avoid these criticisms, a slight modification was made of the list of causes of death used by the Perinatal Mortality Committee of Quebec Province, Canada. The methodology and results of 100 consecutive autopsies are described. Respiratory distress syndrome (31%), congenital anomalies (28%), and extrinsic perinatal hypoxia (17%) were the three commonest causes. Maternal, placental, or labor and delivery problems were associated with about half the cases of extrinsic perinatal hypoxia. In one case of unexplained death, sudden infant death syndrome may be considered as a possibility.