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Preeclampsia is a devastating medical complication of pregnancy that can lead to significant maternal and fetal morbidity and mortality. It is currently believed that there is abnormal placentation in as early as the first trimester in women destined to develop preeclampsia. Although the etiology of the abnormal placentation is being debated, numerous epidemiologic and experimental studies suggest that imbalances in circulating angiogenic factors released from the placenta are responsible for the maternal signs and symptoms of preeclampsia. In particular, circulating levels of soluble fms-like tyrosine kinase 1, an antiangiogenic factor, are markedly increased in women with preeclampsia, whereas free levels of its ligand, placental, growth factor are markedly diminished. Alterations in these angiogenic factors precede the onset of clinical signs of preeclampsia and correlate with disease severity. Recently, the availability of automated assays for the measurement of angiogenic biomarkers in the plasma, serum, and urine has helped investigators worldwide to demonstrate a key role for these factors in the clinical diagnosis and prediction of preeclampsia. Numerous studies have reported that circulating angiogenic biomarkers have a very high negative predictive value to rule out clinical disease among women with suspected preeclampsia. These blood-based biomarkers have provided a valuable tool to clinicians to accelerate the time to clinical diagnosis and minimize maternal adverse outcomes in women with preeclampsia. Angiogenic biomarkers have also been useful to elucidate the pathogenesis of related disorders of abnormal placentation such as intrauterine growth restriction, intrauterine fetal death, twin-to-twin transfusion syndrome, and fetal hydrops. In summary, the discovery and characterization of angiogenic proteins of placental origin have provided clinicians a noninvasive blood-based tool to monitor placental function and health and for early detection of disorders of placentation. Uncovering the mechanisms of altered angiogenic factors in preeclampsia and related disorders of placentation may provide insights into novel preventive and therapeutic options.

Fetuses with congenital heart disease are at increased risk of perinatal morbidity and mortality, which is highly influenced by their prenatal health. Placental function is vital for the health of the fetus, but increased rates of pathologic lesions of the placenta have been observed in pregnancies complicated by fetal congenital heart disease.This study aimed to determine the prevalence of both gross and histologic placental pathologies in a cohort of pregnancies complicated by fetal congenital heart disease vs healthy controls using the Amsterdam Placental Workshop Group Consensus Statement sampling and definitions of placental lesions.This single-center retrospective cohort study included placental examinations from pregnancies diagnosed prenatally with fetal congenital heart disease between 2010 and 2019; moreover, control placentas were collected from pregnancies without maternal or fetal complications. Placentas were sampled and evaluated according to the Amsterdam Placental Workshop Group Consensus Statement and gross and histopathologic diagnoses determined.Approximately 80% of fetuses diagnosed with congenital heart disease (n=305) had a placental examination for comparison with controls (n=40). Of note, 239 placentas (78%) in the group with fetal congenital heart disease had at least 1 gross or histopathologic lesion compared with 11 placentas (28%) in the control group (P.01). One-third of placentas complicated by fetal congenital heart disease met the criteria for small for gestational age, and 48% of placentas had one or more chronic lesions, including maternal vascular malperfusion (23% vs 0%; P.01), villitis of unknown etiology (22% vs 0%; P.01), fetal vascular malperfusion (20% vs 0%; P.01), and other chronic lesions (16% vs 0%; P.01). Acute inflammation was equally present in both the group with fetal congenital heart disease and the control group (28% vs 28%; P=1.00). Although gestational age and birthweight z score were similar between the 2 groups, birth head circumference was 1.5 cm less in pregnancies complicated by fetal congenital heart disease with a significantly lower z score compared with the control group (-0.52±1.22 vs 0.06±0.69; P.01).Vascular malperfusion lesions and chronic forms of inflammation occur at markedly higher rates in placentas complicated by fetal congenital heart disease, which may contribute to the decreased head circumference at birth. Further work in neuroplacentology is needed to explore connections among cardiac defects, placental vascular malperfusion lesions, and fetal brain development.

Placental pathology assessment following delivery in pregnancies complicated by preeclampsia, fetal growth restriction, abruption, and stillbirth reveals a range of underlying diseases. The most common pathology is maternal vascular malperfusion, characterized by high-resistance uterine artery Doppler waveforms and abnormal expression of circulating maternal angiogenic growth factors. Rare placental diseases (massive perivillous fibrinoid deposition and chronic histiocytic intervillositis) are reported to have high recurrence risks, but their associations with uterine artery Doppler waveforms and angiogenic growth factors are presently ill-defined.To characterize the patterns of serial placental growth factor measurements and uterine artery Doppler waveform assessments in pregnancies that develop specific types of placental pathology to gain insight into their relationships with the timing of disease onset and pregnancy outcomes.A retrospective cohort study conducted between January 2017 and November 2021 included all singleton pregnancies with at least 1 measurement of maternal circulating placental growth factor between 16 and 36 weeks' gestation, delivery at our institution, and placental pathology analysis demonstrating diagnostic features of maternal vascular malperfusion, fetal vascular malperfusion, villitis of unknown etiology, chronic histiocytic intervillositis, or massive perivillous fibrinoid deposition. Profiles of circulating placental growth factor as gestational age advanced were compared between these placental pathologies. Maternal and perinatal outcomes were recorded.A total of 337 pregnancies from 329 individuals met our inclusion criteria. These comprised placental pathology diagnoses of maternal vascular malperfusion (n=109), fetal vascular malperfusion (n=87), villitis of unknown etiology (n=96), chronic histiocytic intervillositis (n=16), and massive perivillous fibrinoid deposition (n=29). Among patients who developed maternal vascular malperfusion, placental growth factor levels gradually declined as pregnancy progressed (placental growth factor10th percentile at 16-20 weeks' gestation in 42.9%; 20-24 weeks in 61.9%; 24-28 weeks in 77%; and 28-32 weeks in 81.4%) accompanied by mean uterine artery Doppler pulsatility index95th percentile in 71.6% cases. Patients who developed either fetal vascular malperfusion or villitis of unknown etiology mostly exhibited normal circulating placental growth factor values in association with normal uterine artery Doppler waveforms (mean [standard deviation] pulsatility index values: fetal vascular malperfusion, 1.14 [0.49]; villitis of unknown etiology, 1.13 [0.45]). Patients who developed either chronic histiocytic intervillositis or massive perivillous fibrinoid deposition exhibited persistently low placental growth factor levels from the early second trimester (placental growth factor10th centile at 16-20 weeks' gestation in 80% and 77.8%, respectively; 20-24 weeks in 88.9% and 63.6%; 24-28 weeks in 85.7% and 75%), all in combination with normal uterine artery Doppler waveforms (mean pulsatility index95th centile: chronic histiocytic intervillositis, 25%; massive perivillous fibrinoid deposition, 37.9%). Preeclampsia developed in 83 of 337 (24.6%) patients and was most common in those developing maternal vascular malperfusion (54/109, 49.5%) followed by chronic histiocytic intervillositis (7/16, 43.8%). There were 29 stillbirths in the cohort (maternal vascular malperfusion, n=10 [9.2%]; fetal vascular malperfusion, n=5 [5.7%]; villitis of unknown etiology, n=1 [1.0%]; chronic histiocytic intervillositis, n=7 [43.8%]; massive perivillous fibrinoid deposition, n=6 [20.7%]). Most patients experiencing stillbirth exhibited normal uterine artery Doppler waveforms (21/29, 72.4%) and had nonmaternal vascular malperfusion pathologies (19/29, 65.5%). By contrast, 28 of 29 (96.5%) patients experiencing stillbirth had ≥1 low placental growth factor values before fetal death.Serial circulating maternal placental growth factor tests, in combination with uterine artery Doppler waveform assessments in the second trimester, may indicate the likely underlying type of placental pathology mediating severe adverse perinatal events. This approach has the potential to test disease-specific therapeutic strategies to improve clinical outcomes. Serial placental growth factor testing, compared with uterine artery Doppler studies, identifies a greater proportion of patients destined to have a poor perinatal outcome because diseases other than maternal vascular malperfusion are characterized by normal uteroplacental circulation.

Background Chronic histiocytic intervillositis (chronic intervillositis) is defined by a diffuse infiltration of monocytes into the intervillous space, which often leads to poor obstetrical outcomes, including recurrent intrauterine growth restriction, miscarriage, and fetal death. The pathogenesis of chronic intervillositis is still poorly defined, and there is an unmet medical need for improved management. Objective This study aimed to demonstrate the role of anti–human leukocyte antigen alloantibodies in the pathogenesis of chronic intervillositis through the application of criteria used in solid-organ transplantation for the diagnosis of antibody-mediated rejection. Study Design A multidisciplinary research study based on thorough immunologic and pathologic investigations was carried out for 2 separate couples who experienced recurrent secondary fetal losses following a first normal pregnancy associated with histologic evidence of chronic intervillositis. Results Very high levels of complement-fixing, fetus-specific antibodies targeting mismatched human leukocyte antigen alleles, harbored by the 2 paternal haplotypes, were identified in both cases. Polymorphic human leukocyte antigens were expressed on the surface of trophoblastic villi of the inflamed placenta but not in healthy placental tissue. The binding of alloantibodies to paternal human leukocyte antigens induced dramatic activation of the complement classical pathway in trophoblastic villi, leading to C4d deposition and formation of the terminal complex C5b-9. All requirements for the diagnosis of antibody-mediated placental rejection were fulfilled according to the criteria used in the Banff classification of allograft pathology. In silico analysis was performed using a human leukocyte antigen epitope viewer to reconstitute the human leukocyte antigen sensitization history. Reactivity against a single mismatched epitope present in the first-born healthy child accounted for a broad sensitization to human leukocyte antigens, including those harbored by the 2 paternal haplotypes. This finding explained the high rates of chronic intervillositis recurrence during subsequent pregnancies. Conclusion This study provides novel mechanistic insights into the pathogenesis of chronic intervillositis and provides new avenues for individualized counseling and therapeutic options.

Severe acute respiratory syndrome coronavirus 2, the disease-causing pathogen of the coronavirus disease 2019 pandemic, has resulted in morbidity and mortality worldwide. Pregnant women are more susceptible to severe coronavirus disease 2019 and are at higher risk of preterm birth than uninfected pregnant women. Despite this evidence, the immunologic effects of severe acute respiratory syndrome coronavirus 2 infection during pregnancy remain understudied.This study aimed to assess the impact of severe acute respiratory syndrome coronavirus 2 infection during pregnancy on inflammatory and humoral responses in maternal and fetal samples and compare antibody responses to severe acute respiratory syndrome coronavirus 2 among pregnant and nonpregnant women.Immune responses to severe acute respiratory syndrome coronavirus 2 were analyzed using samples from pregnant (n=33) and nonpregnant (n=17) women who tested either positive (pregnant, 22; nonpregnant, 17) or negative for severe acute respiratory syndrome coronavirus 2 (pregnant, 11) at Johns Hopkins Hospital. We measured proinflammatory and placental cytokine messenger RNAs, neonatal Fc receptor expression, and tetanus antibody transfer in maternal and cord blood samples. In addition, we evaluated antispike immunoglobulin G, antispike receptor-binding domain immunoglobulin G, and neutralizing antibody responses to severe acute respiratory syndrome coronavirus 2 in serum or plasma collected from nonpregnant women, pregnant women, and cord blood.Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection expressed more interleukin-1 beta, but not interleukin 6, in blood samples collected within 14 days vs14 days after performing severe acute respiratory syndrome coronavirus 2 test. Pregnant women with laboratory-confirmed severe acute respiratory syndrome coronavirus 2 infection also had reduced antispike receptor-binding domain immunoglobulin G titers and were less likely to have detectable neutralizing antibody than nonpregnant women. Although severe acute respiratory syndrome coronavirus 2 infection did not disrupt neonatal Fc receptor expression in the placenta, maternal transfer of severe acute respiratory syndrome coronavirus 2 neutralizing antibody was inhibited by infection during pregnancy.Severe acute respiratory syndrome coronavirus 2 infection during pregnancy was characterized by placental inflammation and reduced antiviral antibody responses, which may impact the efficacy of coronavirus disease 2019 treatment in pregnancy. In addition, the long-term implications of placental inflammation for neonatal health require greater consideration.

Pregnant individuals infected with SARS-CoV-2 have higher rates of intensive care unit admission, oxygen requirement, need for mechanical ventilation, and death than nonpregnant individuals. Increased COVID-19 disease severity may be associated with an increased risk of viremia and placental infection. Maternal SARS-CoV-2 infection is also associated with pregnancy complications such as preeclampsia and preterm birth, which can be either placentally mediated or reflected in the placenta. Maternal viremia followed by placental infection may lead to maternal-fetal transmission (vertical), which affects 1% to 3% of exposed newborns. However, there is no agreed-upon or standard definition of placental infection. The National Institutes of Health/Eunice Kennedy Shriver National Institute of Child Health and Human Development convened a group of experts to propose a working definition of placental infection to inform ongoing studies of SARS-CoV-2 during pregnancy. Experts recommended that placental infection be defined using techniques that allow virus detection and localization in placental tissue by one or more of the following methods: in situ hybridization with antisense probe (detects replication) or a sense probe (detects viral messenger RNA) or immunohistochemistry to detect viral nucleocapsid or spike proteins. If the abovementioned methods are not possible, reverse transcription polymerase chain reaction detection or quantification of viral RNA in placental homogenates, or electron microscopy are alternative approaches. A graded classification for the likelihood of placental infection as definitive, probable, possible, and unlikely was proposed. Manuscripts reporting placental infection should describe the sampling method (location and number of samples collected), method of preservation of tissue, and detection technique. Recommendations were made for the handling of the placenta, examination, and sampling and the use of validated reagents and sample protocols (included as appendices).

Background Group B Streptococcus is a common vaginal bacterium and the leading cause of invasive fetoplacental infections. Group B Streptococcus in the vagina can invade through the cervix to cause ascending uteroplacental infections or can be transmitted to the neonate during vaginal delivery. Some studies have found that women with a “dysbiotic” polymicrobial or Lactobacillus-depleted vaginal microbiota are more likely to harbor group B Streptococcus. Gardnerella vaginalis is often the most abundant bacteria in the vaginas of women with dysbiosis, while being detected at lower levels in most other women, and has been linked with several adverse pregnancy outcomes. Mouse models of group B Streptococcus and Gardnerella vaginalis colonization have been reported but, to the best of our knowledge, the two have not been studied together. The overarching idea driving this study is that certain members of the dysbiotic vaginal microbiota, such as Gardnerella vaginalis, may directly contribute to the increased rate of group B Streptococcus vaginal colonization observed in women with vaginal dysbiosis. Objective We used a mouse model to test the hypothesis that vaginal exposure to Gardnerella vaginalis may facilitate colonization and/or invasive infection of the upper reproductive tract by group B Streptococcus during pregnancy. Study Design Timed-pregnant mice were generated using an allogeneic mating strategy with BALB/c males and C57Bl/6 females. Dams were vaginally inoculated at gestational day 14 with group B Streptococcus alone (using a 10-fold lower dose than previously reported models) or coinoculated with group B Streptococcus and Gardnerella vaginalis. Bacterial titers were enumerated in vaginal, uterine horn, and placental tissues at gestational day 17. The presence (Fisher exact tests) and levels (Mann-Whitney U tests) of bacterial titers were compared between mono- and coinoculated dams in each compartment. Relative risks were calculated for outcomes that occurred in both groups. Tissue samples were also examined for evidence of pathophysiology. Results Inoculation of pregnant mice with 107 group B Streptococcus alone did not result in vaginal colonization or ascending infection. In contrast, coinoculation of group B Streptococcus with Gardnerella vaginalis in pregnant mice resulted in a 10-fold higher risk of group B Streptococcus vaginal colonization (relative risk, 10.31; 95% confidence interval, 2.710–59.04; P=.0006 [Fisher exact test]). Ascending group B Streptococcus infection of the uterus and placenta occurred in approximately 40% of coinoculated animals, whereas none of those receiving group B Streptococcus alone developed uterine or placental infections. Immunofluorescence microscopy revealed group B Streptococcus in both the maternal and fetal sides of the placenta. Histologic inflammation and increased proinflammatory cytokines were evident in the setting of group B Streptococcus placental infection. Interestingly, placentas from dams exposed to group B Streptococcus and Gardnerella vaginalis, but without recoverable vaginal or placental bacteria, displayed distinct histopathologic features and cytokine signatures. Conclusion These data suggest that Gardnerella vaginalis vaginal exposure can promote group B Streptococcus vaginal colonization, resulting in a greater likelihood of invasive perinatal group B Streptococcus infections. These findings suggest that future clinical studies should examine whether the presence of Gardnerella vaginalis is a risk factor for group B Streptococcus vaginal colonization in women. Because Gardnerella vaginalis can also be present in women without bacterial vaginosis, these findings may be relevant both inside and outside of the context of vaginal dysbiosis.

Placental pathology can be useful in a variety of ways including immediate diagnosis of important conditions affecting the mother or infant, identifying conditions that are likely to recur in subsequent pregnancies, separating clinical syndromes into distinct pathological phenotypes for further investigation, and uncovering the underlying cause of unexpected adverse outcomes. Classification of placental lesions has evolved from being a purely descriptive exercise through a stage in which the major pathophysiological processes such as disorders of maternal implantation and the amniotic fluid infection syndrome were first described to a recently proposed comprehensive classification system that includes all of the major maternal and fetal vascular and infectious and idiopathic/immune inflammatory processes (Amsterdam Placental Workshop Group). Implementation of this unified system with reproducible grading and staging should help establish evidence-based recommendations for placental submission and facilitate progress in studying the pathogenesis, diagnosis, and treatment of obstetric disorders with an underlying placental etiology.

Abnormal placentation is responsible for most failures in pregnancy; however, an understanding of placental functions remains largely concealed from noninvasive, in vivo investigations. Magnetic resonance imaging (MRI) is safe in pregnancy for magnetic fields of up to 3 Tesla and is being used increasingly to improve the accuracy of prenatal imaging. Functional MRI (fMRI) of the placenta has not yet been validated in a clinical setting, and most data are derived from animal studies. FMRI could be used to further explore placental functions that are related to vascularization, oxygenation, and metabolism in human pregnancies by the use of various enhancement processes. Dynamic contrast-enhanced MRI is best able to quantify placental perfusion, permeability, and blood volume fractions. However, the transplacental passage of Gadolinium-based contrast agents represents a significant safety concern for this procedure in humans. There are alternative contrast agents that may be safer in pregnancy or that do not cross the placenta. Arterial spin labeling MRI relies on magnetically labeled water to quantify the blood flows within the placenta. A disadvantage of this technique is a poorer signal-to-noise ratio. Based on arterial spin labeling, placental perfusion in normal pregnancy is 176 ± 91 mL × min(-1) × 100 g(-1) and decreases in cases with intrauterine growth restriction. Blood oxygen level-dependent and oxygen-enhanced MRIs do not assess perfusion but measure the response of the placenta to changes in oxygen levels with the use of hemoglobin as an endogenous contrast agent. Diffusion-weighted imaging and intravoxel incoherent motion MRI do not require exogenous contrast agents, instead they use the movement of water molecules within tissues. The apparent diffusion coefficient and perfusion fraction are significantly lower in placentas of growth-restricted fetuses when compared with normal pregnancies. Magnetic resonance spectroscopy has the ability to extract information regarding metabolites from the placenta noninvasively and in vivo. There are marked differences in all 3 metabolites N-acetyl aspartate/choline levels, inositol/choline ratio between small, and adequately grown fetuses. Current research is focused on the ability of each fMRI technique to make a timely diagnosis of abnormal placentation that would allow for appropriate planning of follow-up examinations and optimal scheduling of delivery. These research programs will benefit from the use of well-defined sequences, standardized imaging protocols, and robust computational methods.

During pregnancy, the placenta releases a variety of nucleic acids (including deoxyribonucleic acid, messenger ribonucleic acid, or microribonucleic acids) either as a result of cell turnover or as an active messaging system between the placenta and cells in the maternal body. The profile of released nucleic acids changes with the gestational age and has been associated with maternal and fetal parameters. It also can directly reflect pathological changes in the placenta. Nucleic acids may therefore provide a rich source of novel biomarkers for the prediction of pregnancy complications. However, their utility in the clinical setting depends, first, on overcoming some technical considerations in their quantification, and, second, on developing a better understanding of the factors that influence their function and abundance.

While elevated second-trimester maternal serum alpha fetoprotein has been associated with adverse pregnancy outcomes, the utility of first-trimester maternal serum alpha fetoprotein in predicting these outcomes is limited. Some laboratories have been including maternal serum alpha fetoprotein as part of the first-trimester analyte screening for aneuploidy and preeclampsia, offering its potential utility in predicting pregnancy outcomes.Our primary objective was to determine the association between elevated first-trimester maternal serum alpha fetoprotein and preeclampsia as well as ischemic placental disease (a composite of preeclampsia, fetal growth restriction, and/or placental abruption). Secondary outcomes included early-onset preeclampsia requiring delivery at34 weeks gestation, fetal growth restriction, placental abruption, preterm delivery, fetal demise, and spontaneous abortion.An institutional review board-approved multisite retrospective cohort study was performed including all patients with first-trimester maternal serum alpha fetoprotein as part of routine first-trimester aneuploidy screening from April 2015 through January 2017. Pregnancies with multiple gestations, known structural or chromosomal abnormalities, known malignancy, and incomplete delivery records were excluded. Delivery records were reviewed for baseline characteristics and adverse pregnancy outcomes. The optimal cutoff point for first-trimester maternal serum alpha fetoprotein to predict these outcomes was assessed, and an elevated maternal serum alpha fetoprotein was considered2.0 multiple of the median. A Fisher exact test and odds ratios were used to determine the association between elevated first-trimester maternal serum alpha fetoprotein and adverse pregnancy outcomes. Spearman correlation coefficient assessed the relationship between first- and second-trimester maternal serum alpha fetoprotein.Of 1478 patients with first-trimester maternal serum alpha fetoprotein, 1280 had complete records available for review (86.6%). There was no association demonstrated between elevated first-trimester maternal serum alpha fetoprotein (2.0 multiple of the median) and the primary outcome, overall preeclampsia (5.8% vs 4.6%, odds ratio, 1.29, 95% confidence interval, 0.58-2.91). However, there was an increased incidence of ischemic placental disease, 15.8% vs 7.7% (odds ratio, 2.26, 95% confidence interval, 1.33-3.87) in those with an elevated alpha fetoprotein. Also, elevated first-trimester maternal serum alpha fetoprotein was associated with a higher incidence of fetal growth restriction (7.5% vs 2.3%, odds ratio, 3.40, 95% confidence interval, 1.56-7.42) and preterm birth (18.3% vs 10.3%, odds ratio, 1.95, 95% confidence interval, 1.18-3.21). Also, a positive correlation between first- and second-trimester maternal serum alpha fetoprotein was demonstrated (rho = 0.46, P.0001).Elevated first-trimester maternal serum alpha fetoprotein is associated with ischemic placental disease, fetal growth restriction, and preterm birth. This suggests that elevated maternal serum alpha fetoprotein may help to identify high risk pregnancies as early as the first trimester of pregnancy. Future studies are necessary to determine whether the addition of first-trimester maternal serum alpha fetoprotein to existing algorithms can improve the early detection of ischemic placental disease.

Background The availability and use of frozen embryos after ovarian hyperstimulation for assisted reproduction has increased with improvement in vitrification techniques and the rise of preimplantation genetic testing. However, there are conflicting data regarding whether obstetric outcomes differ between fresh and frozen embryo transfer cycles. Objective To compare placental pathology from live births arising from fresh and frozen embryo transfer cycles. Materials and Methods A cohort of 1140 live births with placental pathology arising from autologous in vitro fertilization cycles with fresh or frozen programmed transfer performed at MGH Fertility Center between 2004 and 2017 was retrospectively reviewed. An experienced placental pathologist categorized the reported placental pathology as anatomic, infectious, inflammatory, or vascular/thrombotic. Our primary outcomes were differences in these placental pathologies between the 2 groups. Patient demographic, cycle, and birth outcomes were compared with the use of χ2 tests, Student t test, or nonparametric tests, as appropriate. Multivariate logistic regression models were used to compare placental pathology between the fresh and frozen transfer groups. Results Of the 1140 cycles included in our analysis, 929 arose from fresh embryo transfers (81.3%) and 211 arose from programmed frozen embryo transfers (18.5%). For both transfer types, the average age of the women at time of treatment was 35 years; mean body mass indices were within the normal range (23.6 kg/m2 for fresh transfers and 23.2 kg/m2 for frozen transfers, P = .26), and mean day 3 follicle-stimulating hormone values were 7.1 and 7.0 IU/L (P = .44), respectively. Deliveries occurred on average at 37.5 and 38.0 weeks’ gestational age (P = .04) in the fresh versus frozen transfer group, with similar rates of obstetric complications. However, frozen transfers were more likely to be associated with marginal cord insertion (adjusted odds ratio, 1.87; confidence interval, 1.21, 2.91; P = .01), accessory lobe formation (adjusted odds ratio, 2.96; confidence interval, 1.12, 7.79; P = 0.03), subchorionic thrombi (adjusted odds ratio, 3.72; confidence interval, 1.80, 7.71; P Conclusion Pregnancies arising from frozen embryo transfers demonstrated more anatomic and vascular placental pathology than those from fresh transfers in our cohort of patients, despite similar maternal outcomes. More research is needed to explore how these differences in pathology may influence obstetric and perinatal outcomes.

Infants born small for gestational age because of pathologic placenta-mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term consequences has been observed. Gene expression studies of fetal growth-restricted placentas also have limited consistency in their findings, which is likely due to the presence of different molecular subtypes of disease. In our previous study on preeclampsia, another heterogeneous placenta-centric disorder of pregnancy, we found that, by clustering placentas based only on their gene expression profiles, multiple subtypes of preeclampsia, including several with co-occurring suspected fetal growth restriction, could be identified.The purpose of this study was to discover placental subtypes of normotensive small-for-gestational-age pregnancies with suspected fetal growth restriction through the use of unsupervised clustering of placental gene expression data and to investigate their relationships with hypertensive suspected fetal growth-restricted placental subtypes.A new dataset of 20 placentas from normotensive small-for-gestational-age pregnancies (birthweight10th percentile for gestational age and sex) with suspected fetal growth restriction (ultrasound features of placental insufficiency) underwent genome-wide messenger RNA expression assessment and blinded detailed histopathologic evaluation. These samples were then combined with a subset of samples from our previously published preeclampsia cohort (n=77) to form an aggregate fetal growth-focused cohort (n=97) of placentas from normotensive small-for-gestational-age, hypertensive (preeclampsia and chronic hypertensive) small-for-gestational-age, and normotensive average-for-gestational-age pregnancies. Gene expression data were subjected to unsupervised clustering, and clinical and histopathologic features were correlated to the identified sample clusters.Clustering of the aggregate dataset revealed 3 transcriptional subtypes of placentas from normotensive small-for-gestational-age/suspected fetal growth-restricted pregnancies, with differential enrichment of clinical and histopathologic findings. The first subtype exhibited either no placental disease or mild maternal vascular malperfusion lesions, and, co-clustered with the healthy average-for-gestational-age control subjects; the second subtype showed more severe evidence of hypoxic damage and lesions of maternal vascular malperfusion, and the third subtype demonstrated an immune/inflammatory response and histologic features of a maternal-fetal interface disturbance. Furthermore, all 3 of these normotensive small-for-gestational-age subtypes co-clustered with a group of placentas from hypertensive small-for-gestational-age pregnancies with more severe clinical outcomes, but very comparable transcriptional and histologic placental profiles.Overall, this study provides evidence for at least 2 pathologic placental causes of normotensive small-for-gestational-age, likely representing true fetal growth restriction. These subtypes also show considerable similarity in gene expression and histopathology to our previously identified "canonical" and "immunologic" preeclampsia placental subtypes. Furthermore, we discovered a subtype of normotensive small-for-gestational-age (with suspected fetal growth restriction) with minimal placental disease that may represent both constitutionally small infants and mild fetal growth restriction, although these cannot be distinguished with the currently available data. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of fetal growth restriction is warranted.

Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction.

Syphilis remains the most common congenital infection worldwide and has tremendous consequences for the mother and her developing fetus if left untreated. Recently, there has been an increase in the number of congenital syphilis cases in the United States. Thus, recognition and appropriate treatment of reproductive-age women must be a priority. Testing should be performed at initiation of prenatal care and twice during the third trimester in high-risk patients. There are 2 diagnostic algorithms available and physicians should be aware of which algorithm is utilized by their testing laboratory. Women testing positive for syphilis should undergo a history and physical exam as well as testing for other sexually transmitted infections, including HIV. Serofast syphilis can occur in patients with previous adequate treatment but persistent low nontreponemal titers (1:8). Syphilis can infect the fetus in all stages of the disease regardless of trimester and can sometimes be detected with ultrasound20 weeks. The most common findings include hepatomegaly and placentomegaly, but also elevated peak systolic velocity in the middle cerebral artery (indicative of fetal anemia), ascites, and hydrops fetalis. Pregnancies with ultrasound abnormalities are at higher risk of compromise during syphilotherapy as well as fetal treatment failure. Thus, we recommend a pretreatment ultrasound in viable pregnancies when feasible. The only recommended treatment during pregnancy is benzathine penicillin G and it should be administered according to maternal stage of infection per Centers for Disease Control and Prevention guidelines. Women with a penicillin allergy should be desensitized and then treated with penicillin appropriate for their stage of syphilis. The Jarisch-Herxheimer reaction occurs in up to 44% of gravidas and can cause contractions, fetal heart rate abnormalities, and even stillbirth in the most severely affected pregnancies. We recommend all viable pregnancies receive the first dose of benzathine penicillin G in a labor and delivery department under continuous fetal monitoring for at least 24 hours. Thereafter, the remaining benzathine penicillin G doses can be given in an outpatient setting. The rate of maternal titer decline is not tied to pregnancy outcomes. Therefore, after adequate syphilotherapy, maternal titers should be checked monthly to ensure they are not increasing four-fold, as this may indicate reinfection or treatment failure.

OBJECTIVE: We sought to evaluate the contribution of different diagnostic tests for determining cause of fetal death. Our goal was to propose a workup guideline.STUDY DESIGN: In a multicenter prospective cohort study from 2002 through 2008, for 1025 couples with fetal death >= 20 weeks' gestation, an extensive nonselective diagnostic workup was performed. A panel classified cause and determined contribution of diagnostics for allocating cause.RESULTS: A Kleihauer-Betke, autopsy, placental examination, and cytogenetic analysis were abnormal in 11.9% (95% confidence interval [CI], 9.8-14.2), 51.5% (95% CI, 47.4-55.2), 89.2% (95% CI, 87.2-91.1), and 11.9% (95% CI, 8.7-15.7), respectively. The most valuable tests for determination of cause were placental examination (95.7%; 95% CI, 94.2-96.8), autopsy (72.6%; 95% CI, 69.2-75.9), and cytogenetic analysis (29.0%; 95% CI, 24.4-34.0).CONCLUSION: Autopsy, placental examination, cytogenetic analysis, and testing for fetal maternal hemorrhage are basic tests for workup after fetal death. Based on the results of these tests or on specific clinical characteristics, further sequential testing is indicated.

Background The diagnosis of twin-to-twin transfusion syndrome (TTTS) usually relies the presence of polyhydramnios in one sac with concomitant oligohydramnios in the other sac in a monochorionic diamniotic twin pregnancy. However, TTTS does not always show a linear progression and may present with cardiac compromise or critically abnormal Doppler velocimetry in either fetus before fluid measurements meet the typically used cutoff. Objective The aim of this study was to investigate the prevalence of atypical presentations of TTTS in a population undergoing laser fetoscopy. Study Design We performed a retrospective review of our database of TTTS laser fetoscopy from 2003 to the present. Our center is the regional referral center in the Pacific Northwest for minimally invasive treatment of complicated monochorionic twin pregnancies. Cases were labeled as “atypical” if fluid discordance did not meet formal TTTS criteria (oligohydramnios defined as maximum vertical pocket [MVP] 8 before 20 weeks and >10 after 20 weeks). The rationale for consideration of laser fetoscopy was other evidence of severe TTTS such as significant cardiac compromise, evidence of twin anemia polycythemia sequence (TAPS), or persistent critically abnormal cord Dopplers. Results Three hundred seventy-nine cases of fetoscopic laser ablation for TTTS and its variants were available for review. Sixteen cases were excluded for a triplet pregnancy, 4 due to septostomy prior to referral to our center, 3 for monoamniotic pregnancy, and 11 for previous laser fetoscopy. Three hundred forty-five cases remained for evaluation. Among these, 25 cases were identified as “atypical,” equaling 7.24% of our population. Eleven of these were for stage 3 recipient disease, 3 were for stage 4 recipient disease, 4 were for stage 3 both in recipient and donor, 4 were for stage 3 donor disease, and 3 were for spontaneous TAPS. Conclusion In TTTS, severity of fetal compromise does not consistently correlate with fluid abnormalities meeting established criteria. This may be especially true in rapidly progressing cases. Attempts at rigid diagnostic amniotic fluid criteria may underestimate the severity and incidence of TTTS. This underscores the importance of careful surveillance, including arterial and venous Doppler velocimetry, of all monochorionic pregnancies.

We sought to evaluate the extent of the association between placental implantation abnormalities (PIA) and preterm delivery in singleton gestations. We conducted a systematic review of English-language articles published from 1980 onward using PubMed, MEDLINE, EMBASE, CINAHL, LILACS, and Google Scholar, and by identifying studies cited in the references of published articles. Search terms were PIA defined as ≥ 1 of the following: placenta previa, placenta accreta, vasa previa, and velamentous cord insertion. Observational and experimental studies were included for review if data were available regarding any of the aforementioned PIA and regarding gestational age at delivery or preterm delivery. Case reports and case series were excluded. Studies were reviewed and data extracted. The primary outcome was gestational age at delivery or preterm delivery37 weeks' gestation. Secondary outcomes included birthweight, 1- and 5-minute Apgar scores, neonatal intensive care unit (NICU) admission, neonatal and perinatal death, and small for gestational age. Of the 1421 studies identified, 79 met the defined criteria; 56 studies were descriptive and 23 were comparative. Based on the descriptive studies, the preterm delivery rates for low-lying/marginal placenta, placenta previa, placenta accreta, vasa previa, and velamentous cord insertion were 26.9%, 43.5%, 57.7%, 81.9%, and 37.5%, respectively. Based on the comparative studies using controls, there was decreased pregnancy duration for every PIA; more specifically, there was an increased risk for preterm delivery in patients with placenta previa (risk ratio [RR], 5.32; 95% confidence interval [CI], 4.39-6.45), vasa previa (RR, 3.36; 95% CI, 2.76-4.09), and velamentous cord insertion (RR, 1.95; 95% CI, 1.67-2.28). Risks of NICU admissions (RR, 4.09; 95% CI, 2.80-5.97), neonatal death (RR, 5.44; 95% CI, 3.03-9.78), and perinatal death (RR, 3.01; 95% CI, 1.41-6.43) were higher with placenta previa. Perinatal risks were also higher in patients with vasa previa (perinatal death rate RR, 4.52; 95% CI, 2.77-7.39) and velamentous cord insertion (NICU admissions [RR, 1.76; 95% CI, 1.68-1.84], small for gestational age [RR, 1.69; 95% CI, 1.56-1.82], and perinatal death [RR, 2.15; 95% CI, 1.84-2.52]). In singleton gestations, there is a strong association between PIA and preterm delivery resulting in significant perinatal morbidity and mortality.

Objective Many previous studies of agreement in identifying placental histopathologic lesions have been based on small sample sizes, and none has examined whether individual histologic features cluster robustly together within and between observers. Study design We studied 767 placental specimens from case-control studies of preterm birth and preeclampsia nested within a prospective cohort of pregnant women recruited from 4 large Montreal maternity hospitals. The specimens were fixed, embedded, stained, and examined using a standardized protocol; a 10% random sample (n = 81) was then blindly reexamined at least 6 months later by the same pathologist and a second pathologist. Results Intra- and interobserver agreement were high (κ ≥ 0.50) for membrane inflammation, funisitis, and umbilical cord vasculitis, and these 3 features were robustly clustered statistically, consistent with an underlying mechanism of ascending infection. Agreement and clustering were also high or moderate for features of placental underperfusion: infarction, decidual vasculopathy, and syncytial knotting. Conclusion Our results should help researchers to interpret future findings relating placental histopathology to preterm birth, preeclampsia, and other adverse pregnancy outcomes, and to their etiologic determinants and causal pathways.

Objective The purpose of this study was to identify risk factors and complications of placenta previa-accreta (PA). Study design Patients with placenta previa (n=347) delivered over 20 years were reviewed, divided into PA (cases, n=22) and no accreta (controls, n=325), and compared. Results Cases were older with a higher incidence of smoking and previous cesarean delivery (CS). Grandmultiparity, recurrent abortions, anterior/central placentae, and low socioeconomic status were similar. PA incidence increased with the number of previous CS: 1.9%, 15.6%, 23.5%, 29.4%, 33.3%, and 50.0% after 0, 1, 2, 3, 4, and 5 previous CS, respectively. Hypertensive disorders (odds ratio [OR] 13.9, 95%CI 2.1-91.2], P =.006), smoking (OR 3.4, 95%CI 1.1-10.2, P =.031) and previous CS (OR 7.9, 95%CI 1.7-37.4, P =.009) were selected by the stepwise logistic regression analysis as predictors of PA. Cases had a longer hospital stay, a higher estimated blood loss, and need for transfusion. Cesarean hysterectomy and hypogastric artery ligation were only performed in PA cases. The 2 groups had a similar delivery gestational age and neonatal outcome. Conclusion Hypertensive disorders, smoking, and previous cesarean are risk factors for accreta in placenta previa patients. Placenta previa-accreta is associated with higher maternal morbidity, but similar neonatal outcome compared with patients with an isolated placenta previa.

The purpose of this study was to investigate the expression of epidermal growth factor receptor and c-erbB-2 oncoprotein in trophoblast populations of placenta accreta.Paraffin sections of 43 placental specimens with (cases) and 43 without (controls) placenta accreta were studied immunohistochemically for epidermal growth factor receptor and c-erbB-2 expression in the syncytiotrophoblast, villous cytotrophoblast, and extravillous cytotrophoblast. Epidermal growth factor receptor and c-erbB-2 protein levels were also performed by Western blot analysis. Controls were matched for gestational age in this case-control study.The percentage of strong/intermediate immunoreactivity of epidermal growth factor receptor in the syncytiotrophoblast was significantly higher in cases (98%) than controls (79%; odds ratio,11.1; 95% CI, 1.3-92.0; P = .03), although strong/intermediate immunoreactivity of c-erbB-2 in the syncytiotrophoblast was significantly lower in cases (35%) than controls (81%; odds ratio, 0.1; 95% CI, 0.1-0.3; P.001). Epidermal growth factor receptor and c-erbB-2 expression in the villous and extravillous cytotrophoblastic cells were not significantly different between controls and cases ( P.05). Most immunoreactive bands on Western blots were consistent with the trends of immunohistochemical findings.The development of placenta accreta is related closely to the differential expression of epidermal growth factor receptor and c-erbB-2 in the syncytiotrophoblast.

Objective The purpose of this study was to determine whether ultrasonography can detect placenta accreta reliably in at-risk patients. Study design All patients with a previous cesarean delivery and an anterior placenta or placenta previa were evaluated prospectively at each visit for sonographic signs of placenta accreta (interruption of the posterior bladder wall–uterine interface, absence of the retroplacental clear zone, and placental lacunae). Results This evaluation involved 2002 patients over a 12-year period. Of the 14 patients with a confirmed diagnosis of placenta accreta who had ultrasound examinations between 15 and 20 weeks of gestation, the diagnosis was suspected strongly in 86% of the patients (12/14 patients). There were 18 false-positive cases (54.5%; 18/33 patients), most of which were due to a lack of visualization of the echolucent area between the placenta and the myometrium (obliteration of the ‘clear space’) during the third trimester. The presence of multiple linear irregular vascular spaces within the placenta (placental lacunae) was the diagnostic sign with the highest positive predictive value for placenta accreta. Conclusion Placenta accreta can be detected as early as 15 to 20 weeks of gestation in most at-risk patients by visualization of irregular vascular spaces within the placenta (placental lacunae). Obliteration of the retroplacental ‘clear space’ is not a reliable diagnostic sign for placenta accreta.

The purpose of this study was to evaluate placental lesions found in women with preeclampsia compared with normotensive control subjects and to determine whether the presence of these lesions are related to gestational age at delivery.Placental disease of women with preeclampsia at 24 to 42 weeks of gestation was compared with the placental disease of normotensive gestational age-matched control subjects. The placental lesions that were studied specifically included decidual arteriolopathy, thrombi in the fetal circulation, central infarction, intervillous thrombi, and hypermaturity of villi. Data analysis involved the chi(2) test, the Student t test, and logistic regression; odds ratios and CIs were estimated.Placentas from women with preeclampsia (n=158) and normotensive control subjects (n=156) were evaluated. Among women with preeclampsia, 67% had severe disease. Placental lesions were studied according to gestational age at delivery:28, 28 to 32, 33 to 36, andor=37 weeks of gestation. Of the placental lesions that were studied, decidual arteriolopathy (odds ratio, 23.8, 95% CI 10.0-57.0), hypermaturity of villi (odds ratio, 12.4; 95% CI 5.3-29.2), intervillous thrombi (odds ratio, 1.95;95% CI 1.0-3.7), central infarction (odds ratio, 5.9; 95% CI 3.1-11.1), and thrombi in the fetal circulation (odds ratio, 2.8; 95% CI 1.2-6.6) were found to have significantly higher rates in the preeclamptic group. In contrast, the rate of chorioamnionitis was significantly lower in the preeclamptic group (odds ratio, 0.2; 95% CI 0.1-0.4). The rates of abruptio placentae and meconium staining were not different between the two groups. Within the preeclamptic group, the rates of decidual arteriolopathy (P.0001), central infarction (P=.0001), and hypermaturity of villi (P.0001) were higher the earlier the gestational age at delivery.Placentas in women with preeclampsia have increased amounts of disease. The rate is increased with lower gestational ages at the time of delivery for women with preeclampsia.

The objective of this study was to determine the clinical significance of the umbilical cord twist direction.Two hundred singleton third-trimester placentas with a right umbilical cord twist and 200 placentas with a left umbilical cord twist, which was determined by pathologic examination, were included. Maternal and neonatal outcomes were compared with the use of Fisher's exact and Mann Whitney U tests; a probability value of.05 considered statistically significant.Placenta previa was more common in patients with a right umbilical cord twist compared with a left umbilical cord twist (6.0% vs 1.5%; P.05). There was a trend towards an increased incidence of single umbilical artery in patients with a right umbilical cord twist (2.5% vs 0%; P=.06). The incidence of fetal demise, intrauterine growth restriction, chromosomal abnormalities, congenital anomalies, preterm delivery, infant gender, birth weight, maternal age, and parity were similar between the 2 groups.Placenta previa is associated with a right umbilical cord twist.

Objective The risk of perinatal death associated with labor after previous cesarean section appears higher than with a repeated cesarean section. On the other hand, repeated cesarean sections are associated with increased maternal morbidity and mortality from placental pathologic conditions (previa or accreta) on subsequent pregnancies. The study was undertaken to analyze the decision for a trial of labor or a repeated cesarean section, after a prior cesarean section, with varying desire for an additional pregnancy. Study design A model was formulated using a decision tree, based on the reported risks of the two approaches. Sensitivity analysis was performed over a variety of probabilities (eg, chance of uterine rupture or neonatal death, chance of rescue cesarean section, desire for an additional pregnancy) and utilities (eg, use of hysterectomy or neonatal death). Results The model favors a trial of labor if it has a chance of success of 50% or above and if the wish for additional pregnancies after a cesarean section is estimated at near 10% to 20% or above because the delayed risks from a repeated cesarean section are greater than its immediate benefit. The model was robust over a wide range of assumptions. Conclusion An optimal decision for a trial of labor or a repeated cesarean section is substantially determined by the wish for future pregnancies. The default option of a repeated cesarean section is not directly applicable in populations in which family planning often extends over two children.

The purpose of the study was to explore the associations of placenta previa with preterm delivery, growth restriction, and neonatal survival.A retrospective cohort study was performed of live births in the United States (1989-1991 and 1995-1997) that used the national linked birth/infant death records from 22,368,235 singleton pregnancies. The diagnosis of previa was restricted to those live births that were delivered (or =24 weeks) by cesarean delivery. We evaluated gestational age and birth weight-specific risk of neonatal deaths (within the first 28 days) in relation to placenta previa. Fetal growth was assessed in centiles of birth weight (3rd, 3rd-4th, 5th-9th, 10th-90th, and90th centile), adjusted for gestational age. All analyses were adjusted for the confounding effects of the year of delivery, maternal age, gravidity, education, prenatal care, marital status, and race/ethnicity.Placenta previa was recorded in 2.8 per 1000 live births (n = 61,711). Neonatal mortality rate was 10.7 with previa, compared with 2.5 per 1,000 among other pregnancies (relative risk, 4.3; 95% confidence interval, 4.0,4.8). At 28 to 36 weeks, babies born to women with placenta previa weighed, on average, 210 g lower than babies born to women without placenta previa (P.001). Compared with babies born to women without previa, the risk of death from placenta previa was lower among preterm babies (37 weeks of gestation), with a crossover at 37 weeks where the mortality rate was higher for babies born to women with placenta previa than for babies born to women without placenta previa. This crossover also persisted in an analysis by birth weight and term births (delivered ator =37 weeks of gestation). Mortality rates for term births were higher among babies born to women with placenta previa than among babies born women without placenta previa who were at the 10th to 90th centile (relative risk, 1.9; 95% confidence interval, 1.3, 2.8), and those at90th centile (relative risk, 3.6; 95% confidence interval, 1.3, 9.6). Among preterm births, however, placenta previa was not associated with increased neonatal mortality by fetal growth centiles.The risk of neonatal mortality was higher for babies born to women with placenta previa than for babies born to women without placenta previa who were delivered ator =37 weeks of gestation. Pregnancies that are diagnosed with placenta previa must be monitored carefully, especially as they approach term.

Births to subfertile women, with and without infertility treatment, have been reported to have lower birthweights and shorter gestations, even when limited to singletons. It is unknown whether these decrements are due to parental characteristics or aspects of infertility treatment.The objective of the study was to evaluate the effect of maternal fertility status on the risk of pregnancy, birth, and infant complications.All singleton live births of ≥22 weeks' gestation and ≥350 g birthweight to Massachusetts resident women in 2004-2010 were linked to hospital discharge and vital records. Women were categorized by their fertility status as in vitro fertilization, subfertile, or fertile. Women whose births linked to in vitro fertilization cycles from the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System were classified as in vitro fertilization. Women with indicators of subfertility but not treated with in vitro fertilization were classified as subfertile. Women without indicators of subfertility or in vitro fertilization treatment were classified as fertile. Risks of 15 adverse outcomes (gestational diabetes, pregnancy hypertension, antenatal bleeding, placental complications [placenta abruptio and placenta previa], prenatal hospitalizations, primary cesarean delivery, very low birthweight [1500 g], low birthweight [2500 g], small-for-gestation birthweight [z-score ≤-1.28], large-for-gestation birthweight [z-score ≥1.28], very preterm [32 weeks], preterm [37 weeks], birth defects, neonatal death [0-27 days], and infant death [0-364 days of life]) were modeled by fertility status with the fertile group as reference and the subfertile group as reference, using multivariate log binomial regression and reported as adjusted risk ratios and 95% confidence intervals.The study population included 459,623 women (441,420 fertile, 8054 subfertile, and 10,149 in vitro fertilization). Women in the subfertile and in vitro fertilization groups were older than their fertile counterparts. Risks for 6 of 6 pregnancy outcomes and 6 of 9 infant outcomes were increased for the subfertile group, and 5 of 6 pregnancy outcomes and 7 of 9 infant outcomes were increased for the in vitro fertilization group. For 4 of the 6 pregnancy outcomes (uterine bleeding, placental complications, prenatal hospitalizations, and primary cesarean) and 2 of the infant outcomes (low birthweight and preterm) the risk was greater in the in vitro fertilization group, with nonoverlapping confidence intervals to the subfertile group, indicating a substantially higher risk among in vitro fertilization-treated women. The highest risks for the in vitro fertilization women were uterine bleeding (adjusted risk ratio, 3.80; 95% confidence interval, 3.31-4.36) and placental complications (adjusted risk ratio, 2.81; 95% confidence interval, 2.57-3.08), and for in vitro fertilization infants, very preterm birth (adjusted risk ratio, 2.13; 95% confidence interval, 1.80-2.52), and very low birthweight (adjusted risk ratio, 2.15; 95% confidence interval, 1.80-2.56). With subfertile women as reference, risks for the in vitro fertilization group were significantly increased for uterine bleeding, placental complications, prenatal hospitalizations, primary cesarean delivery, low and very low birthweight, and preterm and very preterm birth.These analyses indicate that, compared with fertile women, subfertile and in vitro fertilization-treated women tend to be older, have more preexisting chronic conditions, and are at higher risk for adverse pregnancy outcomes, particularly uterine bleeding and placental complications. The greater risk in in vitro fertilization-treated women may reflect more severe infertility, more extensive underlying pathology, or other unfavorable factors not measured in this study.

It is unknown whether the risk of adverse outcomes in twin pregnancies among subfertile women, conceived with and without in vitro fertilization, differs from those conceived spontaneously.We sought to evaluate the effects of fertility status on adverse perinatal outcomes in twin pregnancies on a population basis.All twin live births of ≥22 weeks' gestation and ≥350 g birthweight to Massachusetts resident women in 2004 through 2010 were linked to hospital discharge records, vital records, and in vitro fertilization cycles. Women were categorized by their fertility status as in vitro fertilization, subfertile, or fertile, and by twin pair genders (all, like, unlike). Women whose births linked to in vitro fertilization cycles were classified as in vitro fertilization; those with indicators of subfertility but without in vitro fertilization treatment were classified as subfertile; all others were classified as fertile. Risks of 6 adverse pregnancy outcomes (gestational diabetes, pregnancy hypertension, uterine bleeding, placental complications [placenta abruptio, placenta previa, and vasa previa], prenatal hospitalizations, and primary cesarean) and 9 adverse infant outcomes (very low birthweight, low birthweight, small-for-gestation birthweight, large-for-gestation birthweight, very preterm [32 weeks], preterm, birth defects, neonatal death, and infant death) were modeled by fertility status with the fertile group as reference, using multivariate log binomial regression and reported as adjusted relative risk ratios and 95% confidence intervals.The study population included 10,352 women with twin pregnancies (6090 fertile, 724 subfertile, and 3538 in vitro fertilization). Among all twins, the risks for all 6 adverse pregnancy outcomes were significantly increased for the subfertile and in vitro fertilization groups, with highest risks for uterine bleeding (adjusted relative risk ratios, 1.92 and 2.58, respectively) and placental complications (adjusted relative risk ratios, 2.07 and 1.83, respectively). Among all twins, the risks for those born to subfertile women were significantly increased for very preterm birth and neonatal and infant death (adjusted relative risk ratios, 1.36, 1.89, and 1.87, respectively). Risks were significantly increased among in vitro fertilization twins for very preterm birth, preterm birth, and birth defects (adjusted relative risk ratios, 1.28, 1.07, and 1.26, respectively).Risks of all maternal and most infant adverse outcomes were increased for subfertile and in vitro fertilization twins. Among all twins, the highest risks were for uterine bleeding and placental complications for the subfertile and in vitro fertilization groups, and neonatal and infant death in the subfertile group. These findings provide further evidence supporting single embryo transfer and more cautious use of ovulation induction.

Background Opioid use disorder among pregnant women is associated with adverse perinatal outcomes and is increasing in the United States. The standard of care for pregnant women with opioid use disorder is opioid maintenance therapy including either methadone or buprenorphine, which can be initiated at any time during pregnancy. These medications are known to cross the placenta but their placental and fetal effects have not been well characterized. Delayed villous maturation, a placental finding associated with stillbirth, was observed in placentas exposed to opioid maintenance therapy. Given the association of delayed villous maturation with stillbirth, and the possible relationship between opioid maintenance therapy and delayed villous maturation, this study was undertaken to explore the association between opioid maintenance therapy and this placental finding. Delayed villous maturation was not previously reported in placentas exposed to opioids or opioid maintenance therapy. Objective This study sought to compare risk of delayed villous maturation in term placentas exposed and unexposed to opioid maintenance therapy with buprenorphine or methadone. Study Design This was a retrospective cohort study conducted between 2010 through 2012 at Magee-Womens Hospital comparing delayed villous maturation in placentas of women with opioid use disorder exposed to either buprenorphine (n = 86) or methadone (n = 268) versus women without opioid use disorder (n = 978). Potential covariates were assessed in univariate analyses with none significantly associated with delayed villous maturation. The final model used conditional logistic regression adjusting for smoking status alone. Results Among women without opioid use disorder (and therefore not exposed to opioid maintenance therapy), delayed villous maturation was identified in 5.7% of placentas while the prevalence among women treated with buprenorphine or methadone was 8.1% and 10.8%. Overall, the crude odds of being diagnosed with delayed villous maturation were significantly greater in those exposed to opioid maintenance therapy compared to those not exposed (odds ratio, 1.86; 95% confidence interval, 1.20–2.89). When considered separately, women treated with methadone had significantly greater odds of having a placenta with delayed villous maturation than women without exposure to opioid maintenance therapy (odds ratio, 2.00; 95% confidence interval, 1.52–3.20). Women treated with buprenorphine did not have significantly greater odds of this placental diagnosis when compared to the women unexposed to opioid maintenance therapy (odds ratio, 1.46; 95% confidence interval, 0.64–3.31). Results were similar after accounting for smoking. Conclusion Delayed villous maturation was more common in the placentas of women exposed to opioid maintenance therapy. Further studies are required to characterize rates and extent of delayed villous maturation in the general population as well as to differentiate between possible effects of opioid exposure (eg, heroin, illicit use of prescription opioids) vs those of opioid maintenance therapy (buprenorphine and methadone).

Hypervascular placental polypoid mass is a possible source of acute hemorrhage after pregnancy. We present a case report and literature review of a rare case after spontaneous miscarriage. We describe the diagnosis, imaging, and management of placental polyps, which includes the use of iliac artery occlusion catheters with concomitant hysteroscopic resection.

Background The Management of Myelomeningocele Study was a multicenter randomized trial to compare prenatal and standard postnatal closure of myelomeningocele. The trial was stopped early at recommendation of the data and safety monitoring committee and outcome data for 158 of the 183 randomized women published. Objective In this report, pregnancy outcomes for the complete trial cohort are presented. We also sought to analyze risk factors for adverse pregnancy outcome among those women who underwent prenatal myelomeningocele repair. Study Design Pregnancy outcomes were compared between the 2 surgery groups. For women who underwent prenatal surgery, antecedent demographic, surgical, and pregnancy complication risk factors were evaluated for the following outcomes: premature spontaneous membrane rupture ≤34 weeks 0 days (preterm premature rupture of membranes), spontaneous membrane rupture at any gestational age, preterm delivery at ≤34 weeks 0 days, nonintact hysterotomy (minimal uterine wall tissue between fetal membranes and uterine serosa, or partial or complete dehiscence at delivery), and chorioamniotic membrane separation. Risk factors were evaluated using χ 2 and Wilcoxon tests and multivariable logistic regression. Results A total of 183 women were randomized: 91 to prenatal and 92 to postnatal surgery groups. Analysis of the complete cohort confirmed initial findings: that prenatal surgery was associated with an increased risk for membrane separation, oligohydramnios, spontaneous membrane rupture, spontaneous onset of labor, and earlier gestational age at birth. In multivariable logistic regression of the prenatal surgery group adjusting for clinical center, earlier gestational age at surgery and chorioamniotic membrane separation were associated with increased risk of spontaneous membrane rupture (odds ratio, 1.49; 95% confidence interval, 1.01–2.22; and odds ratio, 2.96, 95% confidence interval, 1.05–8.35, respectively). Oligohydramnios was associated with an increased risk of subsequent preterm delivery (odds ratio, 9.21; 95% confidence interval, 2.19–38.78). Nulliparity was a risk factor for nonintact hysterotomy (odds ratio, 3.68; 95% confidence interval, 1.35–10.05). Conclusion Despite the confirmed benefits of prenatal surgery, considerable maternal and fetal risk exists compared with postnatal repair. Early gestational age at surgery and development of chorioamniotic membrane separation are risk factors for ruptured membranes. Oligohydramnios is a risk factor for preterm delivery and nulliparity is a risk factor for nonintact hysterotomy at delivery.

Background Cardiovascular disease is the leading cause of death among women. Identifying risk factors for future cardiovascular disease may lead to earlier lifestyle modifications and disease prevention. Additionally, interpregnancy development of cardiovascular disease can lead to increased perinatal morbidity in subsequent pregnancies. Identification and implementation of interventions in the short term (within 5 years of first pregnancy) may decrease morbidity in subsequent pregnancies. Objective We identified the short-term risk (within 5 years of first pregnancy) of cardiovascular disease among women who experienced a maternal placental syndrome, as well as preterm birth and/or delivered a small-for-gestational-age infant. Study Design We conducted a retrospective cohort study using a population-based, clinically enhanced database of women in the state of Florida. Nulliparous women and girls aged 15-49 years experiencing their first delivery during the study time period with no prepregnancy history of diabetes mellitus, hypertension, or heart or renal disease were included in the study. The risk of subsequent cardiovascular disease was compared among women who did and did not experience a placental syndrome during their first pregnancy. Risk was then reassessed among women with placental syndrome and preterm birth or delivering a small-for-gestational-age infant vs those without these adverse pregnancy outcomes. Results The final study population was 302,686 women and girls. Median follow-up time for each patient was 4.9 years. The unadjusted rate of subsequent cardiovascular disease among women and girls with any placental syndrome (11.8 per 1000 women) was 39% higher than the rate among women and girls without a placental syndrome (8.5 per 1000 women). Even after adjusting for sociodemographic factors, preexisting conditions, and clinical and behavioral conditions associated with the current pregnancy, women and girls with any placental syndrome experienced a 19% increased risk of cardiovascular disease (hazard ratio, 1.19; 95% confidence interval, 1.07–1.32). Women and girls with >1 placental syndrome had the highest cardiovascular disease risk (hazard ratio, 1.43; 95% confidence interval, 1.20–1.70), followed by those with eclampsia/preeclampsia alone (hazard ratio, 1.42; 95% confidence interval, 1.14–1.76). When placental syndrome was combined with preterm birth and/or small for gestational age, the adjusted risk of cardiovascular disease increased 45% (95% confidence interval, 1.24–1.71). Women and girls with placental syndrome who then developed cardiovascular disease experienced a 5-fold increase in health care–related costs during follow-up, compared to those who did not develop cardiovascular disease. Conclusion Women and girls experiencing placental syndromes and preterm birth or small-for-gestational-age infant are at increased risk of subsequent cardiovascular disease in short-term follow-up. Strategies to identify and improve cardiovascular disease risk in the postpartum period may improve future heart disease outcomes.

OBJECTIVE: We sought to investigate what aspects of the stillbirth evaluation are considered to be essential and what tests can potentially be eliminated. STUDY DESIGN: A retrospective analysis of 745 stillbirths occurring from January 1990 to December 1994 was conducted. A stillbirth was defined by an estimated gestational age >20 weeks' gestational age or fetal weight >500 gm. We attempted to arrive at an apparent cause for each stillbirth after evaluation of genetic or chromosomal abnormalities, obstetric history, maternal medical illnesses, laboratory tests, autopsy findings, and placental pathologic conditions. RESULTS: We found that the most important aspects of stillbirth evaluation were placental pathologic conditions and autopsy. When the placenta was examined, a significant abnormality was detected in 30% (160 of 529) of the cases. When autopsy was performed, only 31% of fetal deaths (142 of 462) were unexplained; however, when no autopsy was performed, 44% (125 of 283) were unexplained ( p = 0.0002). The following laboratory evaluations that were routinely performed were found to yield little definitive information: antinuclear antibody testing, Kleihauer-Betke test, and screening for congenital infections (toxoplasmosis, other viruses, rubella, cytomegalovirus, and herpes simplex virus). Overall, 36% (267 of 745) of stillbirths still remained unexplained despite a thorough evaluation in most cases. CONCLUSION: The causes of stillbirth are many and varied, with a large proportion having no obvious cause. As this study demonstrates, certain laboratory tests can be eliminated in the workup of fetal death. In the evaluation of stillbirth a complete systematic method that incorporates placental pathologic conditions, as well as autopsy findings, should prove to be beneficial. (Am J Obstet Gynecol 1998;178:1121-5.)

The objective of the investigation was to study the association between prior miscarriages and the risks of placental dysfunction disorders, including preeclampsia, stillbirth, birth of a small for gestational age (SGA) infant, placental abruption, and spontaneous preterm birth.In a population-based cohort study including 619,587 primiparous women, we estimated risks of placental dysfunction disorders for women with 1 (n = 68,185), 2 (n = 11,410) and 3 or more (n = 3823) self-reported prior miscarriages. Risks were calculated as odds ratios by unconditional logistic regression analysis and adjustments were made for maternal age, early pregnancy body mass index, height, smoking habits, country of birth, years of formal education, in vitro fertilization, chronic hypertension, pregestational diabetes, hypothyroidism, systemic lupus erythematosis, fetal sex, and year of childbirth.Compared with women with no prior miscarriage, women with 1 prior miscarriage had almost no increased risks. Women with 2 prior miscarriages had increased risks of spontaneous preterm birth, preterm (37 weeks) SGA infant, and placental abruption. The rates of all disorders were higher for women with 3 or more prior miscarriages compared with women without prior miscarriages: preeclampsia, 5.83% vs 4.27%; stillbirth, 0.69% vs 0.33%, SGA infant, 5.09% vs 3.22%, placental abruption, 0.81% vs 0.41%; and spontaneous preterm birth, 6.45% vs 4.40%. The adjusted odds ratios for preterm (37 weeks) disorders in women with 3 prior miscarriages were approximately 2.History of 2 or more miscarriages is associated with an increased risk of placental dysfunction disorders and should be regarded as a risk factor in antenatal care.

OBJECTIVES: Our purpose was to determine the effects of pregnancy at high altitude on the human placental structure. STUDY DESIGN: Histologic material from 22 term placentas delivered at altitudes above 3600 m was examined and compared with control material from 760 m. RESULTS: Intraplacental chorioangiomas were identified in 5 of the 22 high-altitude placentas but in none of the 59 controls. The lesions were not visible on the external surface of the placentas and were not encapsulated. The state of differentiation varied; some contained numerous capillaries that showed sinusoidal dilations, whereas in others at the opposite extreme mesenchymal cells predominated. The presence of chorioangiomas was frequently associated with threatened premature delivery, a circumvallate placenta, and multiple infarction. The lesions represented only a small percentage of the overall placental volume ( CONCLUSIONS: The increased incidence of placental chorioangioma observed at high altitude (above 3600 m) may be due to the prevailing hypobaric hypoxia. Overexpression of angiogenic cytokines such as vascular endothelial growth factor, which is known to be up-regulated by this factor in vitro, may mediate this effect. (AM J OBSTET GYNECOL 1996;174:557-61.)

OBJECTIVE: Our purpose was to compare the incidence and interrelationships of uteroplacental vasculopathy and chronic inflammatory and placental vasoocclusive lesions in preeclampsia and spontaneous delivery before 32 weeks' gestation. STUDY DESIGN: Review of singleton live-born nonanomalous infants born at 22 to 32 weeks' gestation identified 76 cases of preeclampsia and 353 cases of spontaneous prematurity (spontaneous premature membrane rupture [n = 192], preterm labor, intact membranes [n = 161]). Histologic lesions were considered as belonging to one of five major pathophysiologic groups: (1) uteroplacental vascular lesions and related villous lesions, (2) chronic inflammatory lesions, (3) coagulation-related lesions, (4) acute inflammatory lesions, and (5) unclassified lesions. Contingency table analyses considered p < 0.05 significant. Factor analysis extracted combinations of related variables. RESULTS: More frequent in preeclampsia versus spontaneous prematurity were chronic uteroplacental vasculitis (29% vs 20%, p < 0.05), chronic villitis (20% vs 3%, p < 0.001), avascular villi (39% vs 16%, p < 0.001), and “hemorrhagic endovasculitis” (9% vs 2.5%, p < 0.03). In the preeclampsia cases factor analysis extracted 13 categories of related lesions. Four categories contained uteroplacental vascular lesions. Five categories included lesions related to chronic inflammation, and eight included lesions related to coagulation. Four categories loaded lesions from one major pathophysiologic group only. Three categories loaded lesions from all three pathophysiologic groups. Unclassified lesions loaded into two factor categories that were unrelated to the other lesions. CONCLUSIONS: Chronic inflammatory and placental vasoocclusive lesions are more common in preterm preeclampsia than in spontaneous prematurity. Immunopathologic processes and coagulation may be involved in the pathophysiologic mechanisms of preterm preeclampsia independent of uteroplacental vascular pathologic features.

Our purpose was to test the hypothesis that placental histologic lesions reflect abnormal placental respiratory function in preterm gestations.A retrospective study of preterm deliveries from 22 to 32 weeks revealed 431 patients with umbilical venous or arterial blood gas values. Excluded were stillbirth, multiple gestations, placenta previa, maternal medical diseases, and fetal anomalies. Charts were reviewed for principal indication of delivery, diagnosis of labor, and mode of delivery. Blood gases were studied within 10 minutes of delivery on a model 178 automatic pH analyzer (Corning Med, Boston). Placental data included uteroplacental vascular lesions and related villous lesions, lesions of acute inflammation, chronic inflammation, and coagulation. Contingency tables and analysis of variance considered p0.05 as significant.Mean +/- SD umbilical vein pH was 7.36 +/- 0.07 (range 6.94 to 7.56) and umbilical artery pH was 7.30 +/- 0.08 (range 6.83 to 7.55). Increasing severity of uteroplacental thrombosis, villous lesions reflective of uteroplacental vascular pathologic mechanisms, avascular villi, histologic evidence of abruptio placentae, chronic villitis, and increased circulating erythrocytes were associated with decrease in umbilical vein and artery pH, increase in umbilical vein and artery PCO2, and decrease in umbilical vein and artery PO2. Histologic evidence of acute infection and villous edema were associated with a higher pH and PO2 and a lower PCO2 in both umbilical vein and artery. Umbilical vein or artery base excess was not related to placental lesions. Labor was not related to blood gas values in this data set, although a subset of cases of extremely preterm premature rupture of membranes and preterm labor who labored and were delivered by cesarean section had significantly poorer umbilical venous and fetal arterial blood gas values (all p0.005). Lesions related to poorer blood gas values were significantly more frequent in preterm preeclampsia and nonhypertensive abruptio placentae than in premature rupture of membranes or preterm labor.Changes in umbilical vein and artery pH, PO2, and PCO2 are significantly related to lesions of uteroplacental vascular pathologic mechanisms and intraplacental thrombosis. Placental lesions may be associated with chronic fetal distress by altering fetal oxygen availability and acid-base status. Placental immaturity resulting from prematurity may be associated with inefficient placental respiratory function and an increased likelihood of cesarean delivery in cases of premature rupture of membranes or preterm labor. Altered fetal acid-base balance plus excess numbers of circulating nucleated erythrocytes suggests that placental respiratory function is functionally abnormal when these lesions are present and leads to fetal tissue hypoxia.

Objective To identify by an inductive statistical analysis mutually similar and clinically relevant clinicoplacental clusters. Study Design Twenty-nine maternofetal and 49 placental variables have been retrospectively analyzed in a 3382 case clinicoplacental database using a hierarchical agglomerative Ward dendrogram and multidimensional scaling. Results The exploratory cluster analysis identified 9 clinicoplacental (macerated stillbirth, fetal growth restriction, placenta creta, acute fetal distress, uterine hypoxia, severe ascending infection, placental abruption, and mixed etiology [2 clusters]), 5 purely placental (regressive placental changes, excessive extravillous trophoblasts, placental hydrops, fetal thrombotic vasculopathy, stem obliterative endarteritis), and 1 purely clinical (fetal congenital malformations) statistically significant clusters/subclusters. The clusters of such variables like clinical umbilical cord compromise, preuterine and postuterine hypoxia, gross umbilical cord or gross chorionic disk abnormalities did not reveal statistically significant stability. Conclusion Although clinical usefulness of several well-established placental lesions has been confirmed, claims about high predictability of others have not.

OBJECTIVE: This study examined the relationship between two maternal exposures, cigarette smoking and cocaine use, and placenta previa. STUDY DESIGN: A hospital-based case-control study was conducted. Three hundred four cases of placenta previa were compared with 2732 controls with respect to demographic characteristics, substance use, and perinatal characteristics. Logistic regression was used to examine the individual effects of cigarette smoking and cocaine use on placenta previa, independent of other known risk factors. RESULTS: A dose-response relationship between smoking cigarettes and placenta previa was observed independent of other known risk factors (ptrend < 0.01). Pregnant women who smoked ≥20 cigarettes per day were over two times more likely to experience a placenta previa relative to nonsmokers (odds ratio 2.3, 95% confidence interval 1.5 to 3.5). Pregnant women who used cocaine were 1.4 times (95% confidence interval 0.8 to 2.4) as likely to experience a placenta previa as nonusers. CONCLUSIONS: The previously observed association between smoking and placenta previa is supported by the dose-response relationship observed in this study. The potential association of cocaine with placenta previa needs more exploration. (AM J OBSTET GYNECOL 1994;170:884-9.)