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Nitric oxide (NO) deficiency during pregnancy is a key reason for preeclampsia development. Besides its important vasomotor role, NO is shown to regulate the cell transcriptome. However, the role of NO in transcriptional regulation of developing smooth muscle has never been studied before. We hypothesized that in early ontogeny, NO is important for the regulation of arterial smooth muscle-specific genes expression. Pregnant rats consumed NO-synthase inhibitor L-NAME (500 mg/L in drinking water) from gestational day 10 till delivery, which led to an increase in blood pressure, a key manifestation of preeclampsia. L-NAME reduced blood concentrations of NO metabolites in dams and their newborn pups, as well as relaxations of pup aortic rings to acetylcholine. Using qPCR, we demonstrated reduced abundances of the smooth muscle-specific myosin heavy chain isoform, α-actin, SM22α, and L-type Ca 2+ -channel mRNAs in the aorta of newborn pups from the L-NAME group compared to control pups. To conclude, the intrauterine NO deficiency weakens gene expression specific for a contractile phenotype of arterial smooth muscle in newborn offspring.

Cold shock Y-box binding protein-1 (YB-1) coordinates several molecular processes between the nucleus and the cytoplasm and plays a crucial role in cell function. Moreover, it is involved in cancer progression, invasion, and metastasis. As trophoblast cells share similar characteristics with cancer cells, we hypothesized that YB-1 might also be necessary for trophoblast functionality. In samples of patients with intrauterine growth restriction, YB-1 mRNA levels were decreased, while they were increased in preeclampsia and unchanged in spontaneous abortions when compared to normal pregnant controls. Studies with overexpression and downregulation of YB-1 were performed to assess the key trophoblast processes in two trophoblast cell lines HTR8/SVneo and JEG3. Overexpression of YB-1 or exposure of trophoblast cells to recombinant YB-1 caused enhanced proliferation, while knockdown of YB-1 lead to proliferative disadvantage in JEG3 or HTR8/SVneo cells. The invasion and migration properties were affected at different degrees among the trophoblast cell lines. Trophoblast expression of genes mediating migration, invasion, apoptosis, and inflammation was altered upon YB-1 downregulation. Moreover, IL-6 secretion was excessively increased in HTR8/SVneo. Ultimately, YB-1 directly binds to NF-κB enhancer mark in HTR8/SVneo cells. Our data show that YB-1 protein is important for trophoblast cell functioning and, when downregulated, leads to trophoblast disadvantage that at least in part is mediated by NF-κB.

Objective: Adenomyosis is a benign uterine disorder characterized by the invasion of the endometrium within the myometrium, starting from the junctional zone (JZ), the inner hormone dependent layer of the myometrium that plays an important role in sperm transport, implantation and placentation. The resulting histological abnormalities and functional defects may represent the pathogenic substrate for infertility and pregnancy complications. The objective of this paper is to review the literature to evaluate the correlation between inner myometrium alterations and infertility and to assess the role of JZ in the origin of adverse obstetric outcomes of both spontaneous and in vitro fertilization (IVF) pregnancies., Methods: we searched Pubmed for all original and review articles in the English language from January1962 until December 2019, using the MeSH terms of 'adenomyosis', 'junctional zone', combined with 'infertility', 'obstetrical outcomes', 'spontaneous conception', ' in vitro fertilization' and 'classification'. The review was divided into three sections to assess this pathogenic correlation, evaluating also the importance of classification of the disease., Results and Conclusions: Absent or incomplete remodeling of the JZ can affect uterine peristalsis, alter vascular plasticity of the spiral arteries and activate inflammatory pathways, all related to adverse obstetric outcomes. Despite these observations, there is still limited evidence whether adenomyosis is a cause of infertility. However, it is reasonable to screen patients for adenomyosis, to consider pregnant women with diffuse adenomyosis at high risk of adverse obstetric outcomes, and to evaluate the importance of a noninvasive validated classification in the management of women with adenomyosis.

Objectives: To clarify the correlation between preeclampsia and parity and to identify protective factors against preeclampsia in multiparous women with systemic lupus erythematosus (SLE)., Methods: We conducted a single-center, retrospective chart review study of 85 pregnant women. We used multiple logistic regression analysis to assess the association between parity and preeclampsia in women with SLE, and described the detailed clinical courses and management of four women with a history of severe preeclampsia and of a woman who experienced preeclampsia during her latest pregnancy., Results: Multiparity was significantly associated with a low risk of preeclampsia (adjusted odds ratio: 0.08; 95% confidence interval: 0.01-0.95). One multiparous woman without a history of preeclampsia developed preeclampsia during her latest pregnancy; she had critical risk factors for preeclampsia, including chronic kidney disease and hypertension, and was not administered aspirin. In contrast, four multiparous women with a history of severe preeclampsia received adequate medications; they did not develop recurrent preeclampsia and delivered live newborns., Conclusions: Multiparity and maintenance therapy for SLE before and during pregnancy and preventive treatment for preeclampsia may improve outcomes in subsequent pregnancies.

Pregnant women often have to take medication either for pregnancy-related diseases or for previously existing medical conditions. Current maternal medications pose fetal risks due to off target accumulation in the fetus. Nanoparticles, engineered particles in the nanometer scale, have been used for targeted drug delivery to the site of action without off-target effects. This has opened new avenues for treatment of pregnancy-associated diseases while minimizing risks on the fetus. It is therefore instrumental to study the potential transfer of nanoparticles from the mother to the fetus. Due to limitations of in vivo and ex vivo models, an in vitro model mimicking the in vivo situation is essential. Placenta-on-a-chip provides a microphysiological recapitulation of the human placenta. Here, we reviewed the fetal risks associated with current therapeutic approaches during pregnancy, analyzed the advantages and limitations of current models used for nanoparticle assessment, and highlighted the current need for using dynamic placenta-on-a-chip models for assessing the safety of novel nanoparticle-based therapies during pregnancy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To present the data on primary hyperparathyroidism (PHPT) in pregnancy from India obtained from a large database maintained over 15 years., Methods: We retrieved data of all women with gestational PHPT from the Indian PHPT registry between July 2005 and January 2020, and compared their clinical, biochemical, and other characteristics with age-matched non-pregnant women with PHPT., Results: Out of 386 women, eight had gestational PHPT (2.1%). The common presenting manifestations were acute pancreatitis (50%) and renal stone disease (50%); two were asymptomatic. Five women (62.5%) had a history of prior miscarriages. Seven patients (88%) had preeclampsia during the present gestation. Serum calcium and intact parathyroid hormone (iPTH) were not statistically different from the age-matched non-pregnant PHPT group. Six patients with mild-to-moderate hypercalcemia were medically managed with hydration with/without cinacalcet while one patient underwent percutaneous ethanol ablation of the parathyroid adenoma; none underwent surgery during pregnancy. Mean serum calcium maintained from treatment initiation till delivery was 10.5 ± 0.4 mg/dl. One patient had spontaneous preterm delivery at 36 weeks; the remaining patients had normal vaginal delivery at term. None had severe preeclampsia/eclampsia. Fetal outcomes included low birth weight in three newborns (37.5%); two of them had hypocalcemic seizures., Conclusion: The prevalence of gestational PHPT was 2.1% in this largest Indian PHPT cohort, which is higher than that reported from the West (< 1%). Gestational PHPT can lead to preeclampsia and miscarriage. Pregnant PHPT patients with mild-to-moderate hypercalcemia can be managed with hydration/cinacalcet; however, long-term safety data and large-scale randomized controlled trials are required.

Introduction: Brief hypercapnic challenge causes acute placental hypoperfusion with fetal brain sparing on BOLD-MRI. We hypothesize that this non-invasive imaging strategy can distinguish between normal pregnancy and chronic placental hypoperfusion (using the maternal hypoxia model)., Methods: Eighteen pregnant female ICR mice were randomized to three groups: normoxia, late-onset hypoxia (12%O 2 ;E13.5-17.5) and early-onset hypoxia (12%O 2 ;E10.5-17.5). On E17.5, animals were imaged in a 4.7-T Bruker-Biospec MRI scanner. Fast coronal True-FISP was performed to identify organs of interest (placenta and fetal heart, liver and brain). BOLD-MRI was performed at baseline and during a 4-min hypercapnic challenge (5%CO 2 ). %-change in placental and fetal signal was analyzed from T2*-weighted gradient echo MR images. Following MRI, fetuses and placentas were harvested, weighed and immuno-stained., Results: In normoxic mice, hypercapnia caused reduction in BOLD-MRI signal in placenta (-44% ± 7%; p < 0.0001), fetal liver (-32% ± 7%; p < 0.0001) and fetal heart (-54% ± 12%; p < 0.002), with relative fetal brain sparing (-12% ± 5%; p < 0.0001). These changes were markedly attenuated in both hypoxia groups. Baseline fetal brain/placenta SI ratio was highest in normoxic mice (1.14 ± 0.017) and reduced with increasing duration of hypoxia (late-onset hypoxia: 1.00 ± 0.026; early-onset hypoxia: 0.91 ± 0.016; p = 0.02). Both hypoxic groups exhibited fetal growth restriction with prominent placental glycogen-containing cells, particularly in early-onset hypoxia. There was increased fetal neuro- and intestinal-apoptosis in early-onset hypoxia only., Conclusions: BOLD-MRI with brief hypercapnic challenge distinguished between normoxia and both hypoxia groups, while fetal neuroapoptosis was only observed after early-onset hypoxia. This suggests that BOLD-MRI with hypercapnic challenge can identify chronic fetal asphyxia before the onset of irreversible brain injury., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

To better understand age-related disparities in US maternal mortality, we analyzed 2016-2017 vital statistics mortality data with cause-of-death literal text (actual words written on the death certificate) added. We created a subset of confirmed maternal deaths which had pregnancy mentions in the cause-of-death literals. Primary cause of death was identified and recoded using cause-of-death literals. Age-related disparities were examined both overall and by primary cause. Compared to women <35, the 2016-2017 US maternal mortality rate was twice as high for women aged 35-39, four times higher for women aged 40-44, and 11 times higher for women aged 45-54 years. Obstetric hemorrhage was the leading cause of death for women aged 35+ with rates 4 times higher than for women <35, followed by postpartum cardiomyopathy with a 3-fold greater risk. Obstetric embolism, eclampsia/preeclampsia, and Other complications of obstetric surgery and procedures each had a two-fold greater risk of death for women aged 35+. Together these 5 causes of death accounted for 70.9% of the elevated maternal mortality risk for women aged 35+. The excess maternal mortality risk for women aged 35+ was focused among a few causes of death and much of this excess mortality is preventable. Early detection and treatment, as well as continued care during the postpartum year is critical to preventing these deaths. The Alliance for Innovation on Maternal Health has promulgated patient safety bundles with specific interventions that health care systems can adopt in an effort to prevent these deaths., Competing Interests: The authors have declared that no competing interests exist.

We aimed to describe the characteristics of adolescent pregnancy, determine its effect on adverse maternal and perinatal outcomes and explore whether that association varies with gestational age with the goal of proposing specific recommendations for adolescent health in China. This study included 2,366,559 women aged 10-24 years who had singleton pregnancies between 2012 and 2019 at 438 hospitals. Adolescent pregnancy was defined as younger than 20 years of age. We used multivariable logistic regression to estimate the effects. Women aged 20-24 years served as the reference group in all analyses. The proportion of rural girls with adolescent pregnancies rebounded after 2015 even though common-law marriage in rural areas decreased. Higher risks of eclampsia (adjusted odds ratio (aOR) 1.87, 95% confidence interval (CI) 1.57 ~ 2.23), severe anaemia (aOR 1.18, 95% CI 1.09 ~ 1.28), maternal near miss (MNM; aOR 1.24, 95% CI 1.12 ~ 1.37), and small for gestational age (SGA; aOR 1.30, 95% CI 1.28 ~ 1.33) were observed when gestational age was > 37 weeks. Adolescent pregnancy was independently associated with increased risks of other perinatal outcomes. Further implementation of pregnancy prevention strategies and improved health care interventions are needed to reduce adolescent pregnancies and prevent adverse fertility outcomes among adolescent women in China at a time when adolescent fertility rate is rebounding.

Introduction: The incidence of stillbirth has decreased marginally or remained stable during the past decades in high income countries. A recent report has shown Stockholm to have a lower incidence of stillbirth at term than other parts of Sweden. The risk of antepartum stillbirth increases in late term and postterm pregnancies which is one of the factors contributing to the current discussion regarding the optimal time of induction of labor due to postterm pregnancy., Material and Methods: This is a cohort study based on the Stockholm Stillbirth Database which contains all cases of stillbirth from 1998-2018 in Stockholm County. All cases were reviewed systematically and the cause of death was evaluated according to the Stockholm Stillbirth Classification. Stillbirths diagnosed between gestational week (GW) 37+0 and 40+6 n = 605 were compared to stillbirths diagnosed from GW 41+0 and onwards n = 157, according to the cause of stillbirth and pregnancy and maternal characteristics. The aim was to evaluate the incidence of stillbirth over time and the incidence of stillbirth diagnosed from GW 41+0., Results: In Stockholm County the overall incidence of stillbirth has decreased from 4.6/1000 births during the period 1998-2004 to 3.4/1000 births during the period 2014-2018, p-value <0.001. When comparing the same time periods, the incidence of stillbirth diagnosed from GW 41+0 and onwards has decreased from 0.5/1000 births to 0.15/1000 births, p-value <0.001. Among women still pregnant at GW 41+0 the incidence of stillbirth has decreased from 1.8/ 1000 to 0.5/ 1000. When comparing stillbirths diagnosed at GW 37+0-40+6 with stillbirths diagnosed from GW 41+0 and onwards infection was a more common cause of stillbirth in the latter group., Conclusion: In Stockholm County there was a decreasing incidence of stillbirth overall and in stillbirths diagnosed from 41+0 weeks of gestation and onwards during the period 1998-2018. In stillbirths diagnosed from GW 41+0 and onwards infection was a more common cause of death compared to stillbirths diagnosed between GW 37+0 and 40+6., Competing Interests: The authors have declared that no competing interests exist.

Pancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell mass and increasing insulin secretion. Previously, using a transgenic mouse with global, heterozygous deletion of prolactin receptor (Prlr +/- ), we found Prlr signaling is important for this adaptation. However, since Prlr is expressed in tissues outside of islets as well as within islets and prolactin signaling affects β-cell development, to understand β-cell-specific effect of prolactin signaling in pregnancy, we generated a transgenic mouse with an inducible conditional deletion of Prlr from β-cells. Here, we found that β-cell-specific Prlr reduction in adult mice led to elevated blood glucose, lowed β-cell mass and blunted in vivo glucose-stimulated insulin secretion during pregnancy. When we compared gene expression profile of islets from transgenic mice with global (Prlr +/- ) versus β-cell-specific Prlr reduction (βPrlR +/- ), we found 95 differentially expressed gene, most of them down regulated in the Prlr +/- mice in comparison to the βPrlR +/- mice, and many of these genes regulate apoptosis, synaptic vesicle function and neuronal development. Importantly, we found that islets from pregnant Prlr +/- mice are more vulnerable to glucolipotoxicity-induced apoptosis than islets from pregnant βPrlR +/- mice. These observations suggest that down regulation of prolactin action during pregnancy in non-β-cells secondarily and negatively affect β-cell gene expression, and increased β-cell susceptibility to external insults.

Background and Aims: Robust evidence regarding the impact of disease activity on pregnancy outcomes in women with inflammatory bowel disease [IBD] is crucial for both clinicians and patients in preparing a birth plan. We sought to perform a systematic review and meta-analysis to assess the pooled influences of disease activity on pregnancy outcomes in women with IBD., Methods: We searched MEDLINE, EMBASE and the COCHRANE library to identify articles comparing pregnancy outcomes between active and inactive IBD at the time of conception or during pregnancy. A meta-analysis was performed using a random-effects model to pool estimates and report odds ratios [ORs]., Results: A total of 28 studies were identified as eligible for the meta-analysis. In women with active IBD, the pooled ORs for low birth weight [LBW], preterm birth, small for gestational age [SGA], spontaneous abortion and stillbirths were respectively 3.81 (95% confidence interval [CI] 1.81-8.02), 2.42 [95% CI 1.74-3.35], 1.48 [95% CI 1.19-1.85], 1.87 [95% CI 1.17-3.0] and 2.27 [95% CI 1.03-5.04] compared to women with inactive IBD. In the subgroup analysis based on disease type, women with active ulcerative colitis had an increased risk of LBW, preterm birth and spontaneous abortion. Women with active Crohn's disease had a higher risk of preterm birth, SGA and spontaneous abortion., Conclusions: Active IBD during the periconception period and pregnancy is associated with an increased risk of adverse pregnancy outcomes. Our data suggest that pregnancy should be planned when the disease is quiescent, and continuous disease control is important even during pregnancy., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The forkhead box O3a protein (FoxO3a) has been reported to regulate tumour invasion and migration, but little is known about the molecular mechanism or its role in trophoblast invasion and migration into the uterus. In this study, we aim to explore its role in trophoblast development and placenta-related pregnancy complications and the potential mechanism. Levels of FoxO3a and its phosphorylated form (p-FoxO3a) in placental tissue from healthy pregnant women and pre-eclampsia patients were first compared. Then, HTR-8/SVneo cells were transfected with lentiviral vectors to deplete and overexpress FoxO3a. Western blot, immunohistochemistry, Cell Counting Kit-8, wound-healing assay, Matrigel invasion assay, cell apoptosis, cell cycle assay, RNA sequencing, qRT-PCR and ChIP-qPCR were performed on the cells to study the potential role of FoxO3a and the underlying mechanism. We found the expression of FoxO3a was decreased, whereas p-FoxO3a was increased in pre-eclampsia placentae. FoxO3a depletion significantly reduced transcription of the promoter region of intercellular cell adhesion molecule-1 (ICAM1) gene in ChIP assays and led to reduced invasion and migration of trophoblast cells, arrested cell cycle in G1 phase and increased apoptosis under oxidative stress. Our results suggested that FoxO3a may play a role in the regulation of trophoblast invasion and migration during placental development, which may be because of its affinity to the ICAM1 promotor., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Atomic force microscopy is not very popular in practical health care, therefore, its potential is not studied enough, for example, in obstetrics when studying the "mother-placenta-fetus" system. Our study summarizes the possibilities of using atomic force microscopy for detection of various circulatory disorders and vascular changes at the microscopic level in the uterus (endometrium and myometrium), placenta, and umbilical cord in the main variants of obstetric and endocrine pathology. For instance, in the case of endocrine pathologies, changes in the form of stasis, sludge, diapedesis, ischemia, destruction and separation of endotheliocytes in villous blood vessels were found in the mother. The oxygen content in erythrocytes also naturally decreased in pathologies; poikilo- and anisocytosis were observed.

Chronic fetal hypoxia is one of the most common outcomes in complicated pregnancy in humans. Despite this, its effects on the long-term health of the brain in offspring are largely unknown. Here, we investigated in rats whether hypoxic pregnancy affects brain structure and function in the adult offspring and explored underlying mechanisms with maternal antioxidant intervention. Pregnant rats were randomly chosen for normoxic or hypoxic (13% oxygen) pregnancy with or without maternal supplementation with vitamin C in their drinking water. In one cohort, the placenta and fetal tissues were collected at the end of gestation. In another, dams were allowed to deliver naturally, and offspring were reared under normoxic conditions until 4 months of age (young adult). Between 3.5 and 4 months, the behavior, cognition and brains of the adult offspring were studied. We demonstrated that prenatal hypoxia reduced neuronal number, as well as vascular and synaptic density, in the hippocampus, significantly impairing memory function in the adult offspring. These adverse effects of prenatal hypoxia were independent of the hypoxic pregnancy inducing fetal growth restriction or elevations in maternal or fetal plasma glucocorticoid levels. Maternal vitamin C supplementation during hypoxic pregnancy protected against oxidative stress in the placenta and prevented the adverse effects of prenatal hypoxia on hippocampal atrophy and memory loss in the adult offspring. Therefore, these data provide a link between prenatal hypoxia, placental oxidative stress, and offspring brain health in later life, providing insight into mechanism and identifying a therapeutic strategy., (© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Using a rabbit model, we investigated whether maternal intake of a high-fat and high-carbohydrate diet (HFCD) before and during pregnancy induces an increase in micronuclei frequency and oxidative stress in offspring during adulthood. Female rabbits received a standard diet (SD) or HFCD for two months before mating and during gestation. The offspring from both groups were nursed by foster mothers fed SD until postnatal day 35. After weaning, all the animals received SD until postnatal day 440. At postnatal day 370, the frequency of micronuclei in peripheral blood reticulocytes (MN-RETs) increased in the male offspring from HFCD-fed mothers compared with the male offspring from SD-fed mothers. Additionally, fasting serum glucose increased in the offspring from HFCD-fed mothers compared with the offspring from SD-fed mothers. At postnatal day 440, the offspring rabbits were challenged with HFCD or continued with SD for 30 days. There was an increase in MN-RET frequency in the male rabbits from HFCD-fed mothers, independent of the type of challenging diet consumed during adulthood. The challenge induced changes in serum cholesterol, LDL and HDL that were influenced by the maternal diet and offspring sex. We measured malondialdehyde in the liver of rabbits as an oxidative stress marker after diet challenge. Oxidative stress in the liver only increased in the female offspring from HFCD-fed mothers who were also challenged with this same diet. The data indicate that maternal overnutrition before and during pregnancy is able to promote different effects depending on the sex of the animals, with chromosomal instability in male offspring and oxidative stress and hypercholesterolemia in female offspring. Our data might be important in the understanding of chronic diseases that develop in adulthood due to in utero exposure to maternal diet., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: The aim was to explore the potential role of the placenta for the risk of stillbirth at term in pregnancies of obese women., Methods: This was a case-control study comparing placental findings from term stillbirths with placental findings from live born infants. Cases were singleton term stillbirths to normal weight or obese women, identified in the Stockholm stillbirth database, n = 264 and n = 87, respectively. Controls were term singletons born alive to normal weight or obese women, delivered between 2002-2005 and between 2018-2019. Placentas were compared between women with stillborn and live-born infants, using logistic regression analyses., Results: A long and hyper coiled cord, cord thrombosis and velamentous cord insertion were stronger risk factors for stillbirth in obese women compared to normal weight women. When these variables were adjusted for in the logistic regression analysis, also adjusted for potential confounders, the odds ratio for stillbirth in obese women decreased from 1.89 (CI 1.24-2.89) to 1.63 (CI 1.04-2.56)., Conclusion: Approximately one fourth of the effect of obesity on the risk of stillbirth in term pregnancies is explained by umbilical cord associated pathology., Competing Interests: No authors have competing interests.

Background: A uterine manipulator cannot be used to elevate the ovary in benign ovarian surgery during pregnancy. This report describes our method of elevation of the ovary using a metreurynter with the success rate of the procedure and a comparison of surgical results and pregnancy outcomes between the successful and unsuccessful cases., Methods: Between August 2003 and February 2020, 11 pregnant patients with a tumor found sunk in the Cul-de-sac underwent laparoscopic cystectomy for a benign ovarian cyst with a metreurynter. The surgical results, success and failure of the elevation by a metreurynter, pregnancy outcomes, and fetal status at delivery were evaluated., Results: Elevation of ovarian tumors with a metreurynter was successful in nine cases. However, it was unsuccessful in the remaining two cases wherein the ovary was lifted with forceps while the uterus was in a compressed state. The operative time was also longer in these cases. The pregnancy prognosis, however, was good for both, successful and unsuccessful cases., Conclusions: The metreurynter is an inexpensive and practical obstetric device, and its optimal use allows the performance of a procedure with minimal burden on a pregnant uterus. Therefore, we recommend the appropriate use of this method to enable effective laparoscopic cystectomy of ovarian tumors during pregnancy.

Sleep-disordered breathing (SDB) worsens over pregnancy, and obstructive sleep apnea is associated with serious maternal complications. Intrauterine exposures that provoke insulin resistance (IR), inflammation, or oxidative stress may have long-term offspring health consequences. In obesity, worsening maternal SDB appears to be an exposure that increases the risk for both small- or large-for-gestational-age (SGA, LGA, respectively), suggesting distinct outcomes linked to a common maternal phenotype. The aim of this paper is to systematically review and link data from both mechanistic rodent models and descriptive human studies to characterize the impact of maternal SDB on fetal development. A systematic review of the literature was conducted using PubMed, Embase, and CINAHL (01/2000-09/2019). Data from rodent (9 studies) and human models (48 studies, 5 meta-analyses) were included and reviewed using PRISMA guidelines. Evidence from rodent models suggests that intermittent maternal hypoxia results in mixed changes in birth weight (BW) followed by accelerated postnatal growth, while maternal sleep fragmentation results in normal BW followed by later metabolic derangement. Human studies support that maternal SDB is associated with both SGA and LGA, both of which may predispose offspring to later obesity. Evidence also suggests a link between SDB, inflammation, and oxidative stress that may impact maternal metabolism and/or placental function. SDB is common in pregnancy and affects fetal growth and development. Given that SDB has significant potential to adversely influence the intrauterine metabolic environment, larger, prospective studies in humans are urgently needed to fully elucidate the effects of this exposure on offspring metabolic risk.

Objectives: To explore the effects of maternal and fetal outcomes after different diagnostic timings of placenta accreta and its types., Methods: We retrospectively collected the clinical information of 1178 pregnant women with placenta accreta in Fujian Maternity and Children Health Hospital from January 2012 to January 2017. According to the different diagnostic timings of placenta accreta, they were divided into groups of prenatal diagnosis and postpartum diagnosis; and according to the types of placenta accreta, they were divided into groups of accreta group, increta group, and percreta group., Results: 1. Women with antenatal diagnosis more often had placenta previa and history of previous cesarean section. 2. Women with antenatal diagnosis had a higher rate in blood loss and blood transfusion. 3. The rate of blood loss, blood transfusion, infection,disseminated intravascular coagulation (DIC), secondary laparotomy, hysterectomy had statistically significant differences (P < 0.05) in different types of placenta accreta. The deeper of placenta accreta, the higher the incidence of complications., Conclusion: It is important to pay attention for risk factors of the placenta accreta, then improve prenatal diagnostic rate of the placenta accreta and its types, which can forecast the severity of illness to improve maternal and fetal outcomes., Competing Interests: None

Context: Maternal obesity has a significant impact on placental development. However, this impact on the placenta's structure and function (ie, nutrient transport and hormone and cytokine production) is a controversial subject., Objective: We hypothesized that maternal obesity is associated with morphologic, secretory, and nutrient-related changes and elevated levels of inflammation in the placenta., Design: We collected samples of placental tissue from 2 well-defined groups of pregnant women from 2017 to 2019. We compared the 2 groups regarding placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions., Setting: Placenta were collected after caesarean section performed by experienced clinicians at Centre Hospitalier Intercommunal (CHI) of Poissy-Saint-Germain-en-Laye., Patients: The main inclusion criteria were an age between 27 and 37 years old, no complications of pregnancy, and a first-trimester body mass index of 18-25 kg/m2 for the nonobese (control) group and 30-40 kg/m2 for the obese group., Results: In contrast to our starting hypothesis, we observed that maternal obesity was associated with (1) lower placental IL-6 expression and macrophage/leukocyte infiltration, (2) lower placental expression of GLUT1 and SNAT1-2, (3) a lower placental vessel density, and (4) lower levels of placental leptin and human chorionic gonadotropin production., Conclusion: These results suggest that the placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Vitiligo is perceived as an autoimmune skin disease. Previous studies showed conflicting data about vitiligo and pregnancy outcomes. To delineate the associations between vitiligo and the pregnancy outcomes, we used the National Health Insurance Research Database of Taiwan to conduct a retrospective cohort study from January 1, 2000 to December 31, 2015. This study population was composed of 1,096 women with vitiligo and 4,384 women without vitiligo, who were all matched according to age, comorbidity, and index year. Compared with the non-vitiligo controls, women with vitiligo had a higher risk of abortion (aHR 1.158, 95% confidence interval (CI) 1.095-1.258, P < .001). Perinatal events, such as preterm delivery, pre-eclampsia/eclampsia, gestational diabetes mellitus, stillbirth, and intrauterine growth retardation, were not different between both groups (aHR 1.065, 95% CI 0.817-1.157, P = .413). To determine if systemic treatment before conception decreases the risk of abortion, we assessed the medical history of pregnant women with vitiligo 1 year before pregnancy. Patients who were treated with oral medications had a lower risk of abortion than those who were not (aHR: 0.675, 95% CI: 0.482-0.809, P < .001). Our study indicates that there is a higher risk of abortion in pregnant women with vitiligo and the control of disease activity with systemic treatment before conception could improve pregnancy outcomes., Competing Interests: The authors have declared that no competing interests exist.

Pregnancy is an immunological paradox, a phenomenon in which the foetus and the placenta, containing foreign antigens to the mother, develop without inducing rejection by the maternal immune system. Cell-to-cell communication between the foetus and the mother is mediated by secreted factors such as cytokines, hormones and extracellular vesicles (EVs) for a successful pregnancy and to avoid rejection. Exosomes, the smallest of EVs, are released extracellularly, where they are taken up by proximal or distant recipient cells. Here, we discuss the role of EVs, especially exosomes in feto-maternal communication during pregnancy. This review will provide an overview of the functional roles exosomes may play during embryo implantation, modulating immune responses during pregnancy and the onset of labour. Moreover, we will discuss exosomal function in obstetric pathology, and the development of pregnancy-associated complications such as preeclampsia and preterm birth as well as the biomarker potential of exosomes for detecting such conditions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

The amniotic fluid (AF) is a complex biofluid that reflects fetal well-being during development. AF con be divided into two fractions, the supernatant and amniocytes. The supernatant contains cell-free components, including placenta-derived microparticles, protein, cell-free fetal DNA, and cell-free fetal RNA from the fetus. Cell-free mRNA (cfRNA) analysis holds a special position among high-throughput analyses, such as transcriptomics, proteomics, and metabolomics, owing to its ease of profiling. The AF cell-free transcriptome differs from the amniocyte transcriptome and alters with the progression of pregnancy and is often associated with the development of various organ systems including the fetal lung, skin, brain, pancreas, adrenal gland, gastrointestinal system, etc. The AF cell-free transcriptome is affected not only by normal physiologies, such as fetal sex, gestational age, and fetal maturity, but also by pathologic mechanisms such as maternal obesity, and genetic syndromes (Down, Edward, Turner, etc.), as well as pregnancy complications (preeclampsia, intrauterine growth restriction, preterm birth, etc.). cfRNA in the amniotic fluid originates from the placenta and fetal organs directly contacting the amniotic fluid as well as from the fetal plasma across the placenta. The AF transcriptome may reflect the fetal and placental development and therefore aid in the monitoring of normal and abnormal development.

Burns injuries during pregnancy are rarely reported in developed countries, but an increasing in mortality and morbidity has been observed. The authors describe their experience in the treatment of pregnant women in a burn unit. A 12-year retrospective study of burns in pregnant women hospitalized was conducted. Since 2008, two pregnant women were admitted in their unit. Patient 1, a 32-year-old pregnant woman on second trimester (27s6d), suffered a second-degree burn injury, 16% total body surface area (TBSA), caused by fire. She was admitted in their burn unit and submitted to medical treatment, wound dressing, and surgical treatment. Cerium nitrate and silver sulfadiazine were used in burn lesions and the patient was submitted to debridement and skin graft surgery. No uneventful events occurred with the fetus. Patient 2 was a 32-year-old pregnant woman on second trimester (26s), HVC positive, admitted with a second-degree flash burn, 8% TBSA. She was submitted to endotracheal intubation before arriving to the hospital due to risk of airway burn. Dexamethasone was administered for fetus lung maturation. No uneventful events were observed. The incidence of thermal injury in pregnancy in Portugal is low. Active medical treatment together with conservative wound care should be the standard in each trimester of pregnancy. Although there is limited safety information on cerium nitrate or silver sulfadiazine during pregnancy, those were used with no adverse effects on one of their patients. Obstetrical management should be individualized., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Burn Association. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: Prospective data are limited on pregnancy outcomes among women with psoriasis who may be receiving biologic or conventional systemic therapy., Objective: To report pregnancy outcomes observed in the Psoriasis Longitudinal Assessment and Registry (PSOLAR)., Design, Setting, and Participants: This cohort study used data from PSOLAR, a multicenter, disease-based, observational registry evaluating long-term safety and clinical outcomes for patients receiving or eligible to receive treatment for psoriasis with biologics and/or conventional systemic therapies. Of 12 090 enrollees, 5456 were women (45.1%), and 2224 women were of childbearing age (18-45 years). Participants had a total of 12 929 patient-years of follow-up (median, 7.2 [range, 3.3-8.0] years per patient). Data were collected from June 20, 2007, to August 23, 2019, and analyzed from April 23 to June 23, 2020., Exposures: Exposure to biologics within the prenatal period (≤1 year before birth or ≤6 months before spontaneous abortion) or at any other time., Main Outcomes and Measures: Descriptive summaries of pregnancies and pregnancy-related outcomes were self-reported in PSOLAR, including births, stillbirths, spontaneous abortions, and elective terminations. Live birth characteristics collected in PSOLAR include whether a birth was full-term (≥37 weeks) or premature (<37 weeks) and whether neonatal adverse events or congenital anomalies occurred., Results: A total of 298 pregnancies occurred among 220 women (mean [SD] age, 27.8 [5.2] years), and the general fertility rate was 18.9 per 1000 women aged 18 to 45 years. Of the 298 pregnancies, 244 (81.9%) resulted in birth, 41 (13.8%) ended in spontaneous abortion, and 13 (4.4%) were electively terminated. Gestational age was available for 243 births; 221 infants (90.9%) were full-term, and 22 (9.1%) were born prematurely. Birth outcomes included 231 healthy newborns, 10 infants with a neonatal problem, 2 infants with a congenital anomaly, and 1 stillbirth. Of the 298 pregnancies, 252 were associated with biologic exposure before or during pregnancy. Pregnancy outcomes for women exposed to biologics were similar to those for women exposed to nonbiologics. Among women who became pregnant, mean (SD) age at the time of pregnancy outcome was 30.9 (4.8) years; at enrollment into the registry, 74 of 219 (33.8%) had obesity, and 121 of 220 (55.0%) were past or current smokers., Conclusions and Relevance: The findings of this cohort study suggest that pregnancy outcomes in PSOLAR have remained consistent with previous reports. Overall and live birth outcomes were similar to those for the general population.

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD)., Design and Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder., Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4)., Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

Objective: To investigate the clinical outcomes of different treatment options on singleton short cervix and its influence factors. Methods: Totally 435 cases of singleton pregnancies who were diagnosed with short cervix (≤25 mm) between 12 to 33 +6 gestational weeks in Peking University First Hospital from January 2018 to December 2018 were enrolled, including 21 cases with cervical length <10 mm, 414 cases with cervical length between 10 to 25 mm. The onset time was <24 gestational weeks in 106 cases, while 104 cases were at 24-29 +6 gestational weeks and 225 cases of ≥30 gestational weeks. Gestational outcomes including delivery before 37 weeks, delivery before 34 weeks, neonatal birth weight (NBW) and adverse neonatal outcome (ANO) were compared among three treatment groups: rest group, progesterone group and cerclage group. Influence factors were also investigated. Results: (1) The incidence of short cervix in pregnancy was 7.07% (435/6 155), while 106 cases were at <24 gestational weeks (1.72%, 106/6 155), 104 cases (1.69%, 104/6 155) at 24-29 +6 gestational weeks and 225 cases (3.66%, 225/6 155) at ≥30 gestational weeks. (2) In the group of cervical length <10 mm, rate of delivery before 37 and 34 weeks were 62% (13/21) and 57% (12/21) respectively. One case of progesterone treatment underwent miscarriage. Compared with rest group ( n =8), delivery weeks [28.5 (25.0-40.0) vs 37.0 (28.0-40.0), P =0.020] and NBW [1 245 g (630-3 830 g) vs 2 648 g (1 560-3 830 g), P =0.028] were higher in cerclage group ( n =9), while ANO was not statistically different ( P >0.05). (3) In the group of cervical length ≥10 mm before 24 gestational weeks, the delivery weeks, incidence of delivery before 34 weeks, adjusted incidence of delivery before 37 weeks, NBW and ANO were not statistically different ( P >0.05) among rest group ( n =36), progesterone group ( n =26) and cerclage group ( n =34). In vitro fertilization ( OR =11.97, 95% CI : 1.88-76.44, P =0.009), infection ( OR =46.03, 95% CI : 5.12-413.58, P =0.001), sludge on sonography ( OR =9.87, 95% CI : 1.69-57.60, P =0.011) and history of short cervix ( OR =7.24, 95% CI : 1.04-50.24, P =0.045) were independent risk factors of preterm birth. (4) In the group of cervical length ≥10 mm and gestational weeks between 24-29 +6 , the delivery weeks, incidence of delivery before 37 weeks, incidence of delivery before 34 weeks, NBW and ANO were not statistically different ( P >0.05) among rest group ( n =52), progesterone group ( n =34) and cerclage group ( n =9). Infection was an independent risk factor of preterm birth ( OR =56.40, 95% CI : 4.67-680.61, P =0.002). (5) Outcomes of 223 cases were relatively good in the group of cervical length ≥10 mm beyond 30 gestational weeks. The incidence of delivery before 34 weeks was 6.3% (14/223). The delivery weeks, incidence of delivery before 37 and 34 weeks, NBW and ANO were not statistically different ( P >0.05) among 3 groups. Infection ( OR =10.91, 95% CI : 2.21-53.96, P =0.003) and history of preterm birth ( OR =8.63, 95% CI : 1.25-59.65, P =0.029) were independent risk factors of preterm birth. Conclusions: Short cervix is a common complication of pregnancy. Cervical cerclage is related with better outcome for patients with cervical length <10 mm. Neither progesterone nor cervical cerclage improves pregnancy outcome for >10 mm cervical length patients comparing with rest. Infection, sludge, in vitro fertilization, history of short cervix and history of preterm birth are independent risk factors of preterm birth in short cervix pregnancies.

The prevalence of overweight and obesity amongst reproductive women has been increasing worldwide. Our aim was to compare pregnancy outcomes and infant neurocognitive development by different BMI classifications and investigate whether early pregnancy BMI was associated with risks of adverse outcomes in a Southwest Chinese population. We analysed data from 1273 women enrolled in the Complex Lipids in Mothers and Babies (CLIMB) randomized controlled trial in Chongqing, China. Maternal BMI was classified as underweight, normal weight and overweight/obese according to the Chinese, WHO Asian, and WHO European standards. For the adverse pregnancy outcomes, after adjustment for potential confounders, an underweight BMI was associated with increased risk of small for gestational age (SGA) babies, and an overweight/obese BMI was associated with increased risk of maternal gestational diabetes mellitus (GDM), caesarean section (C-section), macrosomia and large for gestational age (LGA) babies. For infant neurocognitive development, 1017 mothers and their children participated; no significant differences were seen in the Mental Development Index (MDI) or the Psychomotor Development Index (PDI) between the three BMI groups. Our findings demonstrate that abnormal early pregnancy BMI were associated with increased risks of adverse pregnancy outcomes in Chinese women, while early pregnancy BMI had no significant influence on the infant neurocognitive development at 12 months of age.

Objectives: There is emerging evidence that First Nations women with diabetes in pregnancy and their offspring have poorer health outcomes than non-First Nations women. The aim of this study was to describe the perinatal outcomes of pregnancies complicated by type 2 diabetes., Methods: The Next Generation longitudinal study is a First Nations birth cohort of children born to mothers diagnosed in childhood with type 2 diabetes. Pregnant women were prospectively enrolled in the birth cohort, and a review of medical records (including stored fetal ultrasound images) was performed to determine perinatal outcomes for 112 child-mother pairs between 2005 and 2015. Maternal demographics, antenatal variables, fetal ultrasound findings, obstetric and delivery information and neonatal birth outcomes were collected and analyzed., Results: Mothers in our cohort were young and most were overweight at the start of pregnancy. Most had suboptimal glycemic control in the first trimester (median glycated hemoglobin, 9.3%). The cesarean section rate was high at 41%. Over one-half of newborns had macrosomia at birth, and almost 1 in 5 were born with a structural anomaly, mainly renal. Fetal ultrasound significantly underestimated the proportion of infants born with macrosomia (p<0.05) and missed 3 of 7 cardiac defects in this cohort., Conclusions: High rates of anomalies, macrosomia and cesarean deliveries provide insight into pregnancy management and disease processes for First Nations women with pregestational type 2 diabetes and their offspring, and highlights opportunities for improvement in prenatal care of these women., (Copyright © 2020 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.)

Implantation of the embryo is a rate-limiting step for a successful pregnancy, and it requires an intricate crosstalk between the embryo and the endometrium. Extracellular vesicles (EVs) are membrane-enclosed, nano-sized structures produced by cells to mediate cell to cell communication and modulate a diverse set of biological processes. Herein, we review the involvement of EVs in the process of embryo implantation and endometrial diseases. EVs have been isolated from uterine fluid, cultured endometrial epithelial/stromal cells and trophectodermal cells. The endometrial epithelial and stromal/decidual cell-derived EVs and its cargo are internalized bythe trophoblast cells, and they regulate a diverse set of genes involved in adhesion, invasion and migration. Conversely, the embryo-derived EVs and its cargo are internalized by epithelial and immune cells of the endometrium for biosensing and immunomodulation required for successful implantation. EVs have also been shown to play a role in infertility, recurrent implantation failure, endometriosis, endometritis and endometrial cancer. Further research should set a stage for EVs as non-invasive "liquid biopsy" tools for assessment of endometrial health., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Chorangiosis is a vascular change involving the terminal chorionic villi in the placenta. It results from longstanding, low-grade hypoxia in the placental tissue, and is associated with such conditions as intrauterine growth restriction (IUGR), diabetes, and gestational hypertension in pregnancy. Chorangiosis rarely occurs in normal pregnancies. However, its prevalence is 5-7% of all placentas from infants admitted to newborn intensive care units. The present study was aimed at determining the association of chorangiosis with pregnancy complications and perinatal outcomes., Methods: In this case-control study, 308 chorangiosis cases were compared with 308 controls (with other diagnoses in pathology) in terms of maternal, placental, prenatal, and neonatal characteristics derived from the medical records of participants retrospectively. R and SPSS version 22 software tools were used, and the statistical significance level was considered 0.05 for all the tests., Results: Preeclampsia, diabetes mellitus, maternal hemoglobin, maternal hematocrit, C/S, oligohydramnios, fetal anomaly, dead neonates, NICU admissions were significantly higher in the chorangiosis group OR = 1.6, 3.98, 1.68, 1.92, 2.1, 4.47, 4.22, 2.9, 2.46, respectively (p-value< 0.05 for all). Amniotic fluid index, birth weight, cord PH amount, 1st, and 5th Apgar score was lower in the chorangiosis group OR = 0.31, 1, 0.097, 0.83, 0.85, respectively (p-value< 0.05 for all). Moreover, fundal placenta, retro placental hemorrhage, perivillous fibrin deposition, calcification, and acute chorioamnionitis were higher in the chorangiosis group OR = 2.1, 11.8, 19.96, 4.05, and 6.38 respectively, (p-value< 0.05). There was a high agreement between the two pathologists, and the power of the study was estimated at 99%., Conclusion: Although chorangiosis is an uncommon condition, it is associated with a higher incidence of perinatal and neonatal morbidity and mortality. Therefore, it should be considered an important clinical sign of adverse pregnancy outcomes and should be reported in the pathology evaluation.

Background: Pregnancy-related acute kidney injury (PRAKI) is still a common serious problem in developing countries. Insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor metalloproteinases-2 (TIMP-2) can identify critically ill patients at risk for the development of severe AKI., Aim: To identify main causes and timing of PRAKI and to study the G1 cell cycle arrest biomarkers in cases diagnosed with (PRAKI) as a diagnostic tool., Methods: 80 pregnant women diagnosed with PRAKI were recruited from a single hospital as well as 30 age-matched pregnant women with normal pregnancy participated in the present study. A urine specimen was collected from all study participants with established AKI within 24 h of ICU admission to measure [TIMP-2]*[IGFBP7]., Results: The incidence of PRAKI was 1.1%. The most common cause of PRAKI is pre-eclampsia/eclampsia spectrum (61%). Most of the cases occur in the third trimester (60%) and postpartum period (23%). At a cutoff 0.33 ng/ml, the estimated sensitivity and specificity of urinary [TIMP-2]*[IGFBP7] in predicting PRAKI is 100% (95% CI) with NPV and PPV are 100%., Conclusion: Urinary [TIMP-2]*[IGFBP7] serves as a sensitive and specific biomarker in the diagnosis of PRAKI., (© 2021 The Author(s).)

Background: The incidence of gestational breast cancer (GBC) is increasing in high-income countries. Our study aimed to examine the epidemiology, management and outcomes of women with GBC in New South Wales (NSW), Australia., Methods: A retrospective cohort study using linked data from three NSW datasets. The study group comprised women giving birth with a first-time diagnosis of GBC while the comparison group comprised women giving birth without any type of cancer. Outcome measures included incidence of GBC, maternal morbidities, obstetric management, neonatal mortality, and preterm birth., Results: Between 1994 and 2013, 122 women with GBC gave birth in NSW (crude incidence 6.8/ 100,000, 95%CI: 5.6-8.0). Women aged ≥35 years had higher odds of GBC (adjusted odds ratio (AOR) 6.09, 95%CI 4.02-9.2) than younger women. Women with GBC were more likely to give birth by labour induction or pre-labour CS compared to women with no cancer (AOR 4.8, 95%CI: 2.96-7.79). Among women who gave birth by labour induction or pre-labour CS, the preterm birth rate was higher for women with GBC than for women with no cancer (52% vs 7%; AOR 17.5, 95%CI: 11.3-27.3). However, among women with GBC, preterm birth rate did not differ significantly by timing of diagnosis or cancer stage. Babies born to women with GBC were more likely to be preterm (AOR 12.93, 95%CI 8.97-18.64), low birthweight (AOR 8.88, 95%CI 5.87-13.43) or admitted to higher care (AOR 3.99, 95%CI 2.76-5.76) than babies born to women with no cancer., Conclusion: Women aged ≥35 years are at increased risk of GBC. There is a high rate of preterm birth among women with GBC, which is not associated with timing of diagnosis or cancer stage. Most births followed induction of labour or pre-labour CS, with no major short term neonatal morbidity., Competing Interests: The authors have declared that no competing interests exist.

Macrophages are key components of the innate immune system and exhibit extensive plasticity and heterogeneity. They play a significant role in the non-pregnant cycling uterus and throughout gestation they contribute to various processes underpinning reproductive success including implantation, placentation and parturition. Macrophages are also present in breast milk and impart immunomodulatory benefits to the infant. For a healthy pregnancy, the maternal immune system must adapt to prevent fetal rejection and support development of the semi-allogenic fetus without compromising host defense. These functions are dependent on macrophage polarization which is governed by the local tissue microenvironmental milieu. Disruption of this microenvironment, possibly by environmental factors of infectious and non-infectious origin, can affect macrophage phenotype and function and is linked to adverse obstetric outcomes, e.g. spontaneous miscarriage and preterm birth. Determining environmental influences on cellular and molecular mechanisms that control macrophage polarization at the maternal-fetal interface and the role of this in pregnancy complications could support approaches to alleviating adverse pregnancy outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chambers, Rees, Cronin, Nair, Jones and Thornton.)

In Japan, uterine cancer screening during pregnancy is subsidized by public funds. We examined the current status of the results of cervical cytology conducted during pregnancy in Japan. We requested 2,293 obstetrical facilities to provide information on cervical cytology in pregnant women who delivered between October 2018 and March 2019. A total of 1,292 obstetrical facilities responded, with valid information on a total of 238,743 women. The implementation rate of cervical cytology during pregnancy was 86.8% in Japan. The prevalence of abnormal cervical cytology during pregnancy was 3.3% in total and 4.9% using a spatula/brush with liquid-based cytology (LBC). The prevalence of positive high-risk human papillomavirus (HPV) in teenagers with atypical squamous cells of undetermined significance (ASC-US) was significantly higher than women of other ages (p < 0.01). Because HPV vaccine coverage has dropped to less than 1% in Japan, a further study with various conditions will be needed to improve the accuracy of cervical cancer screening during pregnancy., Competing Interests: The authors declare that no competing interests exist.

Background: Although uterine fibroids are a common gynecologic neoplasm, uterine diverticulum accompanied by a uterine fibroid is unique. In addition, pregnancy complicated with uterine diverticulum is extremely rare. We experienced a case of a uterine fibroid that was associated with a uterine diverticulum that enlarged during pregnancy and puerperium., Case Presentation: A 25-year-old nulligravida woman had an abnormal uterine cavity surrounded by myomatous mass. After natural conception, the mass and pouch had enlarged during pregnancy. Six months after elective cesarean delivery, she underwent laparotomy because of abdominal pain caused by the myomatous mass and the fluid inside. The tumor was connected to the midline of the posterior wall of the normal uterus. The resected tumor was pathologically diagnosed as leiomyoma and diverticulum., Conclusions: Pregnancy can stimulate uterine fibroids to form uterine diverticula. Resection of the diverticulum and fibroid is a useful option for symptomatic patients with desired future fertility.

The exact prevalence of mirror syndrome remains unclear, and the precise clinical features need to be disclosed. We retrospectively reviewed 85 cases of foetal hydrops from a total of 98,484 deliveries. Of these 16 showed mirror syndrome, while 69 did not. The incidence of mirror syndrome among all deliveries was 0.0162%, while that among patients with foetal hydrops was 23.2%. Maternal symptoms of mirror syndrome included anaemia ( n  = 15), hypertension ( n  = 7), proteinuria ( n  = 8), pulmonary oedema ( n  = 3), cardiac failure ( n  = 2) and HELLP syndrome ( n  = 2). Placental thickness, placental weight and amniotic fluid index were significantly different between the groups. In the mirror syndrome group, uric acid, lactate dehydrogenase, creatinine and D-dimer levels were significantly higher ( p  < .05), whereas haemoglobin, serum albumin levels, haematocrit value and platelet count were significantly lower ( p  < .05). Elevated uric acid, lactate dehydrogenase and D-dimer levels may be useful as predictors of mirror syndrome.Impact statement What is already known on this subject? As mirror syndrome is uncommon and under-diagnosed, its exact incidence is not yet clear, and most publications are case reports or reviews of case reports. What the results of this study add? The incidence of mirror syndrome among all deliveries was 0.0162%, while that among patients with foetal hydrops was 23.2%. Pregnant women who develop mirror syndrome may show severe complications of pregnancy. Attention should be paid to the further progress of the condition. Placental thickness, placental weight and amniotic fluid index were significantly different between those with mirror syndrome and those without. In the mirror syndrome group, the uric acid, lactate dehydrogenase, creatinine and D-dimer levels were significantly higher ( p  < .05), whereas haemoglobin level, haematocrit value, platelet count and serum albumin level were significantly lower ( p  < .05). What the implications are of these findings for clinical practice and/or further research? Mirror syndrome is not rare among patients with foetal hydrops. Elevated uric acid, lactate dehydrogenase and D-dimer levels may be useful as predictors of mirror syndrome.

Objective: We aimed to compare obstetric and neonatal outcomes of deliveries complicated by meconium stained amniotic fluid (MSAF), according to placental histology of continuous vs. acute meconium associated changes., Methods: This was a retrospective cohort study of singleton deliveries complicated by MSAF at a single university-affiliated medical center during 2008-2018. Obstetric and neonatal outcomes were compared between cases with placental acute vs. continuous meconium exposure associated changes (columnar epithelial changes and meconium-laden macrophages, respectively). Regression analysis was used to identify independent associations with adverse neonatal outcomes., Results: The medical records of 294 deliveries at our institution were reviewed, along with medical records of the neonates and the histopathological reports of their placentas. Ninety-two cases were classified as an acute placental reaction to meconium (acute exposure group) and 200 as continuous placental exposure (continuous exposure group). Patient demographics did not differ between groups. Placentas from the continuous exposure to meconium were associated with a higher rate of placental weight <10th percentile (p = 0.03) while the acute exposure group was associated with a shorter time between rupture of membranes and delivery (p = 0.02). and higher rates of non-reassuring fetal heart rate in labor (p = 0.003), and of adverse neonatal outcome (p = 0.02). In multivariable analysis adverse neonatal outcome was associated with acute histologic exposure to meconium independent of background confounders (aOR = 1.51, 95% CI 1.12-3.67)., Conclusions: Acute histological changes of MSAF were independently associated with adverse neonatal outcomes as compared to continuous histologic MSAF., Competing Interests: Declaration of competing interest The authors declare no conflict of interest, including any financial, personal or professional interests., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Context.—: Women with diabetes have increased stillbirth risk. Although the underlying pathophysiological processes are poorly understood, stillbirth is frequently related to abnormal placental structure and function., Objective.—: To investigate placental morphology and cellular characteristics in the placentas of women with diabetes who had stillbirths and stillbirths of unexplained cause., Design.—: Placentas from women with uncomplicated live births, live births in women with diabetes, unexplained stillbirths, and stillbirths related to diabetes (n = 10/group) underwent clinical histopathologic assessment and were also investigated using immunohistochemical staining to quantify syncytial nuclear aggregates, proliferation, trophoblast area, vascularization, T cells, placental macrophages (Hofbauer cells), and the receptor for advanced glycation end products., Results.—: Ki67+ cells were decreased in unexplained stillbirths compared with live births in women with diabetes. Both stillbirth groups had increased cytokeratin 7+/nuclear area compared with controls. Blood vessels/villi were decreased in unexplained stillbirth compared with live births from women with diabetes. Compared with uncomplicated controls, CD163+ macrophages were increased in live births in women with diabetes and unexplained stillbirths, and further increased in stillbirths related to diabetes. There was no change in CD3+ T cells or syncytial nuclear aggregates. Receptor for advanced glycation end products-positive cells were decreased in both stillbirth groups compared with diabetes-related live births. Co-localization of receptor for advanced glycation end products in macrophages was increased in both stillbirth groups compared with live birth groups., Conclusions.—: Stillbirths related to diabetes exhibit placental phenotypic differences compared with live births. Further investigation of these parameters may provide understanding of the pathologic mechanisms of stillbirth and aid the development of stillbirth prevention strategies., (© 2021 College of American Pathologists.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare but devastating disease characterized by dysregulated immune response and hyperinflammation. To our knowledge, pregnancy-induced HLH has been rarely reported in the literature. A 30-year-old pregnant woman presented persistent fever for 21 days since 17 weeks of pregnancy. The possible etiologies such as infection, autoimmune disorder, and malignancy had been ruled out based on a series of exhaustive examinations. The disease progressed despite the use of broad-spectrum antibiotics and dexamethasone. The patient was diagnosed as pregnancy-induced HLH, and finally recovered completely after termination of pregnancy by caesarean and the continuous use of glucocorticoid which played a crucial part in controlling hyperinflammation. Pregnancy-induced HLH could be fatal if effective treatment was not initiated timely. Further studies are needed to improve early diagnosis and etiology identification of HLH.

Neurological manifestations of hypothyroidism include peripheral neuropathy and pituitary hyperplasia. However, these associations are rarely encountered during pregnancy. We report a case of a known hypothyroid with very high thyroid stimulating hormone (TSH) values (512 μIU/mL) in the second trimester. At 24 weeks she developed facial palsy and pituitary hyperplasia which responded to a combination of steroids and thyroxine. She had caesarean delivery at 35 weeks and 3 days gestation in view of pre-eclampsia with severe features and was discharged on oral antihypertensives and thyroxine. On follow-up at 5 months, TSH normalised and pituitary hyperplasia showed a greater than 50% reduction in size. To our knowledge, this is the first reported case of facial palsy and pituitary hyperplasia associated with hypothyroidism during pregnancy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, with a prevalence that has increased significantly in the last decade, coming to affect 12-18% of all pregnancies. GDM is believed to be the result of a combination of genetic, epigenetic and environmental factors. Following the identification of susceptibility genes for type 2 diabetes by means of genome-wide association studies, an association has also been demonstrated between some type 2 diabetes susceptibility genes and GDM, suggesting a partial similarity of the genetic architecture behind the two forms of diabetes. More recent genome-wide association studies, focusing on maternal metabolism during pregnancy, have demonstrated an overlap in the genes associated with metabolic traits in gravid and non-gravid populations, as well as in genes apparently unique to pregnancy. Epigenetic changes-such as DNA methylation, histone modifications and microRNA gene silencing-have also been identified in GDM patients. Metabolomics has been used to profile the metabolic state of women during pregnancy, based on the measurement of numerous low-molecular-weight metabolites. Measuring amino acids and conventional metabolites has revealed changes in pregnant women with a higher insulin resistance and high blood glucose levels that resemble the changes seen in non-gravid, insulin-resistant populations. This would suggest similarities in the metabolic profiles typical of insulin resistance and hyperglycemia whether individuals are pregnant or not. Future studies combining data obtained using multiple technologies will enable an integrated systems biology approach to maternal metabolism during a pregnancy complicated by GDM. This review highlights the recent knowledge on the impact of genetics and epigenetics in the pathophysiology of GDM and the maternal and fetal complications associated with this pathology condition., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Dalfrà, Burlina, Del Vescovo and Lapolla.)

Human placenta is a complex and heterogeneous organ interfacing between the mother and the fetus that supports fetal development. Alterations to placental structural components are associated with various pregnancy complications. To reveal the heterogeneity among various placenta cell types in normal and diseased placentas, as well as elucidate molecular interactions within a population of placental cells, a new genomics technology called single cell RNA-seq (or scRNA-seq) has been employed in the last couple of years. Here we review the principles of scRNA-seq technology, and summarize the recent human placenta studies at scRNA-seq level across gestational ages as well as in pregnancy complications, such as preterm birth and preeclampsia. We list the computational analysis platforms and resources available for the public use. Lastly, we discuss the future areas of interest for placenta single cell studies, as well as the data analytics needed to accomplish them.

Objective: We report data from the Raoul Wallenberg Australian Register of Antiepileptic Drugs in Pregnancy (APR) to see if there are significant differences in relation to the courses and outcomes of the twin pregnancies contained in the register, as compared with the singleton ones., Methods: The APR has been under the oversight of Melbourne institutional Human Ethics Research Committees; all women enrolled in the APR have provided written informed consent. Data from the APR were transferred to a spreadsheet and then analyzed using simple statistical techniques including logistic regression., Results: The population studied comprised 44 twin and 2261 singleton pregnancies; thus, twin pregnancies accounted for 1.91% of all pregnancies studied. The women carrying twins tended to be older than the women with singleton pregnancies to a statistically significant extent, their pregnancies more often originated from assisted fertilization techniques, and their babies were more often delivered by cesarean section. There were no statistically significant differences in relation to antiepileptic drug (AED) therapy. Individual twins had statistically significantly lower mean birthweights than singleton babies and they were statistically significantly more often involved structurally malformed foetuses. In the first year of life, the twin pregnancies statistically significantly more often produced offspring that were affected by seizures in infancy., Significance: The data suggest that there may be an increased hazard of fetal malformation in the offspring of twin pregnancy in women with epilepsy, but that with contemporary standards of management of epilepsy and pregnancy, there is unlikely to be an increased hazard of seizure-affected pregnancy., (© 2020 International League Against Epilepsy.)

A lobular capillary hemangioma, previously known as a pyogenic granuloma, is a benign vascular lesion of the skin or mucous membrane. We report a case of capillary hemangioma of lobular subtype in the calvarium of a 28-year-old pregnant woman which presented as a sore and rapidly growing bulge over the left fronto-parietal region. Magnetic resonance imaging of the brain and skull showed an expansive tumor with brain displacement, skull erosion, and scalp infiltration. The tumor was surgically removed, and histopathological examination showed a capillary hemangioma of lobular subtype. To the best of our knowledge, this is the first report of a lobular capillary hemangioma in the calvarium, and it represents a rarity to be considered among the many other differential diagnoses for neurosurgical lesions involving the skull, especially in pregnant women.

Pregnancy complications including preeclampsia, preterm birth, intrauterine growth restriction, and gestational diabetes are the main adverse reproductive outcomes. Excessive inflammation and oxidative stress play crucial roles in the pathogenesis of pregnancy disorders. Curcumin, the main polyphenolic compound derived from Curcuma longa, is mainly known by its anti-inflammatory and antioxidant properties. There are in vitro and in vivo reports revealing the preventive and ameliorating effects of curcumin against pregnancy complications. Here, we aimed to seek mechanisms underlying the modulatory effects of curcumin on dysregulated inflammatory and oxidative responses in various pregnancy complications., (© 2020 International Union of Biochemistry and Molecular Biology.)