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There are approximately 5 million pregnancies per year in the USA, with 1 million ending in miscarriage (a loss occurring prior to 20 weeks of gestation) and over 20,000 ending in stillbirth at or beyond 20 weeks of gestation. As many as 50% of these losses are unexplained. Our objective was to evaluate the effect of expanding the placental pathology diagnostic categories to include the explicit categories of (1) dysmorphic chorionic villi and (2) small placenta in examining previously unexplained losses. Using a clinical database of 1256 previously unexplained losses at 6–43 weeks of gestation, the most prevalent abnormality associated with each loss was determined through examination of its placental pathology slides. Of 1256 cases analyzed from 922 patients, there were 878 (69.9%) miscarriages and 378 (30.1%) antepartum stillbirths. We determined the pathologic diagnoses for 1150/1256 (91.6%) of the entire series, 777/878 (88.5%) of the miscarriages (< 20 weeks’ gestation), and 373/378 (98.7%) of the stillbirths (≥ 20 weeks’ gestation). The most common pathologic feature observed in unexplained miscarriages was dysmorphic chorionic villi (757 cases; 86.2%), a marker associated with genetic abnormalities. The most common pathologic feature observed in unexplained stillbirths was a small placenta (128 cases; 33.9%). Our classification system reinforced the utility of placental examination for elucidating potential mechanisms behind pregnancy loss. The improved rate of diagnosis appeared to be the result of filling a gap in previous pregnancy loss classification systems via inclusion of the categories of dysmorphic chorionic villi and small placenta. Graphical Abstract

Gestational hypoxia inhibits mitochondrial function in the fetal heart and placenta contributing to fetal growth restriction and organ dysfunction. NAD + deficiency may contribute to a metabolic deficit by inhibiting oxidative phosphorylation and ATP synthesis. We tested the effects of nicotinamide riboside (NR), an NAD + precursor, as a treatment for reversing known mitochondrial dysfunction in hypoxic fetal hearts. Pregnant guinea pigs were housed in room air (normoxia) or placed in a hypoxic chamber (10.5%O 2 ) for the last 14 days of gestation (term = 65 days) and administered either water or NR (1.6 mg/ml) in the drinking bottle. Fetuses were excised at term, and NAD + levels of maternal liver, placenta, and fetal heart ventricles were measured. Indices of mitochondrial function (complex IV activity, sirtuin 3 activity, protein acetylation) and ATP synthesis were measured in fetal heart ventricles of NR-treated/untreated normoxic and hypoxic animals. Hypoxia reduced fetal body weight in both sexes ( p  = 0.01), which was prevented by NR. Hypoxia had no effect on maternal liver NAD + levels but decreased ( p  = 0.04) placenta NAD + levels, the latter normalized with NR treatment. Hypoxia had no effect on fetal heart NAD + but decreased ( p  < 0.05) mitochondrial complex IV and sirtuin 3 activities, ATP content, and increased mitochondrial acetylation, which were all normalized with maternal NR. Hypoxia increased ( p  < 0.05) mitochondrial acetylation in female fetal hearts but had no effect on other mitochondrial indices. We conclude that maternal NR is an effective treatment for normalizing mitochondrial dysfunction and ATP synthesis in the hypoxic fetal heart.

Fetal growth restriction (FGR) is associated with uteroplacental insufficiency, and neurodevelopmental and structural brain deficits in the infant. It is currently untreatable. We hypothesised that treating the maternal uterine artery with vascular endothelial growth factor adenoviral gene therapy (Ad.VEGF-A 165 ) normalises offspring brain weight and prevents brain injury in a guinea pig model of FGR. Pregnant guinea pigs were fed a restricted diet before and after conception and received Ad.VEGF-A 165 (1 × 10 10 viral particles, n  = 18) or vehicle ( n  = 18), delivered to the external surface of the uterine arteries, in mid-pregnancy. Pregnant, ad libitum-fed controls received vehicle only ( n  = 10). Offspring brain weight and histological indices of brain injury were assessed at term and 5-months postnatally. At term, maternal nutrient restriction reduced fetal brain weight and increased microglial ramification in all brain regions but did not alter indices of cell death, astrogliosis or myelination. Ad.VEGF-A 165 increased brain weight and reduced microglial ramification in fetuses of nutrient restricted dams. In adult offspring, maternal nutrient restriction did not alter brain weight or markers of brain injury, whilst Ad.VEGF-A 165 increased microglial ramification and astrogliosis in the hippocampus and thalamus, respectively. Ad.VEGF-A 165 did not affect cell death or myelination in the fetal or offspring brain. Ad.VEGF-A 165 normalises brain growth and markers of brain injury in guinea pig fetuses exposed to maternal nutrient restriction and may be a potential intervention to improve childhood neurodevelopmental outcomes in pregnancies complicated by FGR.

We evaluated whether the sheep constitutes a useful translational model to evaluate anatomical and surgical aspects of cesarean delivery (CD) from a human medical perspective with the aim of both maternal and neonatal well-being. Our hypothesis was that CD in contraction-free ewes is not associated with major complications. Primary endpoint was the transferability of anatomical conditions and surgical techniques of CD from the ewe to the human. Secondary endpoints were maternal and fetal survival, occurrence of retained fetal membranes, metritis, mastitis, or wound infections. Forty-eight Merino ewes were delivered by CD after 95% gestation (142–144 days). Both ewes and newborn lambs were cared for intensively after the delivery. Ovine uterine anatomy during CD appeared slightly different but comparable to the human uterus. Uterine incisions were mostly performed in the uterine horns, not in the uterine corpus. The ovine uterine wall is thinner than in humans. All ewes survived without any major complications. Seventy-seven (88.5%) out of 87 live-born lambs survived without any complications. The contraction-free ewe constitutes an appropriate and safe model to evaluate anatomical and surgical aspects of CD from a human medical perspective. We present a step-by-step manual for successfully planned cesarean delivery for sheep including the perioperative management illustrated with photographs and a five-minute video. With adequate planning and a reasonable number of staff, it is possible to safeguard both maternal and neonatal survival. This sustainable translational medicine model offers additional potential for the offspring to be used for further research studies (e.g., transgenerational inheritance research).

Pregnant individuals with obesity (body mass index, BMI ≥ 30 kg/m 2 ) are more likely to experience prolonged labor and have double the risk of cesarean compared with individuals with normal weight (BMI < 25 kg/m 2 ). The aim of this study was to evaluate whether obesity in pregnancy is associated with reduced spontaneous and oxytocin-stimulated myometrial contractile activity using ex vivo preparations. We also assessed the relationship between maternal BMI and the expression of oxytocin (OXTR) and prostaglandin (FP) receptors in the myometrial tissue. We enrolled 73 individuals with a singleton gestation undergoing scheduled cesarean delivery at term in a prospective cohort study. This included 49 individuals with a pre-pregnancy BMI ≥ 30 kg/m 2 and 24 with BMI < 25.0 kg/m 2 . After delivery, a small strip of myometrium was excised from the upper edge of the hysterotomy. Baseline spontaneous and oxytocin stimulated myometrial contractile activity was measured using ex vivo preparations. Additionally, expression of oxytocin and prostaglandin receptors from myometrial samples were compared using qRT-PCR and western blot techniques. Spontaneous and oxytocin-stimulated contraction frequency, duration, and force were not significantly different in myometrial samples from the obese and normal-weight individuals. Myometrial OXTR gene and protein expression was also similar in the two groups. While FP gene expression was lower in the myometrial samples from the obese group, protein expression did not differ. These data help to address an important knowledge gap related to the biological mechanisms underlying the association between maternal obesity and dysfunctional labor.

Introduction There is an increasing incidence of pregnancies with twin gestations. One outcome more likely to occur with multiple gestations is gestational diabetes mellitus. Studies have suggested that in singleton pregnancies, fetal sex may affect insulin resistance. However, the effects of fetal sex in twins and the development of gestational diabetes mellitus are unknown. We hypothesized that rates of gestational diabetes mellitus and degree of insulin resistance might vary in twin gestations based on the fetal sex pairing: male–male, male–female or female–female. We aimed to employ a large population‐based database to ascertain any correlations between fetal sex and gestational diabetes mellitus in multifetal gestations. Material and methods A two‐hospital, single academic institution database comprised of over 39 000 participants with pregnancy data from August 2011 to January 2022 was employed. All twin deliveries of live‐born neonates >24 weeks’ gestational age from gravidae without preexisting diabetes or twin–twin transfusion syndrome were included. Entries were then grouped based on the fetal sex of the pairing. The presence or absence of gestational diabetes and type of gestational diabetes – diet‐controlled (gestational diabetes mellitus classification A1) vs medication‐controlled (gestational diabetes mellitus classification A2) – were identified. Statistical analysis was performed using a generalized linear mixed method, and a P‐value ≤0.05 was considered statistically significant. Results We identified 1924 twin deliveries that met the inclusion criteria in our database (male–male =652; male–female = 638; female–female = 634). We found no association between fetal sex pairing and the development of gestational diabetes mellitus. There was a significant association between the fetal sex pairing and the type of gestational diabetes mellitus developed, with 32.0% of male–male twins, 33.3% of male–female twins and 58.3% of the female–female twin deliveries associated with medication‐controlled gestational diabetes classification A2: male–female vs female–female (P = 0.05) and male–male vs female–female (P = 0.046). Conclusions While gestational diabetes mellitus is of multifactorial origin, we found a significant association between the fetal sex pairing and the treatment needed for gravidae with twins who develop gestational diabetes mellitus. A higher proportion of female–female twins was associated with gestational diabetes classification A2 compared with male–female or male–male deliveries. Further research on the physiology driving this association is warranted. While gestational diabetes mellitus is of multifactorial origin, this study was designed to investigate whether gestational diabetes mellitus and degree of insulin resistance might vary in twin gestations based on the fetal sex pairing: male–male, male–female or female–female. There was no relationship between the development of gestational diabetes mellitus and the fetal sex pairing observed in gravidae with twin gestations, with equal proportions of gravidae with male–male, male–female and female–female twins developing the disease. However, in gravidae with twins that develop gestational diabetes mellitus, a higher proportion of deliveries of female–female twins was associated with medication‐controlled gestational diabetes class A2 compared with deliveries of male–female or male–male twins.

Preeclampsia is a common pregnancy complication affecting 5% to 7% of all pregnancies worldwide annually. While the pathogenesis is not fully understood, maternal endothelium dysfunction is thought to be a central component to preeclampsia development. Studies to dissect maternal endothelial dysfunction, particularly on a patient-specific basis, are hampered by limited access to systemic primary endothelial cells (ECs). The objective of this study was to establish a replenishable, patient-specific in vitro EC model to allow robust mechanistic studies to dissect endothelial dysfunction in preeclampsia. Induced pluripotent stem cells (iPSCs) from three women with a history of normotensive pregnancies were differentiated into ECs. The established ECs were exposed to pooled sera from normotensive pregnancies, preeclamptic pregnancies, normotensive postpartum for non-pregnant comparison and controls. Endothelial functions including nitric oxide (NO) release, cell migration, tube formation and viability were evaluated. Levels of NO release were significantly lower after incubation with preeclamptic sera compared to the fetal bovine serum (FBS) control, and normotensive and non-pregnant (postpartum) sera treatments were also lower than FBS but higher than preeclamptic sera treatments. Tube formation and cell migration were also impaired with preeclamptic sera compared to FBS controls. Cell viabilities remained unaffected by any sera treatment. Consistent outcomes were obtained across all three patient-specific lines treated with the same pooled sera. Establishment of patient-derived iPSC-ECs treated with pregnancy sera serves as a novel model to explore the interplay between individual maternal endothelial health and circulating factors that lead to endothelial dysfunction in preeclampsia.

This study aimed to determine the protective role of boric acid in a pregnant rat model of high fructose corn syrup consumption. Consumption of high fructose corn syrup has been associated with adverse health outcomes in humans and animals. Twenty-eight healthy female Wistar albino rats (250–300 g weight and 16–24 weeks old) were randomly distributed into four equal groups ( n  = 7): Control, Boric acid (BA), High Fructose Corn Syrup (HFCS), HFCS + BA. Boric acid (20 mg/kg) was administered to pregnant rats via oral gavage every day during pregnancy. The prepared 30% HFCS (F30) solution (24% fructose, 28% dextrose) was added to the drinking water throughout pregnancy. At the end of pregnancy (day 19), blood, placenta, uterus, and fetuses were collected from rats. The results indicated that HFCS increases oxidative stress by increasing the level of MDA and decreasing GSH, SOD, and CAT activity in the blood of maternal. However, BA administration significantly decreased MDA levels and increased GSH levels, SOD, and CAT activity ( p  < 0.05). In addition, HFCS consumption significantly increased plasma TNF-α, IL-6, and leptin levels compared to control, BA, and HFCS + BA groups ( p  < 0.05). However, BA administration significantly decreased plasma TNF-α, IL-6, and leptin levels ( p  < 0.05). Furthermore, BA (20 mg/kg) significantly decreased HFCS-induced histopathological and immunohistochemical alterations in the placenta, uterus, and fetal tissue. In conclusion, BA may prevent HFCS toxicity in maternal and fetal tissues, as it regulates oxidative imbalance in pregnant rat and alleviates histopathological and immunohistochemical changes. The findings indicate a need for further studies to assess the potential of boron in preventing or mitigating the effects of HFCS during pregnancy. Graphical Abstract

The aim of this study was to evaluate maternal serological status and fetal sonographic findings of Cytomegalovirus (CMV) infection. This is a retrospective study performed at Perinatology Department of Istanbul Başakşehir Çam and Sakura City Hospital. A computerized search was conducted to identify cases who underwent prenatal diagnosis of fetal CMV infection between September 2020 and December 2023. We identified nine cases with fetal CMV infection. The clinical data of the patients, gestational age at the time of diagnosis, serological, sonographic findings, and pregnancy outcomes were analyzed. A computer search of the database was made for the seroprevalance of CMV-IgM and CMV-IgG in our population. The CMV-IgM and IgG results of the 1235 patients who underwent CMV screening in the first trimester between September 2020 and December 2023 were evaluated. Fetal CMV infection was identified in nine patients. None of the 9 cases showed maternal CMV-IgM positivity. Seven of the 9 patients showed high IgG avidity index. Pregnant population had 98 % positivity for CMV-IgG. The evaluation of serologic tests for CMV is not straightforward in the second and third trimester. IgM and IgG avidity should be interpreted with caution in the second and third trimester. In the presence of ultrasound findings suggesting fetal CMV infection and CMV-IgG positivity, invasive diagnostic tests rather than serological test should be discussed with the patient, and non-primary infections should always be considered to minimize overlooked fetal cytomegalovirus infections and missed antiviral treatment opportunity.

Background: To evaluate maternal and neonatal outcomes of assisted reproductive technology (ART). Materials and Methods: Pregnant women registered from 2015 through 2017 (n = 6994) at five perinatal centers that managed high-risk pregnancies in Mie, Japan, retrospectively. Rates of preterm birth (<37 gestational weeks), early onset preeclampsia (<34 gestational weeks), late onset preeclampsia (≥34 gestational weeks), low-lying placenta, placenta previa, placenta accreta, placental abruption, atonic bleeding, uterine rupture, and amniotic fluid embolism after ART were evaluated. ART was defined as in vitro fertilization and micro-fertilization. Fisher’s exact test, Mann–Whitney’s U test, and logistic regression analysis were used to analyze the data. Results: Rates of obstetrical complications including low-lying placenta, placenta previa, placenta accreta, and atonic bleeding were increased with ART compared to those with the control. Particularly, ART was associated with a significantly increased rate of placenta accreta (adjusted odds ratio: 7.35, 95% confidence interval (CI): 3.20–16.6) and significantly decreased rate of placental abruption (adjusted odds ratio: 0.24, 95% CI: 0.07–0.61). Conclusions: This study showed that ART may reduce placental abruption and increase placenta previa. There is a possibility that the placenta attaches deeper in the myometrium because of ART.