BACKGROUND: What kinds of fetal adverse outcomes beyond stillbirth directly correlate to the severity of intrahepatic cholestasis during pregnancy (ICP) remained tangled. Herein, we conducted a retrospective cohort study and a dose-response meta-analysis to speculate the association between the severity of ICP and its adverse outcomes.
METHODS: We retrospectively collected a cohort of ICP patients from electronic records from Guangzhou Women and Children\'s Medical Center between Jan 1st, 2018, and Dec 31st, 2022. Also, we searched PubMed, Cochrane, Embase, Scopus, and Web of Science to extract prior studies for meta-analysis. The Kruskal-Wallis test, a one-way or two-way variants analysis (ANOVA), and multi-variant regression are utilized for cohort study. One stage model, restricted cubic spline analysis, and fixed-effect model are applied for dose-response meta-analysis. The data analysis was performed using the R programme.
RESULTS: Our cohort included 1,289 pregnant individuals, including 385 mild ICP cases, 601 low moderate ICP cases, 282 high moderate ICP cases, and 21 severe ICP cases. The high moderate bile acid levels were correlated to preterm birth [RR = 2.14, 95%CI 1.27 to 3.62), P < 0.01], and preterm premature rupture of membranes [RR = 0.34, 95%CI 0.19 to 0.62), P < 0.01]. We added our cases to cases reported by other studies included in the meta-analysis. There were 15,826 patients included in dose-response meta-analysis. The severity of ICP was associated with increased risks of stillbirth, spontaneous preterm birth, iatrogenic preterm birth, preterm birth, admission to neonatal intensive care unit, and meconium-stained fluid (P < 0.05).
CONCLUSIONS: Our study shows the correlation between the severity of ICP and the ascending risks of stillbirth, preterm birth, and meconium-stained fluid, providing new threshold TBA levels.
UNASSIGNED: CRD42023472634.

The aim of this study was to evaluate the effects of medroxyprogesterone acetate (MPA) treatment in comparison to those of gonadotropin releasing hormone (GnRH) antagonists for the prevention of premature luteinizing hormone surges during controlled ovarian hyperstimulation (OS) and the impact of these effects on developing embryos and pregnancy outcomes. Data from 757 cycles of GnRH antagonist treatment and 756 cycles of MPA treatment were evaluated at the Akdeniz University Faculty of Medicine Assisted Reproductive Treatment Center between October 2018 and April 2022. Patient records were obtained from the electronic database of the centre and analysed. In our centre, GnRH antagonist protocols were used between 2018 and 2020, and MPA protocols were used between 2020 and 2022. We chose our study population by year. Our study is a comparative retrospective study. All methods in this study were performed in accordance with the relevant guidelines and regulations. Patients using MPA were significantly older (33.9 ± 5.6 vs. 32.6 ± 5.6, p < 0.001) and had a lower number of antral follicles (AFC) (10.7 ± 8.6 vs. 11.9 ± 10.8, p = 0.007) than those using GnRH antagonists. Both MPA (2.9%) and GnRH antagonists (2.2%) had similar effectiveness in preventing premature ovulation (p = 0.415). There was no significant difference between the two groups in terms of the number of total developed embryos (1.3 ± 1.3 vs. 1.2 ± 1.2, p = 0.765). There was no significant difference in the clinical pregnancy rates with the first ET (%35.4 vs. %30.1, p = 0.074), per total number of transfers (35.3% vs. 30.1%, p = 0.077). MPA was found to be effective at preventing premature ovulation during OS treatment, and the incidence of developing embryo and pregnancy outcomes in patients using MPA were similar to those in patients using GnRH antagonists. Therefore, the use of MPA instead of GnRH antagonists during OS may be a viable alternative for patients not scheduled for fresh ET.

BACKGROUND: Scoliosis can be detected on prenatal ultrasonography and may be associated with structural and syndromic abnormalities. Associations and pregnancy outcomes related to the prenatal diagnosis of scoliosis are poorly understood.
METHODS: A retrospective cohort study was undertaken at a tertiary referral center in London. Referred cases with spinal deformities between 1997 and 2021 were identified from the prenatal ultrasonography database. Outcomes were ascertained from the database and electronic notes.
RESULTS: One hundred twenty-three cases of fetal spinal deformities (scoliosis, kyphosis, or kyphoscoliosis) were identified from a referral population of 660,000 pregnancies, giving an incidence of approximately 0.2 per 1000 fetuses. Fifty-eight live births (47.2%) and 65 cases (52.8%) of fetal or neonatal demise or termination were observed. Most live births were isolated spinal deformities with a good postnatal outcome (n = 35, 60.3%). The commonest syndromic diagnosis in this group was VACTERL association (n = 7, 12.1%). Most cases of fetal loss were associated with severe malformations, most commonly spina bifida, body stalk anomaly and amniotic band sequence, or chromosomal abnormalities, except in 2 cases (3.1%).
CONCLUSIONS: This is the largest reported cases series to date of prenatally diagnosed fetal spinal deformity. This confirms that fetal scoliosis and associated vertebral abnormalities are underdiagnosed prenatally, with the reported incidence (0.2 per 1000) lower than the recognized incidence of congenital scoliosis (1 in 1,000). The concurrent finding of severe malformations was strongly associated with fetal loss. When an isolated finding, most fetal spinal deformities had a good postnatal outcome, while 1:8 live births were diagnosed with VACTERL association.

OBJECTIVE: Pregnant mothers are at risk of many adverse pregnancy outcomes, including infants with low birth weight (LBW). The World Health Organization aimed to achieve a 30% reduction in the number of LBW infants by the year 2025. In this study, we aimed to determine the incidence and determinants of LBW infants among pregnant mothers attending government health clinics in Peninsular Malaysia.
METHODS: A prospective cohort study \"Relative Risk of Determinants of Adverse Pregnancy Outcomes Among Pregnant Mothers Attending Government Health Clinics, Peninsular Malaysia, PEN-MUM\" was conducted from March 2022 until March 2023 at 20 government health clinics in Peninsular Malaysia that were randomly selected through a multistage sampling method. Malaysian pregnant mothers between 18 and 49 years old were recruited at 12-18 weeks of gestation and followed up at three time points: 1 (24-28 weeks of gestation), 2 (36-40 weeks of gestation), and 3 (post-delivery). Eight exposure factors of LBW were studied: gestational weight gain, dengue infection, urinary tract infection, COVID-19 infection, gestational hypertension, preeclampsia, maternal anemia, and gestational diabetes mellitus (GDM).
RESULTS: Among 507 participants enrolled in the cohort, 40 were lost to follow-up. A total of 467 were included in the final analysis, giving an attrition rate of 7.9%. The incidence of LBW infants in Peninsular Malaysia was 14.3%. After adjusting for three covariates (ethnicity, employment status, and gestational age at birth), three determinants of LBW were identified. The risk of giving birth to LBW infants was higher among those with inadequate gestational weight gain (aRR = 2.86, 95% CI: 1.12, 7.37, p = 0.03), gestational hypertension (aRR = 4.12; 95% CI: 1.66, 10.43; p = 0.002), and GDM (aRR = 2.21; 95% CI: 1.18, 4.14; p = 0.013) during the second and third trimesters.
CONCLUSIONS: The incidence of LBW infants in Peninsular Malaysia can be considered high. Having inadequate gestational weight gain, gestational hypertension, and GDM in the second and third trimesters increased the risk of LBW infants by threefold, fivefold, and twofold respectively. Thus, intervention strategies should target prevention, early detection, and treatment of gestational hypertension and GDM, as well as promoting adequate weight gain during antenatal care.

BACKGROUND: Recent data in nonpregnant individuals suggest a protective effect of influenza vaccination against SARS-CoV-2 infection and its severity.
OBJECTIVE: Our primary objective was to evaluate whether influenza vaccination was associated with COVID-19 severity and pregnancy and neonatal outcomes among those infected with SARS-CoV-2. The secondary objective was to examine the association between influenza vaccination and SARS-CoV-2 infection.
METHODS: Secondary analysis of a multicenter retrospective cohort of pregnant people who tested positive for SARS-CoV-2 between March and August 2020, and a cohort of random deliveries during the same time period. The associations between 2019 influenza vaccination and the primary outcome of moderate-to-critical COVID-19 as well as maternal and perinatal outcomes were examined among all people who tested positive for SARS-CoV-2 between March and August 2020. The association between 2019 influenza vaccination and having a positive SARS-CoV-2 test was examined among a cohort of individuals who delivered on randomly selected dates between March and August 2020. Univariable and multivariable analyses were performed.
RESULTS: Of 2325 people who tested positive for SARS-CoV-2, 1068 (45.9%) were vaccinated against influenza in 2019. Those who received the influenza vaccine were older, leaner, more likely to have private insurance, and identify as White or Hispanic. They were less likely to smoke tobacco and identify as Black. Overall, 419 (18.0%) had moderate, 193 (8.3%) severe, and 52 (2.2%) critical COVID-19. There was no association between influenza vaccination and moderate-to-critical COVID-19 (29.2% vs. 28.0%, adjusted OR 1.10, 95% CI 0.90-1.34) or adverse maternal and perinatal outcomes among those who tested positive. Of 8152 people who delivered in 2020, 4658 (57.1%) received the influenza vaccine. Prior vaccination was not associated with a difference in the odds of SARS-CoV-2 infection (3.8% vs. 4.2%, adjusted OR 0.94, 95% CI 0.74-1.19).
CONCLUSIONS: Prior influenza vaccination was not associated with decreased severity of COVID-19 or lower odds of SARS-CoV-2 infection in pregnancy.

The effect of paternal age on fertility remains unclear. This retrospective study aims to examine the impact of male age on semen parameters and the reproductive outcomes of men admitted to an infertility center over a 9-year period. A total of 8046 patients were included in the study. Men were divided into four age groups. The groups were evaluated for semen parameters and reproductive outcome. The 21-30 year group presented lower sperm concentrations in comparison to those aged 31-40 and 41-50, yet shared a similar concentration to those over 50 years of age. Moreover, grades A and B decreased significantly in men aged over 50 years. The highest progressive motility and normozoospermia were observed in the age group 31-40 years while men over 50 years of age had the highest rates of asthenozoospermia and oligoasthenozoospermia. Furthermore, live birth results were reported in 5583 of the patients who underwent intracytoplasmic sperm injection (ICSI) and were found highest between 31-40 years of age. To our knowledge, this is the largest study in Turkey focusing on male age-related semen parameters and ICSI pregnancy outcomes. The study demonstrates that age is a significant factor for semen quality and live birth.

BACKGROUND: Maternal obesity and excessive gestational weight gain are associated with adverse maternal and neonatal outcomes. There is uncertainty over the most effective antenatal healthy lifestyle service, with little research determining the impact of different lifestyle intervention intensities on pregnancy outcomes.
METHODS: This retrospective cohort study compared pregnancy and birth outcomes in women with a body mass index of 40 or above who were offered a low intensity midwife-led antenatal healthy lifestyle service (one visit) with women who were offered an enhanced service (three visits). The primary outcome was gestational weight gain.
RESULTS: There were no differences between the two healthy lifestyle service intensities (N = 682) in the primary outcome of mean gestational weight gain [adjusted mean difference (aMD) -1.1 kg (95 % CI -2.3 to 0.1)]. Women offered the enhanced service had lower odds of gaining weight in excess of Institute of Medicine recommendations [adjusted odds ratio (aOR) 0.63 (95 % CI 0.40-0.98)] with this reduction mainly evident in multiparous women. Multiparous women also gained less weight per week [aMD -0.06 kg/week (95 % CI -0.11 to -0.01)]. No overall beneficial effects were seen in maternal or neonatal outcomes measured such as birth weight [aMD 25 g (95 % CI -71 to 121)], vaginal birth [aOR 0.87 (95 % CI 0.64-1.19)] or gestational diabetes mellitus [aOR 1.42 (95 % CI 0.93-2.17)]. However, multiparous women receiving the enhanced service had reduced odds of small for gestational age [aOR 0.52 (95 % CI 0.31-0.87)]. This study was however underpowered to detect differences in some outcomes with low incidences.
CONCLUSIONS: Uncertainty remains over the best management of women with severe obesity regarding effective interventions in terms of intensity. It is suggested that further research needs to consider the different classes of obesity separately and have a particular focus on the needs of nulliparous women given the lack of effectiveness of this service among these women.

OBJECTIVE: To elucidate the clinical and pathological characteristics of gestational diabetes mellitus (GDM) with high and low insulin resistance.
METHODS: In total, 1393 GDM and 1001 non-GDM singleton deliveries were included in this study. Insulin resistance subtypes were classified according to the HOMA2-IR value. Clinical data were analyzed using SPSS 26.0. Placenta samples were collected for pathological analysis.
RESULTS: Maternal age and fasting glucose were identified as independent risk factors for GDM with high insulin resistance (p < 0.01), while fasting glucose was the sole risk factor for GDM with low insulin resistance (p < 0.001). Fetal distress was associated with both of GDM subtypes (both p < 0.01), while anemia, fetal growth restriction, large for gestational age and intrahepatic cholestasis in pregnancy were related to specific GDM insulin resistance subtype. In addition, GDM with high insulin resistance showed an increase of syncytial knots with down-regulation of PI3K/AKT signaling, while GDM with low insulin resistance showed normal syncytial knot counts and up-regulation of PI3K/AKT signaling.
CONCLUSIONS: Our findings provide novel perspectives to the clinical and pathological comprehensions of GDM with high and low insulin resistance, which might facilitate the mechanism study of GDM and its precision pregnancy management.

UNASSIGNED: Little attention has been given to prenatal cobalamin insufficiency in settings where dietary cobalamin intake is presumed adequate, such as populations with habitual intake of foods from animal sources.
UNASSIGNED: However, low cobalamin status in women of fertile age has been reported in Europe, United States, and Canada. In India, where cobalamin deficiency is highly prevalent, it has been associated with an increased risk of miscarriage, intrauterine growth retardation, as well as insulin resistance and lower neurodevelopment scores in the offspring. Low cobalamin status in pregnancy has been associated with similar outcomes as those reported in the Indian studies although the evidence is scant and conflicting.
UNASSIGNED: Consideration should be given to maternal cobalamin status in the context of prevention of adverse pregnancy outcomes as well as cobalamin insufficiency both in the mother and the offspring during lactation. Further attention is now justified with the increasing tendency toward plant-based diets. Reference intervals for cobalamin status during each trimester of pregnancy are needed and further investigation of the long-term conse-quences of low cobalamin status during pregnancy for health and development in the offspring is warranted.
Plain language titleInadequate cobalamin status during critical periods of growth and development can have negative consequences on maternal and childhood health.

BACKGROUND: Toxoplasma gondii infection causes adverse pregnancy outcomes by affecting the expression of immunotolerant molecules in decidual immune cells. Galectin-9 (Gal-9) is widely expressed in decidual macrophages (dMφ) and is crucial for maintaining normal pregnancy by interacting with the immunomodulatory protein T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3). However, the effects of T. gondii infection on Gal-9 expression in dMφ, and the impact of altered Gal-9 expression levels on the maternal-fetal tolerance function of decidual natural killer (dNK) cells, are still unknown.
METHODS: Pregnancy outcomes of T. gondii-infected C57BL/6 and Lgals9-/- pregnant mice models were recorded. Expression of Gal-9, c-Jun N-terminal kinase (JNK), phosphorylated JNK (p-JNK), and Forkhead box protein O1 (FOXO1) was detected by western blotting, flow cytometry or immunofluorescence. The binding of FOXO1 to the promoter of Lgals9 was determined by chromatin immunoprecipitation-polymerase chain reaction (ChIP-PCR). The expression of extracellular signal-regulated kinase (ERK), phosphorylated ERK (p-ERK), cAMP-response element binding protein (CREB), phosphorylated CREB (p-CREB), T-box expressed in T cells (T-bet), interleukin 10 (IL-10), and interferon gamma (IFN-γ) in dNK cells was assayed by western blotting.
RESULTS: Toxoplasma gondii infection increased the expression of p-JNK and FOXO1 in dMφ, resulting in a reduction in Gal-9 due to the elevated binding of FOXO1 with Lgals9 promoter. Downregulation of Gal-9 enhanced the phosphorylation of ERK, inhibited the expression of p-CREB and IL-10, and promoted the expression of T-bet and IFN-γ in dNK cells. In the mice model, knockout of Lgals9 aggravated adverse pregnancy outcomes caused by T. gondii infection during pregnancy.
CONCLUSIONS: Toxoplasma gondii infection suppressed Gal-9 expression in dMφ by activating the JNK/FOXO1 signaling pathway, and reduction of Gal-9 contributed to dysfunction of dNK via Gal-9/Tim-3 interaction. This study provides new insights for the molecular mechanisms of the adverse pregnancy outcomes caused by T. gondii.