Spontaneous Preterm Birth Research Articles

Impact of disease-modifying therapies on pregnancy outcomes in multiple sclerosis: a prospective cohort study from the German multiple sclerosis and pregnancy registry.

In recent decades, relapsing remitting multiple sclerosis (MS) became more treatable through new disease-modifying therapies (DMTs). Identifying safe treatments with minimal fetal risks for family planning is needed. In this prospective cohort from the German MS and Pregnancy Registry (DMSKW), we analyzed pregnancy and neonatal outcomes in MS-patients using descriptive statistics and logistic/linear regression models to compare DMT-exposed pregnancies to DMT-unexposed pregnancies. In 2885 DMT-exposed and 837 DMT-unexposed pregnancies, exposure was not associated with spontaneous abortions, preterm births or major congenital anomalies (MCAs). Severe infections were rare, but more frequent in the Fumarates-group (11/395: 2.8% vs. 8/837 unexposed-group: 1.0%, p-value: 0.03). Antibiotic-use was associated with 2nd-trimester (OR: 2.47, CI: 1.47, 4.05, p-value: <0.001), 3rd-trimester Natalizumab-exposure (OR: 1.75, CI: 1.15, 2.63, p-value: 0.01), and anti-CD20-exposure (OR: 2.16, CI: 1.41, 3.29, p-value: <0.001). Birthweight was significantly reduced in the Sphingosine-1-phosphate-group (β:-132g, CI:-205,-60, p-value: <0.001), and 3rd-trimester Natalizumab-subgroup (β:-74g, CI:-138,-9.4, p-value: 0.02). Small for gestational age (SGA) neonates were common in the Sphingosine-1-phospate- (OR: 1.65, CI: 1.07, 2.50, p-value: 0.02) and anti-CD20-group (OR: 1.54, CI: 1.01, 2.32, p-value: 0.04), and also the entire cohort (651/3459: 18.8%), exceeding the general German population rate (10%) (p-value: <0.001). We observed an increased SGA risk, especially following highly-effective DMTs, although the pathomechanisms remain unclear. More research is needed on infection risks and MCAs, perhaps by linking different registries. The DMSKW is partly supported by Almirall, Biogen, Hexal, Merck, Novartis, Roche, Sanofi Genzyme, Teva Pharma and Viatris.

Assessment of the thymus in fetuses prior to spontaneous preterm birth using functional MRI

Assessment of the thymus in fetuses prior to spontaneous preterm birth using functional MRI

Correlation between perinatal abnormalities and decreased fetal movement as counted by a fetal movement acceleration measurement recorder: A prospective cohort study.

The objective was to study the relationship between a decrease in gross fetal movement during maternal night sleep counted by an objective method and abnormal perinatal outcomes. This was a prospective cohort study. A total of 470 pregnant women recorded fetal movement with the fetal movement acceleration measurement recorder weekly after 28 weeks. The ratio of 10-s epochs with fetal movement to all epochs was calculated as the fetal movement parameter. When the parameter was below the 10th percentile of the previously made reference curve, it was defined as decreased movement. Women who showed a decreased movement at least once were classified into a study group, and the other women were classified into a control group. Abnormal perinatal outcomes between the two groups were compared with the Chi-square test. There were more preterm births (19%) in the study group than in the control group (10%) (P = 0.0210). There was a significant difference for iatrogenic preterm birth (P = 0.0241) but not for spontaneous preterm birth (P = 0.4566). There were more hypertensive disorders of pregnancy (11.6%), small-for-gestational-age newborns (10.7%), and Apgar scores below 7 points at 1 min (7.4%) in the study group than in the control group (5.2%, 4.8%, and 2.6%, respectively) (P = 0.0329, 0.0459, and 0.0487, respectively). A decrease in gross fetal movement during maternal night sleep was related to iatrogenic preterm births, small-for-gestational-age newborns, hypertensive disorders of pregnancy, and low Apgar scores at 1 min.

Molecular profiling unveils pyroptosis markers in preterm birth.

Through a comprehensive examination of pyroptosis-related differential expressed genes (PRDEGs), this work investigates the molecular complexities of spontaneous preterm birth (SPTB), also known as premature delivery, before the due date. Through the process of merging and correcting batch effects in the GSE120480 and GSE73714 datasets, we were able to identify 36 PRDEGs that exhibited significant expression differentiation in SPTB. Through functional enrichment and pathway analysis, their importance in amino acid transport and cytokine receptor interaction has been highlighted. Among the genes that have emerged as crucial, CEBPA, APOA1, and CEP55 have been identified. The relevance of these molecules was demonstrated using experimental knockdowns, which also suggested that they could be used as molecular biomarkers and therapeutic targets for SPTB.

MTHFR Gene Polymorphisms and DNA Methylation in Idiopathic Spontaneous Preterm Birth

Background and Objectives: Preterm birth (PTB) is a complex condition with various contributing factors, including genetic and epigenetic influences such as DNA methylation. Methylenetetrahydrofolate reductase (MTHFR) plays a critical role in DNA methylation and the remethylation of homocysteine. This study aimed to investigate the association between maternal MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation levels, and the risk of idiopathic spontaneous preterm birth (SPTB) in Caucasian women from Croatia and Slovenia. Materials and Methods: A total of 50 women with SPTB (&lt;34 weeks of gestation) and 50 control women were included in the study. MTHFR polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), and LINE-1 DNA methylation levels were quantified using the MethyLight method. Results: The study found no significant differences in MTHFR C677T and A1298C polymorphisms’ genotype or allele frequencies between women with SPTB and controls. Additionally, no statistical significance of LINE-1 DNA methylation was found between the genotypes of the MTHFR polymorphisms analyzed. Conclusions: The study suggests no conclusive association between MTHFR C677T and A1298C polymorphisms, LINE-1 DNA methylation, and SPTB in Croatian and Slovenian women. Considering prior evidence connecting MTHFR polymorphisms, hyperhomocysteinemia, and PTB, the lack of homocysteine measurements and unassessed impact of folate or vitamin B supplementation limit the conclusions.

Anxiety, depression, and perceived wellbeing in antenatal women at risk of preterm birth: a retrospective cohort study.

Women identified at risk for preterm may be vulnerable to developing mental health difficulties due to the increased likelihood of poor pregnancy outcome and uncertainty surrounding their delivery. Formal assessment of mental wellbeing in specialist preterm birth clinics is not routinely offered, but may offer the opportunity for early intervention. We aimed to investigate if demographic characteristics and obstetric risk factors were associated with psychological wellbeing in women at risk of preterm birth. We explored associations between mental wellbeing and risk factors for preterm birth using hierarchical regression analyses. When demographic variables were considered alone, high body mass index (BMI) was significantly associated with anxiety (p = .026), however became non-significant when obstetric risk factors were also considered. Previous late miscarriage was associated with high anxiety (p = .049). Lower maternal age at estimated date of delivery (p = .019) and non-European ethnic heritage (p = .029) were significantly associated with depression. High maternal BMI (p < .001), being of any other non-European ethnic heritage (p = .043), currently smoking (p = .002), and previous spontaneous preterm birth (p = .017) were associated with lower perceived wellbeing. The results of this study highlight the importance of routinely monitoring mental health in women with relevant risk factors, particularly if they are already at risk of preterm birth.

Association between infertility and incident onset of systemic autoimmune rheumatic disease after childbirth: a population-based cohort study.

What is the association between infertility with or without fertility treatment and incident onset of systemic autoimmune rheumatic disease (SARD) among women who give birth? Women who experienced infertility but did not use fertility treatment had a higher incidence of SARD up to 9 years after delivery than those who did not experience infertility, even after accounting for their higher rates of preeclampsia, spontaneous preterm birth, and stillbirth. Infertility is increasingly common and is an under-appreciated risk marker for chronic diseases in women. Despite several studies documenting abnormal immune activity in women with infertility, little is known about the association between infertility and incidence of autoimmune diseases such as SARD which disproportionately develops in reproductive-aged women. This population-based cohort study using linked administrative data for all of ON, Canada, 2012-2021 and included 568053 singleton births among 465078 women aged 18-50 years without known pre-existing SARD. The exposures were: (i) no infertility with unassisted conception (referent [88.0% of the cohort]); (ii) infertility without fertility treatment (9.2%); (iii) infertility with non-invasive fertility treatment (ovulation induction or intrauterine insemination [1.4%]); and (iv) infertility with invasive fertility treatment (IVF or ICSI [1.4%]). SARD was identified by a validated algorithm based on diagnostic codes at two physician visits, one rheumatologist visit, or one hospitalization and measured from the index delivery date, with censoring at death, loss of health insurance, or study end of 31 March 2021. Marginal structural Cox proportional hazards models generated hazard ratios (HR) and 95% CIs representing total effects adjusted for sociodemographic characteristics, comorbidities, and smoking, and controlled direct effects additionally accounting for adverse pregnancy outcomes. The median (IQR) duration of follow-up was 6.5 (4-9) years. The incidence rate of SARD was 9.3 per 10000 person-years in women without infertility, 12.5 per 10000 person-years in those with infertility and no fertility treatment, 10.9 per 10000 person-years following non-invasive fertility treatment, and 10.9 per 10000 person-years after invasive fertility treatment. Infertility without treatment was associated with an elevated risk of SARD, even after accounting for adverse pregnancy outcomes (controlled direct effect HR 1.25, 95% CI 1.12-1.40). Neither non-invasive (total effect HR 1.06, 95% CI 0.79-1.42) nor invasive (total effect HR 0.97, 95% CI 0.69-1.36) fertility treatments were associated with SARD. Exposure and outcome misclassification is possible as this study used published algorithms in health administrative data with unknown or imperfect sensitivity and specificity. Data on individual-level social and lifestyle factors and underlying causes of infertility were not available and thus were not included in the analysis. Infertility in the absence of fertility treatment may be an important risk marker for SARD in women who give birth. Greater health provider awareness of SARD symptoms and related gynaecological issues that may be present in women with infertility could facilitate earlier detection and treatment of SARD during the reproductive years. This research was funded by the Canadian Institutes of Health Research through a Banting Postdoctoral Fellowship to N.V.S. and Canada Research Chair to H.K.B. (2019-00158) and was supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and the Ministry of Long-Term Care. The analyses, conclusions, opinions, and statements expressed herein are solely those of the authors and do not reflect those of the funding organizations; no endorsement is intended or should be inferred. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. M.Y.C. has consulted for Celltrion, Werfen, Organon, MitogenDx, AstraZeneca, Mallinckrodt Canada Inc, and Glaxo Smith Kline. All other authors have no conflicts of interest. N/A.

Nonhuman primate models of pediatric viral diseases.

Infectious diseases are the leading cause of death in infants and children under 5 years of age. In utero exposure to viruses can lead to spontaneous abortion, preterm birth, congenital abnormalities or other developmental defects, often resulting in lifelong health sequalae. The underlying biological mechanisms are difficult to study in humans due to ethical concerns and limited sample access. Nonhuman primates (NHP) are closely related to humans, and pregnancy and immune ontogeny in infants are very similar to humans. Therefore, NHP are a highly relevant model for understanding fetal and postnatal virus-host interactions and to define immune mechanisms associated with increased morbidity and mortality in infants. We will discuss NHP models of viruses causing congenital infections, respiratory diseases in early life, and HIV. Cytomegalovirus (CMV) remains the most common cause of congenital defects worldwide. Measles is a vaccine-preventable disease, yet measles cases are resurging. Zika is an example of an emerging arbovirus with devastating consequences for the developing fetus and the surviving infant. Among the respiratory viruses, we will discuss influenza and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). We will finish with HIV as an example of a lifelong infection without a cure or vaccine. The review will highlight (i) the impact of viral infections on fetal and infant immune development, (ii) how differences in infant and adult immune responses to infection alter disease outcome, and emphasize the invaluable contribution of pediatric NHP infection models to the design of effective treatment and prevention strategies, including vaccines, for human infants.

Maternal genetic risk factors for spontaneous preterm birth: A systematic review and meta‐analysis

AbstractBackgroundDespite various genomic approaches used in prior studies investigating the association of maternal genetic variability with spontaneous preterm birth (sPTB), results show inconsistency and contradictions.ObjectivesTo conduct a systematic review of studies analyzing the association between maternal genetic variants and sPTB, evaluate retrieved studies based on selection criteria, classify studies into hypothesis‐based and hypothesis‐free, and perform a meta‐analysis to identify the strongest associations.Search strategyPubMed, Scopus, and reference lists were searched until October 2024.Selection criteriaEnglish‐language, case–control, cross‐sectional, and prospective cohort studies examining the association between maternal genetic variations and sPTB were included.Data collection and analysisData on authors, publication year, ethnicity, genes/variants, P values, study type, sample size, inclusion criteria, and methods were collected. The association strength was estimated using odds ratios with 95% confidence intervals.ResultsEighty‐one studies met eligibility criteria: 73 utilized a hypothesis‐based and 14 a hypothesis‐free approach. Thirty‐five studies qualified for a meta‐analysis, revealing a significant association in tumor necrosis factor α (rs1800629) gene for alleles and additive and recessive genetic models (P ≤ 0.05). From the hypothesis‐free approach, 13 genes reached global significance in association with sPTB (P &lt; 5 × 10−8).ConclusionsNo single gene or variant was consistently associated with sPTB risk among studies. Hypothesis‐based analyses highlighted tumor necrosis factor α (rs1800629) as a modest signal, while hypothesis‐free approaches identified 13 genes with genome‐wide significance, pointing to new research directions in understanding sPTB genetics.

Mapping genetic susceptibility to spontaneous preterm birth: Analysis of Utah pedigrees to find inherited genetic factors.

Spontaneous preterm birth (SPTB) is the leading cause of neonatal morbidity and mortality. It is a final common pathway for multiple etiologies, some of which are well known while others likely remain to be identified. Despite recent advancements in identifying genetic risk factors, the mechanisms of many SPTBs remain poorly understood due to the phenotypic heterogeneity and complexity. Large family-based studies decrease heterogeneity and improve power to identify genetic causes of SPTB. To identify inherited genetic factors in SPTB etiology using large families. Using the Utah Population Database, which links a 4.5 million-person genealogy to state birth certificate and fetal death records, we identified large pedigrees containing multiple women with early SPTB (<34 weeks' gestation) and any SPTB (<37 weeks' gestation). We reviewed birth certificate data to exclude those with maternal and fetal diagnoses associated with iatrogenic preterm birth, resulting in 74 large multiplex pedigrees for early SPTB. Enrolled women with SPTB underwent comprehensive clinical phenotyping with review of primary medical records. Seven pedigrees, each containing at least 3 sampled women with SPTB, were the focus of this genetic study. High-density single-nucleotide polymorphism genotyping was conducted in maternal peripheral blood samples from women in the seven pedigrees. Shared genomic segments analysis was performed to identify genome-wide significant chromosomal regions shared in excess by women with SPTB. We identified two genome-wide significant chromosomal regions. In single-pedigree SGS analysis, a 1.75 Mega base region in chromosome 8 (8q24.23) was shared by 5 out of 6 women with SPTB in a single large pedigree (false positive rate=0.028). In duo-pedigree analysis, a 1.05 Mega base region in the same 8q24.23 locus was identified in a second pedigree (false-positive rate [duo]= 0.0019). The intersecting region at the 8q24.23 locus contains FAM135B (family with sequence similarity 135 member B) and KHDRBS3 (KH RNA binding domain containing, signal transduction associated 3) genes, which have previously been implicated in oncogenesis and ovarian cancer, respectively. Duo-pedigree SPTB analysis also identified a second genome-wide significant 67 kilo base locus in chromosome 12 (12q21.1-q21.2) that was shared by all women with SPTB in two independent pedigrees (false-positive rate [duo] =0.01). The intersecting region at the 12q21.1-q21.2 locus contains CAPS2 (calcyphosine 2) and KCNC2 (potassium voltage-gated channel subfamily C member 2) genes, both implicated in vascular-related complications of pregnancy and preterm labor. Using large SPTB families, we identified shared chromosomal regions (8q24.23 and 12q21.1-q21.2), providing evidence for inherited (segregating) risk loci in SPTB etiology. Further investigation into genes in SPTB etiology, including functional validation may provide avenues for novel therapeutic development and guide efforts for SPTB prevention to prolong pregnancy and improve outcomes.

Pessary or Cerclage (PC study) to prevent recurrent preterm birth: a non-inferiority, randomised controlled trial

Previous spontaneous preterm birth (sPTB) is a strong risk indicator for recurrent preterm birth (PTB). Cervical cerclage is an accepted intervention to prevent recurrent PTB in high risk patients. Cervical pessary might be a less invasive alternative. The objective of this study is to determine whether a cervical pessary is non-inferior to cerclage in the prevention of recurrent PTB. We performed an international, open-label, non-inferiority, randomised controlled trial in 21 hospitals between March 2014 and December 2022. We included singleton pregnancies with an indication for cerclage based on either multiple previous sPTBs <34 weeks or with a previous sPTB <34 weeks and an asymptomatic mid-trimester short cervix (≤25mm). Randomisation was 1:1, stratified by centre and indication, to cervical pessary or vaginal cerclage. Primary outcome was PTB <32 weeks. Secondary outcomes included (s)PTB rates, obstetric, and maternal outcomes and a composite of adverse perinatal outcomes including perinatal mortality and severe neonatal morbidity. Analysis was by intention-to-treat. Treatment effect was expressed as relative risk (RR), absolute risk difference (aRD) and 95% confidence intervals (CI). Sample size was calculated at 400 participants with a non-inferiority margin for pessary of 10%, meaning that non-inferiority is proven if the upper limit of the CI of the risk difference is <10%. Trial registration at ICTRP: NL-OMON26958. We randomised 261 participants to pessary (n=133) or cerclage (n=128). After the third interim analysis (n=228 participants), recruitment was halted due to safety concerns and the apparent challenge in establishing non-inferiority of pessary treatment. PTB <32 weeks occurred in 44/130 cases after pessary vs 30/125 cases after cerclage (33.8% vs 24.0% aRR 1.4, 95% CI 0.95-2.1, p=0.09, aRD 9.8% 95% CI-1.2 to 20.9). The composite of adverse perinatal outcomes occurred in 42 cases after pessary compared to 29 cases in cerclage (32.2% vs 23.2%; RR 1.4 95% CI 0.93-2.1 p=0.1) and consisted mainly of perinatal death (22.3% vs 14.4% RR 1.5 95% CI 0.9-2.6 p=0.1). Non-inferiority of cervical pessary compared to cerclage in preventing recurrent PTB <32 weeks was not proven. Cerclage is the recommended treatment. ZonMw (#837002406), a Dutch Organisation for Health Research and Development.

Immunophenotyping and Activation Status of Maternal Lymphocytes to Predict Spontaneous Preterm Birth in Women With Threatened Preterm Labor: A Prospective Observational Study.

Preterm birth (PTB) remains the leading cause of neonatal morbidity and mortality. Identifying women at high risk of spontaneous preterm labor (PTL) is challenging due to limited efficient diagnostic markers. Since human parturition involves inflammatory immune processes, we hypothesized that phenotyping of maternal peripheral lymphocytes might predict PTL. Therefore, we aimed to explore the relationship between maternal lymphocyte subpopulations and labor onset characterized by delivery within 7 days of admission in women hospitalized for PTL between 24 and 34 weeks of gestation. Lymphocyte subpopulations were obtained from peripheral blood samples and characterized by flow cytometry: activated and regulatory T cells, natural killer and B cells, and TH1/TH2/TH17 lymphocytes. Data analysis was conducted retrospectively based on the delivery within 7 days of admission. Among 167 women admitted for PTL, less than 10% delivered within 7 days post-admission. HLA-DR expression was significantly increased on CD4+CD8-, CD4-CD8+, and CD4+CD8+ lymphocytes in women who delivered within 7 days. Subset levels below 5% of CD4+CD8-HLA-DR+ lymphocytes and 20% of CD4+CD8+HLA-DR+ lymphocytes were associated with no probability of delivering within 7 days. Our study suggests that combining these two consecutive markers allowed us to identify 57% of women hospitalized for PTL with no probability of delivering within 7 days while retaining patients who delivered within 7 days. If prospectively validated, these markers may be able to identify patients at high risk of PTB and avoid a significant number of unnecessary admissions and healthcare costs. ANSM number: 2010-A00516-33; ClinicalTrials.gov identifier: NCT01340222.

A simplified pre-conceptional laparoscopic cervical cerclage for cervical insufficiency: a retrospective study from a single center

BackgroundCervical insufficiency is a pathological condition in obstetrics in which the cervix fails to retain the fetus before uterine contractions or labor (painless cervical dilatation). Patients usually have fetal loss in the mid-trimester or spontaneous pre-term birth due to painless cervical dilation. For non-pregnant women with cervical insufficiency, prophylactic laparoscopic abdominal cerclage (LAC) has been reported to improve pregnancy outcomes, such as live birth, neonatal survival, and full-term delivery rate. Conventional LAC involves opening the vesicular space and separating the anterior broad ligament leaves. In our surgical procedure, these two steps were omitted.MethodsAn observational study was conducted retrospectively on patients who underwent a simplified pre-conceptional LAC between January 2015 and December 2022 at West China Second University Hospital, Sichuan University. Follow-ups for all the patients ended at the delivery of the fetus. Subsequently, clinical characteristics, perioperative data, and obstetric outcomes were recorded and analyzed.ResultsIn total, 108 patients were included in a pre-conception LAC group Mean operation time was 56.8 ± 22.8 min, and mean estimated blood loss was 21.4 ± 23.6 mL. Only one case of urinary retention was classified as a grade I postoperative complication, according to the Clavien–Dindo classification. No severe complications or sequelae were observed during the perioperative period. Obstetric outcomes from 98 patients were collected: three patients had miscarriages, and 95 had live births. Of the 95 live births, 4 were twins and 91 were singletons. Two patients had vaginal delivery, and 93 underwent Cesarean section; mean neonatal weight was 3310.2 ± 382.1 g.ConclusionA simplified pre-conceptional LAC is a simple, safe, and effective method for women with cervical insufficiency. Thus, it is worthy of promotion to assist women with cervical insufficiency in achieving improved obstetric outcomes. Vaginal delivery after LAC is possible once the tape is removed before labor.

Cost-effectiveness of a randomized controlled trial comparing low-dose aspirin to placebo for the prevention of recurrent preterm birth.

To assess the cost-effectiveness of low-dose aspirin compared to placebo for the prevention of recurrent preterm birth from a healthcare perspective. This was a cost-effectiveness analysis alongside a multicenter, randomized, double-blinded, placebo-controlled trial. We included women with a singleton pregnancy and a previous spontaneous preterm birth <37 weeks of gestation of a singleton. Women were randomized between aspirin 80 mg daily and placebo, initiated between 8 and 16 weeks of gestation. We estimated the difference in preterm births (<37 weeks of gestation), and maternal and neonatal healthcare costs using seemingly unrelated linear regression analyses. Bootstrapping was performed to estimate statistical uncertainty. A total of 387 women were included: 194 in the aspirin group and 193 in the placebo group. We observed a small, statistically non-significant difference in preterm birth (21.2% vs. 25.4%; risk difference -4.3%; 95% CI: -12.7% to 4.1%) and healthcare costs (mean -€99; 95% CI: -€2385 to €2325) in the aspirin group compared to placebo. The cost-effectiveness acceptability curve showed that the probability of aspirin being cost-effective was 54% for a willingness to pay threshold of €0 for one prevented preterm birth and 78% for €50 000 for one prevented preterm birth. Our findings suggest that aspirin is the dominant strategy over placebo for the prevention of preterm birth. However, there was substantial uncertainty around the results and definite conclusions regarding the cost-effectiveness of aspirin cannot be drawn.

Parental epigenetic age acceleration and risk of adverse birth outcomes: the Norwegian mother, father and child cohort study

BackgroundFew studies have examined associations between maternal epigenetic age acceleration and adverse birth outcomes, and none have investigated paternal epigenetic age acceleration. Our objective was to assess the associations of parental (both maternal and paternal) epigenetic age acceleration in relation to birth outcomes.MethodsParental epigenetic age was estimated using seven established epigenetic clocks in 2198 mothers and 2193 fathers from the Norwegian Mother, Father, and Child Cohort Study (MoBa). Individual epigenetic age acceleration was then calculated as residuals from linear regressions of estimates from the epigenetic clocks on chronological age. Further, linear regression was used to analyze differences in continuous outcomes (gestational length and standardized birthweight), while logistic regression was used for binary outcomes (preterm birth, post-term birth, small-for-gestational age [SGA], large-for-gestational age [LGA], and pre-eclampsia), adjusting for chronological age, parity, educational level, smoking, and BMI.ResultsIncreasing maternal, but not paternal, epigenetic age acceleration was associated with decreased gestational length for five out of six clocks, with adjusted estimates ranging from a mean 0.51-day decrease (95% CI − 1.00, − 0.02; p-value 0.043) for the Horvath clock to a 0.80-day decrease (95% CI − 1.29, − 0.31; p-value 0.002) for the Levine clock. An association with increasing maternal epigenetic age acceleration according to the DunedinPACE clock was also seen with greater standardized birthweight [mean difference 0.08 (95% CI 0.04, 0.12; p-value < 0.001]. These results were also reflected in an increased risk of spontaneous preterm birth and LGA. No associations were observed with post-term birth, SGA, or pre-eclampsia.ConclusionsMaternal, but not paternal, epigenetic age acceleration is associated with shorter pregnancies and an increased risk of spontaneous preterm birth. This may suggest that women’s biological age acceleration, including factors such as metabolic and physiologic state, is an additional risk factor for preterm delivery, beyond chronological age.

Vaginal administration of 17-alpha hydroxyprogesterone caproate appears to be safe in non-pregnant female rats and rabbits

Intramuscular (250 mg once weekly) or subcutaneous (275 mg once weekly) injections of 17-hydroxyprogesterone caproate (17-OHPC) has been utilised to prevent recurent spontaneous preterm birth in pregnant women with a short cervix or those with a prior preterm birth but its efficacy in these conditions has been questioned. It is unclear whether adequate concentrations of 17-OHPC reach the suspected target organs such as the cervix and uterus following either IM or SC administration. The objective of this study was to determine feasibility and safety of vaginal administration of 17-OHPC in adult female Sprague Dawley rats and female New Zealand rabbits. Gels containing 17-OHPC were administered intravaginally to rats and rabbits for 10 consecutive days. After the last dose, serial blood samples and terminal uterine and adipose tissue samples were collected. 17-OHPC concentrations were measured by LC-MS-MS. Tissue histology showed that intravaginal administration of 17-OHPC was safe. There was no renal or hepatic toxicity as measured by liver function and kidney function tests. Intravaginal administration of 17-OHPC resulted in low systemic plasma concentrations but substantially higher uterus and adipose tissue concentrations of 17-OHPC. Composition of the formulation affected the tissue distribution of 17-OHPC. Future studies warrant further evaluation of the effect and safety of daily intravaginal administration of 17-OHPC gel in pregnant animals.

Analysis of risk factors for very early preterm and early preterm birth in twins following invitro fertilization and intracytoplasmic sperm injection-assisted pregnancy: Aretrospective study.

To investigate the risk factors influencing very early preterm and early preterm births in twin pregnancies after invitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI). This retrospective study analyzed 2042 twin pregnancies that underwent embryo transfer via IVF/ICSI at the Reproductive Center of Sir Run Run Shaw Hospital between January 2019 and December 2022. Spontaneous very early, early preterm, and provider-initiated preterm births were examined separately. Based on gestational age, participants were categorized into three groups: very early preterm birth (<28 weeks), early preterm birth (≥28 to <34 weeks), and ongoing pregnancy (≥34 weeks). Univariate analysis was conducted to assess general conditions, among the three groups. Multiple logistic regression analysis was performed to identify independent risk factors for very early and early spontaneous preterm birth in twin pregnancies. A total of 2042 twin pregnancies were included in the study, with birth rates of 4.36% (89 of 2042) <28 weeks, 12.14% (248 of 2042) ≥28 to <34 weeks, and 83.50% (1705 of 2042) ≥34 weeks. The primary cause of provider-initiated preterm birth <28 weeks was placental factors, while hypertensive disorders of pregnancy (31.11%) were the predominant cause for preterm births ≥28 to <34 weeks. Multiple logistic regression analysis identified the independent risk factors for births <28 weeks (P < 0.05) as cervical cerclage, history of late miscarriage or premature birth, uterine adhesions, primary infertility of polycystic ovary syndrome (PCOS), monochorionic pregnancies, history of cervical surgery, uterine malformations, body mass index ≥25 kg/m2, and uterine longitudinal axis lengths <3.6 cm. Cervical cerclage, main factors of infertility (PCOS), adenomyosis, and uterine longitudinal axis lengths <3.6 cm were identified as independent risk factors for ≥28 to 34 weeks (P < 0.05). It is crucial to consider risk factors during IVF/ICSI treatment because of the high incidence of very early and early preterm twin pregnancies, which can be identified early and properly managed.

The Intensity of BCL2A1 Expression Increases According to the Stage Progression of Acute Histologic Chorioamnionitis in the Extra-Placental Membranes of Spontaneous Preterm Birth.

Our prior findings showed that BCL2A1 in neutrophils is highly expressed in the extra-placental membranes (EPMs) of both the human spontaneous preterm-birth (PTB) (i.e., PTL or preterm PROM) and nonhuman-primate PTB model. However, no data exist on whether the intensity of BCL2A1 expression quantitatively increases according to the stage progression of acute histologic chorioamnionitis (acute HCA) in EPM. The objective is to investigate whether the intensity of BCL2A1 expression quantitatively increases according to the stage progression of acute HCA in EPM among spontaneous PTB cases, as measured using QuPath. The study population included 121 singleton PTBs (gestational age [GA] at delivery < 34 weeks) due to either preterm labor or preterm PROM. With digital image analysis, we calculated the percentage of BCL2A1-positive cells in immunohistochemistry according to the stage progression of acute HCA in EPMs as the primary outcome and examined the relationship between the percentage of BCL2A1-positive cells and either the GA at delivery or the amniotic-fluid (AF) WBC count as the secondary outcome. The median percentage of BCL2A1-positive cells progressively increases with the stage progression of acute HCA in EPM (group-1 vs. group-2 vs. group-3 vs. group-4 vs. group-5; 7.62 vs. 5.15 vs. 43.57 vs. 71.07; γ = 0.552, p < 0.000001). The percentage of BCL2A1-positive cells in EPMs and the AFWBC count shows a positive correlation (γ = 0.492, p = 0.000385). Moreover, the percentage of BCL2A1-positive cells in EPMs continuously decreased with increasing GA at delivery (γ = -0.253, p = 0.005148). In conclusion, the intensity of BCL2A1 expression increases according to the stage progression of acute HCA in EPMs and the elevation of AFWBC among spontaneous PTB cases. This finding suggests BCL2A1 in EPMs may be a promising marker and target for acute HCA.

Association of Acute Histological Chorioamnionitis and Other Placental Lesions With Subsequent Pregnancy Outcomes After Spontaneous Preterm Birth

ObjectivesAcute histological chorioamnionitis (HCA) is detected in over 50% of spontaneous preterm birth (PTB) and is associated with worse neonatal prognosis. We aim to investigate whether the presence of HCA impacts subsequent pregnancy outcomes. MethodsThis retrospective cohort study included deliveries at a tertiary centre from 2014 to 2020. Participants were individuals with a history of spontaneous PTB or pregnancy loss >16 weeks and available placental pathology (index pregnancy) with a subsequent pregnancy followed at the same institution. Placentas were classified according to the presence of HCA, other placental lesions, or no lesions. Subsequent pregnancy outcomes were analyzed. The primary outcome was the rate of overall and spontaneous PTB (<37 weeks) in the subsequent pregnancy. ResultsA total of 292 individuals met the study criteria, of which 133 had HCA, 61 had other placental lesions, and 98 had no lesions. Individuals with HCA in the index delivery had a higher risk of PTB <28 weeks in the subsequent pregnancy, compared to the no-lesion group (10.4% vs. 1.0%, P = 0.004). Rates of PTB >28 weeks did not significantly differ. The risk of neonatal adverse composite outcomes was higher in the HCA group (13.9% vs. 4.2%, P < 0.01). In a subanalysis of different placental lesions at the index PTB, only maternal vascular malperfusion was associated with recurrent PTB (adjusted odds ratio 2.57, P = 0.01). ConclusionsPTB with HCA is associated with higher rates of extreme PTB and adverse neonatal outcomes in the subsequent pregnancy. The inclusion of placental pathology analysis may improve individualized risk assessment in future pregnancies.

Longitudinal change in cervical length measured after prophylactic cerclage in predicting spontaneous preterm birth.

To evaluate the value of serial post-cerclage cervical length measurements in predicting preterm birth. This was a retrospective study of women with a singleton pregnancy who underwent prophylactic transvaginal cerclage from 2017 to 2023. Prophylactic cerclage was performed in women with an obstetric history of cervical insufficiency. After cerclage, all participants underwent routine transvaginal cervical measurement every 2-4 weeks until 32-34 weeks of gestation. Trajectory patterns of changes in cervical length were identified through latent class trajectory modeling. The association of patterns with spontaneous preterm birth and pregnancy interval was analyzed by multivariable logistic regression analysis and Cox proportional hazards regression models. The specific characteristics of changes in cervical length associated with preterm birth were identified. We involved 225 women and acquired a total of 1248 measurements of cervical length. Two distinct trajectories of cervical length change along gestation were identified: Class 1 (persistent shortening of cervix, n = 52 [23.11%]) and class 2 (stable cervix, n = 173 [76.89%]). Women in class 1 were highly associated with spontaneous preterm birth, with a hazard ratio (95% confidence interval [CI]) of 2.00 (1.36, 2.96). The average shortening rate ≥0.24 cm per week and cervical length ≤1.1 cm was significantly associated with spontaneous preterm birth at different gestational age. Serial sonographic cervical length measurements after prophylactic cerclage are valuable in predicting preterm birth.