Preterm Birth Research Articles

In this introduction, we summarize the research papers, review articles, opinion pieces and important aspects of the facilitated discussion from the meeting 'The indirect effects of cytomegalovirus infection: mechanisms and consequences' held at the Royal Society, London, on 14-15 October 2024. The term 'indirect effects' describes a statistical excess of pathologies seen in people with human cytomegalovirus (CMV) in the absence of histopathological hallmarks of direct CMV tissue damage. This meeting brought together laboratory scientists, paediatric and adult clinical academics, epidemiologists, and trialists, to discuss the latest research on indirect effects, from biological mechanisms to potential clinical consequences. Important questions regarding the impact of CMV remain unanswered in areas important to human health, such as preterm birth and fetal growth restriction, asymptomatic congenital infection, susceptibility to non-CMV infections, cardiovascular and respiratory disease, transplant, cancer and mental health. Further research is needed to better describe the biology and, critically, to robustly quantify its clinical impact and develop interventions to mitigate any harms.This article is part of the discussion meeting issue 'The indirect effects of cytomegalovirus infection: mechanisms and consequences'.

This paper examines the impacts of the Nitrogen Oxide Budget Program (NBP), a program that created a cap-and-trade market to regulate ozone pollution, on infant health outcomes. I employ the universe of birth records in the US from 1995 to 2008 and estimate how in-utero exposure to the NBP affected infant health using a triple-differences strategy. I find that exposure to the NBP improved infant health. Full exposure to the NBP reduces the incidence of low birth weight and very preterm birth by about 5.5% and 13%, respectively. Heterogeneity analyses suggest larger effects among Black mothers, low-educated mothers, and single mothers. I provide empirical evidence suggesting that endogenous changes in fertility behavior are unlikely to confound the estimates. A series of event studies do not support concerns that the effects reflect pre-existing trends in birth outcomes. Finally, I discuss the economic significance of the results in light of other exposures and their later-life impacts.

Pregnant women are prone to developing iron deficiency anemia from increased blood volume and iron demand. Iron deficiency increases risks for low birth weight and preterm birth, which are leading causes of infant death in the United States. This project investigates the relationship between iron intake during the third trimester and birth weight and gestational age. Data for this study was collected from the Breastfeeding and Early Child Health (BEACH) study, a longitudinal birth cohort that evaluated the impact of maternal obesity on infant outcomes in exclusively breastfed infants. Diet records at 3rd trimester were available in 41 participants. ESHA Food Processor was used to process the diet records and iron intakes were based on dietary reference intakes. We used R-statistical programming for statistical analysis. The primary predictors were iron intake adequacy risk and mean iron intake, and the primary outcomes were birth weight and gestational age. We used linear regression to model mean iron intakes relationship with birth weight. Covariates included pre-pregnancy weight, height, and gestational age. We found that infant birth weight is lower among mothers with a 70% risk for inadequate iron intake than infant birth weights of mothers with a 50% risk for inadequate iron intake, while there is no difference in gestational age between the groups. Mean iron intake was positively associated with birth weight and not associated with gestational age.

Introduction: Adverse pregnancy outcomes (APOs) increase the risk for maternal cardiovascular disease, but the effect of APO exposure in utero on offspring cardiovascular health (CVH) across the life course remains unclear. Research Question: What are the associations of in utero exposures to hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and preterm birth (PTB) with offspring CVH and early arterial injury in early adulthood? Methods: In the Future of Families-Cardiovascular Health Among Young Adults prospective longitudinal observational cohort (1998-2023) that enrolled mother-child dyads at the time of child’s birth from 20 U.S. sites, with offspring followed through early adulthood, we evaluated in utero exposures to HDP, GDM, PTB as assessed by maternal health records. We evaluated associations of APOs with offspring individual clinical cardiovascular risk factors, composite CVH by American Heart Association Life’s Essential 8 score, and arterial injury measures by carotid ultrasound in early adulthood, using multivariable-adjusted linear regression. Results: Among 1,140 offspring participants (mean age 22.4 years at follow-up, 55% female), 51% were non-Hispanic Black, 27% Hispanic, and 21% non-Hispanic White. The sample included 6.9% with HDP exposure, 3.5% with GDM exposure, and 7.7% with PTB. In adjusted analyses (Table), exposure to HDP was associated with higher body mass index (β 3.1 kg/m2 [1.2, 5.0]), higher diastolic blood pressure (β 2.9 mmHg [0.59, 5.2]), and higher hemoglobin A1c (β 0.2% [0.0004, 0.3]), as well as higher likelihood of moderate CVH vs. high CVH (OR 2.43 [95% CI 1.07, 5.51]), in early adulthood. Additionally, exposure to HDP was associated with higher mean carotid intima-media thickness (β 0.025 mm [0.012, 0.039]), and lower carotid grayscale median (β -3.9 [95% CI -6.9, -0.9]) by ultrasound, after accounting for cardiovascular risk factor burden. In secondary analysis, these associations were independent of restricted or excessive fetal growth (not shown). There were no associations of GDM exposure or PTB with offspring CVH or arterial injury in young adulthood. Conclusions: HDP exposure was associated with suboptimal CVH and early arterial injury in early adulthood. Peripartum interventions to support blood pressure control may promote offspring CVH across the life course.

Background: Women with a history of adverse pregnancy outcomes (APOs) have an increased risk for heart disease and stroke; however, data on risk for peripheral arterial disease (PAD) are scarce. Hypothesis: We hypothesized that women with a history of an APO were at greater risk for incident PAD. Methods: Data from the Women’s Health Initiative, which enrolled 161,808 postmenopausal women, aged 50-79 years, between 1993 and 1998, were used for the present analysis. Participants who completed survey items in 2017 on APO history were eligible for this study. Incident PAD was defined as ≥ one of the following in a lower extremity artery: stenosis or ulceration (≥50% diameter or ≥75% cross-sectional area) on imaging; absence of arterial pulse by Doppler; claudication on exercise testing; surgery, angioplasty or thrombolysis for PAD; amputation of or part of the lower extremity due to ischemia or gangrene; physician diagnosed claudication; or an ankle-brachial index (ABI) of ≤ 0.8. Events were adjudicated from baseline to 2010. Participants were eligible for this analysis if they did not have a history of PAD at baseline, had ≥1 pregnancy lasting > 6 months, and had non-missing data on APOs (n=47,370). Multivariable models examined the association between APOs and incident PAD, adjusting for age, race/ethnicity, education, income, physical activity, diet, sleep, and alcohol intake. Results: A history of APOs was reported by 13,666 women (28.8%), with 8,325 reporting one APO and 5,341 reporting two or more APOs. The most common APO reported was pre-term delivery (6,910 [14.6%]), followed by low birth weight (5,866 [12.4%]). Women who reported at least one APO had higher odds for incident PAD (adjusted odds ratio [aOR] 2.02, 95% confidence interval [CI] 1.43-2.85) compared to women without an APO. Individual APOs including gestational hypertension/preeclampsia (aOR 2.31, 95% CI 1.35-3.95), low birth weight (aOR 2.50, 95% CI 1.71-3.66), and preterm delivery (aOR 1.71, 95% CI 1.15-2.56) were associated with incident PAD, while gestational diabetes demonstrated a higher, but nonsignificant, odds for PAD (aOR 1.87, 95% CI 0.68-5.12). Conclusion: In this large cohort of multiethnic women, APOs were associated with a doubled risk for incident PAD. Gestational hypertension/preeclampsia, low birth weight, and preterm delivery were independently associated with incident PAD. Additional research is warranted to understand the underlying mechanisms linking APOs and PAD.

Background: Advances in heart transplant (HTx) have increased the number of reproductive-aged women with grafts considering pregnancy. However, this remains a high-risk scenario due to maternal morbidity, graft rejection, hypertensive disorders such as preeclampsia, and adverse neonatal outcomes. Current literature on comprehensive pregnancy outcomes and long-term graft implications remains limited. Objective: Evaluate maternal, and neonatal morbidity outcomes among HTx recipients. Methods: A meta-analysis was conducted using data from 1982 to 2022, derived from multiple database searches that included 7 retrospective cohort studies. Outcomes assessed included maternal and neonatal mortality, preeclampsia, neonatal preterm, low birth weight, graft rejection in pregnancy, miscarriage, chronic and gestational hypertension (HTN), congenital malformation, cesarians, unplanned pregnancy, and maternal infection within a 15 years follow-up time. Prevalences were pooled using events per 100 observations, along with 95% confidence intervals (CIs), and I2 for heterogeneity, employing a random-effects model. Results: Among 653 pregnancies and 477 pregnant women studied in 7 observational studies, preeclampsia occurred in 20.10% and was associated with increased maternal mortality (12.15%). Preterm birth (38.34%; median 35.1 weeks), and lower birth weights (37.58%; median 2490 g), were expressive. Congenital malformations were identified in 6.44%, while neonatal mortality proportion was 0.00%. However, low rates of graft loss during pregnancy 3.57% were observed. HTN was presented as a chronic manifestation in 30.56%, whether gestational 19.74%. Cesarians were performed in 47.76% patients and the data of unplanned pregnancy reached 47.12%. Conclusion: Pregnancy after HTx is feasible but high-risk, with elevated rates of HTN, preterm birth, neonatal complications, and maternal morbidity. Preeclampsia significantly worsens neonatal outcomes but does not impair short-term graft survival. Multidisciplinary care, individualized immunosuppressive management, and rigorous preconception counseling are crucial for optimizing outcomes. These findings inform clinical decision-making and reproductive planning for HTx women.

Introduction: Psychosocial stressors in early pregnancy are associated with a higher risk of adverse pregnancy outcomes (APOs), including hypertensive disorders of pregnancy (HDP), gestational diabetes, and preterm birth. However, the biological pathways underlying these associations are not well delineated. This study aims to investigate proteomic markers that may underlie the association between early pregnancy psychosocial stress and APOs. Methods: Data were from the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be, a prospective study conducted from 2010-13. Participants were selected using a case-control design (508 HDP cases and 1081 controls). An aptamer-based assay was used to quantify 6,894 proteins in blood serum collected at the first-trimester study visit. Psychosocial stress during the month preceding the same visit was defined as a score greater than 13 on the 10-item Perceived Stress Scale. We used linear regression, adjusted for age and gestational age, to estimate the associations between stress and proteomic analytes. We then used logistic regression models to estimate the associations of these analytes with APOs. To identify potential biological pathways, we constructed a knowledge graph integrating Human Phenotype Ontology terms and STRING protein-protein interactions. Results: Among 1,589 pregnant participants, the mean (SD) age was 27 (6) years and 42% reported psychosocial stress. Heparan sulfate 6-O-sulfotransferase 3 (HS6ST3) was significantly associated with both stress and APOs after FDR correction. Higher psychosocial stress was associated with lower expression of HS6ST3 (-0.27 [95% CI -0.32, -0.22]). Also, a lower expression in HS6ST3 was associated with higher risk of HDP (aOR 0.72 [0.61, 0.85]), gestational diabetes (aOR 0.59 [0.48, 0.71]), and preterm birth (aOR 0.75 [0.61, 0.92]). Proteomic values were expressed in SD units of log2-transformed SomaScan measurements. A knowledge graph was created, which identified close connections between anxiety (phenotype term closest to stress), APOs, and HS6ST3 with shared biological pathways, including GPC* gene clusters, SHH, LYN, and PTCH1 ( Figure ). Conclusions: Early pregnancy psychosocial stress was significantly associated with lower HS6ST3 expression and increased risk of APOs. Genes known to interact with HS6ST3, which are involved in neuroimmune signaling, placental development, and vascular function, may represent plausible pathways linking psychosocial stress to APOs.

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently gained prominence as both anti-diabetic medications and treatments for obesity in pregnancy. Nevertheless, the safety profile concerning maternal and fetal outcomes remains inadequately investigated. This meta-analysis examines the safety of GLP-1 RA utilization in pregnant women, providing valuable insights into maternal and fetal outcomes. Methods: Per PRISMA guidelines, a comprehensive literature search was performed in PubMed, Google Scholar, and Embase, along with snowballing to identify relevant studies reporting adverse maternal or fetal outcomes in pregnant women who used GLP-1 RA or other anti-diabetic medications either preconceptionally or periconceptionally. Maternal outcomes included hypertensive disorders of pregnancy, gestational diabetes, cesarean delivery, and pregnancy loss. Fetal outcomes included preterm birth, major congenital anomalies, and abnormal birth weight. Binary random-effects models were utilized to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). A p-value <0.05 was considered statistically significant. Results: Four studies with 36,963 pregnancies were analyzed. GLP-1 RA was significantly associated with reduced adverse maternal outcomes (OR: 0.72, 95% CI: 0.66-0.79, p < 0.00001) and preterm birth (OR: 0.66, 95% CI: 0.53 - 0.82, p = 0.0001). However, no increased risk of major congenital anomalies was found compared to other medications (OR: 1.08, 95% CI: 0.86-1.37, p = 0.51) or insulin (OR: 1.00, 95% CI: 0.77-1.28, p = 0.98) (Fig 1). Although there was a noticeable trend toward reduced adverse fetal outcomes, the heterogeneity was significant. This variability is likely due to differences in baseline risk, timing of exposure, and how outcomes were defined in the various studies. Conclusion: GLP-1 RA use during pregnancy is associated with improved maternal outcomes and reduced preterm birth, without increased risk of congenital anomalies. Considering the cardiometabolic interplay between pregnancy complications and future cardiovascular disease, these findings support the necessity for future prospective cardio-obstetric studies aimed at assessing the long-term cardiovascular risks for both mothers and their offspring following GLP-1 RA exposure.

Introduction: Substance use disorder (SUD) in pregnancy is associated with co-occurring psychological health conditions, and both are independently linked to an increased risk of adverse pregnancy outcomes (APOs). Previous studies have evaluated their effects on APOs in isolation, with limited research examining their combined effects. Research Question: What is the impact of SUD on APOs (hypertensive disorders of pregnancy, preterm delivery, fetal growth restriction, abruptio placentae, and gestational diabetes mellitus) among hospitalized pregnant women with psychological health conditions? Methods: Using ICD-10 codes for diagnoses and procedures, along with the National Inpatient Sample (NIS) data from 2016 to 2022, we identified the population hospitalized for pregnancy and delivery as well as those with a history of psychological disturbances (major depressive disorder, anxiety disorder, bipolar disorder, post-traumatic stress disorder, and adverse childhood experiences), and SUD (amphetamine/methamphetamine, cocaine, opioid, cannabis, or alcohol use disorder). Propensity scores for SUD were estimated using logistic regression based on sociodemographic and clinical variables. One-to-one greedy matching was used to create a balanced cohort. Logistic regression was then conducted on the matched sample to estimate odds ratios for APOs, comparing those with SUD to those without SUD. Results: There was a total of 1,154,465 weighted pregnancy and delivery-related hospitalizations with psychological concerns. After propensity score matching, 86,725 weighted pregnancy and delivery-related hospitalizations with SUD were matched with 89,460 hospitalizations without SUD. Compared to the group without SUD, the SUD group was associated with higher odds of all APOs OR: 1.21 (95% C.I.: 1.18 - 1.23), hypertensive disorders of pregnancy OR: 1.17 (95% C.I.: 1.14 - 1.20), preterm delivery OR: 1.57 (95% C.I.: 1.51 - 1.63), fetal growth restriction OR: 1.45 (95% C.I.: 1.40 - 1.51), and abruptio placenta OR: 1.79 (95% C.I.: 1.68 - 1.90) but not for gestational diabetes mellitus OR: 0.62 (95% C.I.: 0.59 - 0.64). Conclusions: SUD was associated with higher odds of all APOs except for gestational diabetes among pregnant patients with psychological health conditions. These patients may benefit from tailored interventions and support beyond routine screening. Further research is needed to evaluate the risk interactions between SUD and psychological conditions on APOs.

Introduction: Preeclampsia is a multisystem progressive disease of pregnancy, characterized by a new onset of hypertension (≥ 140/90 mm Hg) with proteinuria after the 20th week of gestation. There is a conflict between United States guidelines that recommend Low-dose aspirin (LDA) and United Kingdom guidelines that recommend High-dose aspirin (HDA) for the prevention of preeclampsia in high-risk pregnant women. After the latest study that recommends HDA and the absence of pairwise meta-analyses comparing two doses, we aimed to conduct a comprehensive pairwise meta-analysis to assess whether HDA is better than LDA in the prevention of preeclampsia. Methods: We conducted a systematic search on PubMed, Scopus, Cochrane Central, and Web of Science (WOS) from inception until June 2025. All randomized controlled trials (RCTs) comparing LDA and HDA in high-risk pregnant women were included. Our primary outcome was the incidence of preeclampsia (PE), while secondary outcomes were Placental abruption, Pre-term delivery, and Intrauterine Growth Restriction (IUGR). Using random-effects models, we calculated risk ratios (RR) with 95% confidence intervals (CIs). Results: A total of 8 RCTs with 1,290 patients from the United States, Canada, England, and different Asian countries were included, among whom 642 (49.8%) patients were randomized to HDA. All studies compared HDA (≥ 150 mg) and LDA (75 mg to 81 mg). Patients with LDA had a higher risk of Preeclampsia (RR: 1.71, 95% CI: 1.19 to 2.44, p<0.001) compared to HDA. There was no significant difference between the LDA and HDA regarding Placental abruption, Pre-term delivery, and IUGR. With a pooled RR with a 95% CI (1.8, [0.91 to 3.54], P = 0.09), (1.25, [0.79 to 1.97], P = 0.34), (1.5, [0.93 to 2.42], P = 0.1), respectively. Conclusion: Among high-risk pregnant women, LDA was associated with a 71% higher incidence of preeclampsia than HDA. These results support the use of HDA as a preventive medication for preeclampsia in high-risk pregnant women.

Introduction: Cardiac arrest during pregnancy is rare but presents a critical challenge requiring rapid stabilization and multidisciplinary coordination. Advanced maternal age increases cardiovascular risk, and management is complicated in heart failure with reduced ejection fraction (HFrEF), where guideline-directed medical therapy (GDMT) may be teratogenic. Though pregnancy is often discouraged in high-risk patients, it may still occur. This case highlights multidisciplinary strategies when a patient continues pregnancy despite significant hemodynamic risk. Case Vignette: A 38-year-old woman with obesity (BMI 33), PCOS, asthma, and two prior miscarriages was hospitalized after an out-of-hospital ventricular fibrillation arrest. Workup showed non-ischemic cardiomyopathy with LVEF 45–49%, 2–3+ mitral regurgitation, normal RV function, and a previously unknown 10-week pregnancy. After counseling, she chose to continue the pregnancy despite high risk. She was categorized as mWHO class III–IV (19–100%) and CARPREG I score of 41%, with concerns for recurrent arrhythmias, worsening function, hemodynamic instability, and preterm delivery. Holter monitoring showed 20% PVC burden. She was started on metoprolol succinate, hydralazine, and aspirin. Genetic testing was negative for cardiomyopathy and channelopathies. Delivery planning included ICU admission, early epidural, vasopressors, arterial line with possible PA catheter, and ECMO backup. Her ICD was deactivated with a magnet during labor. She had an uncomplicated vaginal delivery. Postpartum FDG-PET showed no uptake but a perfusion defect suggestive of fibrosis, not definitive for sarcoidosis. She later underwent PVC ablation. Maternal and fetal outcomes were favorable. Discussion: This case illustrates management of high-risk cardiac pregnancy post–cardiac arrest, guided by risk stratification and multidisciplinary care. Involvement of cardio-obstetrics, electrophysiology, heart failure, maternal-fetal medicine, anesthesiology, critical care, neonatology, and imaging was essential. Suspected etiologies included post-viral myocarditis, sarcoidosis, and PVC-induced cardiomyopathy; diagnosis was deferred postpartum. Key strategies included early planning, tailored protocols, and postpartum care. Conclusion: This case underscores collaborative management of heart failure and arrhythmias in pregnancy. A patient-centered approach supports favorable outcomes. Cardio-obstetrics program growth will advance such care.

Background: Due to teratogenic risks of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), the current guideline recommends prescribing ACEI and ARB for women of childbearing age concurrently with contraceptives to prevent unexpected pregnancy. However, adherence to this guideline in patient care settings is unknown. Research Hypothesis: This study examines patterns of concomitant contraceptive use with antihypertensive treatment and pregnancy outcomes among women of reproductive ages using Veterans Affairs electronic health records data. Methods: The study includes 131,598 women veterans and active military service members aged 20-50 on antihypertensive medication who received care from the Veterans Health Care System or the Military Health System between January 1, 2007 to December 31, 2022. Average age of women was 39 years, and majority (45.5%) were Non-Hispanic White (Table 1). Types of contraceptive medication include combined oral contraceptive pills (yaz, ortho tri-cyclen), progestin-only pills (emicronor), vaginal rings (NuvaRing), transdermal patch (Ortho Evra), and injection (Depo-Provera). Results: The most prescribed antihypertensive medication were beta blockers (43.78%), followed by diuretics (39.91%), alpha blockers (32.80%) and ACEI/ARBs (30.79%, n=40,518). Twelve percent (n=4,862) of those on an ACEI/ARB (n=40,518) were concurrently on contraceptives, while 17% and 19% of those on beta blockers and alpha blockers were concomitantly on contraceptives, respectively. Furthermore, 1.5% (n=588) women on ACEI/ARB, 3.5% on beta blockers, and 3.7% on alpha blockers were pregnant (Figure 1). An increasing number of women were prescribed an ACEI/ARB over 12 years (p=0.0089), but the percent of women concurrently on ACEI/ARBs and contraceptives has significantly decreased (p=0.0022; Figure 2). Conclusion: Despite the current guideline, very low concomitant use of contraceptives (12%) with ACEI/ARB was observed in the study. While ACEI/ARB is the least prescribed medication to treat hypertension for reproductive age women, its use has been steadily increasing over the past decade, while rates of concurrent contraceptive use has decreased placing women at an increased risk of teratogenic exposure during pregnancy. Future studies are warranted to investigate the cause and barriers of suboptimal concomitant contraceptive utilization with ACEI/ARBs and pregnancy outcomes, including low birth weight and preterm delivery.

Background: Adverse pregnancy outcomes (APOs) are increasingly recognized as risk indicators for future cardiovascular disease (CVD), yet their long-term implications across diverse populations remain insufficiently understood. Current guidelines lack comprehensive strategies for post-APO CVD screening. Objective: To assess the association between APOs and subsequent CVD and cardiovascular risk factors (CRF) in a racially and socioeconomically diverse cohort, and to identify demographic and socioeconomic risk factors for CVD/CRF among individuals with APOs. Methods: This retrospective cohort study included pregnant adult members of Kaiser Permanente Northern California who delivered between July 1, 2008, and June 30, 2013, with follow-up through December 31, 2023. Patients with APOs—defined as hypertensive disorders of pregnancy, gestational diabetes, preterm delivery, placental abruption, and/or small for gestational age—were matched 1:3 by age and delivery date to those without APOs. The primary outcome was incident CVD, including coronary artery disease, acute coronary syndrome, ischemic or hemorrhagic stroke, cardiomyopathy, and atrial fibrillation/flutter. The secondary outcome was CRF, defined as incident type 2 diabetes or hypertension. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were estimated. Results: Among 41,502 participants, 12,612 (30.4%) experienced one or more APOs. Over a mean follow-up of 12.5 years, APO-exposed individuals had higher adjusted risk of CVD (aHR 1.39; 95% CI 1.08-1.79), CRF (aHR 1.53; 95% CI 1.41-1.66), and the composite outcome CVD/CRF (aHR 1.51; 95% CI 1.40-1.63). In the APO-exposed group, significant risk factors of CVD/CRF included advancing age (aHR 1.30 per 5 years; 95% CI 1.25-1.35), parity >=3 (aHR 1.38; 95% CI 1.20-1.59) vs. nulliparity, Black (aHR 2.10; 95% CI 1.84-2.40) and Asian/Pacific Islander (aHR 1.97; 95% CI 1.79-2.16) compared to White, highest neighborhood deprivation index quintile (aHR 1.56; 95% CI 1.33-1.82) vs. lowest quintile, and pre-pregnancy BMI >=40 kg/m2 (aHR 4.97; 95% CI 4.15-5.95) vs. BMI <25. Conclusions: APOs are associated with long-term increased risk of CVD and CRF. This risk is influenced by demographic and socioeconomic factors, emphasizing the importance of integrating reproductive history and social determinants into cardiovascular risk stratification and screening efforts.

Background: Preeclampsia is a heterogeneous disorder, with emerging evidence indicating the presence of multiple phenotypes. Identifying distinct clinical phenotypes may facilitate precise therapies and improve the clinical outcomes. This study aims to identify and validate preeclampsia phenotypes using machine learning and evaluate their associations with adverse pregnancy outcomes. Hypothesis: Machine learning-based clustering methods applied to routinely-collected clinical variables can identify distinct preeclampsia phenotypes, each associated with unique clinical profiles and differential risks of adverse pregnancy outcomes. Methods: In the derivation cohort (n=2,386), phenotypes were derived using k-means clustering applied to 26 routinely-collected clinical variables. A machine learning classifier incorporating key biomarkers was developed and externally validated to assign phenotypes within the validation cohort (n=1,570). Biological markers, clinical outcomes (primary outcome: composite of small for gestational age [SGA], preterm delivery, stillbirth, and neonatal death), and heterogenous impacts of delivery timing in term preeclampsia were analyzed across phenotypes. Results: Four distinct phenotypes were identified in the derivation cohort. Phenotype A exhibited hypocoagulation, while Phenotype B displayed relative thrombocytopenia. Phenotype C demonstrated hypercoagulation, and Phenotype D presented with hepatic and renal dysfunction, elevated potassium, and coagulation abnormalities. These findings were replicated in the validation cohort. Compared with Phenotype A, Phenotype D had the highest risk for the primary outcome (relative risk [RR] 2.83, 95% CI 2.48–3.23, P < 0.001), followed by Phenotypes C (RR 1.72, 95% CI 1.49–1.99) and B (RR 1.28, 95% CI 1.08–1.50). In term preeclampsia, delivery at 37 weeks increased adverse outcome risks relative to after 40 weeks in Phenotypes A, B, and D; Phenotype C exhibited elevated risks from 37–39 weeks. Conclusion: Four clinical phenotypes of preeclampsia were identified by using routinely-collected health data, each characterized by unique maternal feature profiles and associated with varying fetal outcomes. These phenotypes reflect diverse underlying pathophysiological processes, and may inform individualized decisions regarding delivery timing. Machine learning-based phenotyping represents a promising strategy to advance precision obstetrics and improve the understanding and management of preeclampsia.

Introduction: Fetal ductus arteriosus constriction (DAC) can cause hydrops, pulmonary arterial (PA) hypertension and even death. Maternal drug/dietary factors can cause DAC and resolve with withdrawal. Data on DAC postnatal outcomes is limited. In the current study we sought to explore the pre- and postnatal evolution and outcomes of DAC. Methods: We identified all pregnancies with structurally normal hearts and DAC in our program from 2009-2024. Those with ductal systolic velocity >1.4 m/s, diastolic velocity >0.35 m/s, pulsatility index <1.9 were included. Fetal and neonatal clinical/echo parameters were collected. Right ventricular systolic dysfunction (RVDys) was defined as fractional area change (FAC) <35%. Results: Of 41 fetuses with DAC, 17(41%) were referred for suspected fetal heart disease. Only 7 (17%) had an identifiable cause (5 drug related, 2 dietary). See Table 1 for fetal echo data. At diagnosis 2 had hydrops (1 with a non-cardiac cause) and none developed hydrops at review. The majority (9/15, 60%) with tricuspid regurgitation had gradients >1/2 estimated systemic pressure. Four of 13 (31%) with RVDys received prenatal treatment (3 digoxin, 1 oxygen). Four fetuses had complete ductal closure (DC), all idiopathic and diagnosed at > 33 weeks gestational age (GA). Of 32 with serial fetal echo, 14(43%) had resolution of DAC, including 5 with known cause, and of 6 with RVDys, 3(50%) improved when the cause was discontinued and 4 had ongoing RVDys. The fetus with hydrops due to DAC was delivered urgently on presentation at 36 weeks GA. Two of the 4 with DC required urgent preterm delivery due to RVDys and abnormal venous Dopplers. Postnatal data were available for 32(78%), all were admitted to the neonatal intensive care unit. One died from noncardiac causes. Three(9%) required invasive ventilation (including 2 with DC) and 18(56%) required CPAP. Only 2 received pulmonary vasodilators (2 nitric oxide, 1 sildenafil for <2 weeks). Of 26(81%) postnatal echoes, 21(81%) had >1/2 systemic PA pressure at 1 st echo, of whom 7(33%) normalized prior to discharge and a further 8(38%) on follow-up, with no follow up in 6(29%). Of 12 with prenatal RVDys and neonatal followup, all normalised by discharge. Five had genetic abnormalities and 9 had significant extracardiac pathologies. Conclusions: Despite a worse trajectory in cases with idiopathic DAC, postnatal outcomes are favorable in both subsets with resolved RVDys and resolved PA hypertension in infancy.

Endometriosis is a chronic inflammatory condition, typically associated with pelvic pain and menorrhagia, affecting 10% of women of reproductive age. Inflammation is known to contribute to pregnancy complications, including preterm birth. Recent evidence suggested that women with endometriosis have a higher risk of preterm birth. However, the underlying mechanism remains unclear. Systemic inflammation indices, increasingly used as markers of inflammation in pregnancy-related conditions, may provide insights into this association. In this study, we aimed to investigate whether systemic inflammation contributes to preterm birth in pregnant women with endometriosis. A total of 75 pregnant women with endometriosis confirmed at cesarean sections were included. Clinical and obstetric data were collected and compared with hospital-wide cesarean section data during the same period. Systemic inflammation indices were calculated from peripheral blood tests taken before delivery. Among the 75 women with endometriosis, 15 (20%) experienced preterm birth, which was significantly higher than the 11.4% incidence observed among all other women who delivered by cesarean section at our hospital during the same study period (p = 0.019). The increased incidence of preterm birth was observed across all subtypes of endometriosis. However, systemic inflammation indices, including systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), neutrophil to lymphocyte ratio (NLR), and pan-immune inflammation value (PIV), derived from blood tests shortly before delivery, did not differ significantly between women with endometriosis who had preterm birth and those who delivered at term. In conclusion, systemic inflammatory indices measured shortly before delivery were not associated with preterm birth in this cohort. Without evaluation of the localized uterine inflammation and systemic inflammation changes earlier in gestation, and the small sample size, our findings are hypothesis-generating and require confirmation in larger studies in the future.

In absence of direct comparisons, consensus on the preferred preventive treatment for multiple pregnancies with a short cervix is lacking. Therefore, we compared the effectiveness of a cervical pessary and vaginal progesterone in the prevention of adverse perinatal outcomes and preterm birth (PTB) in women with a multiple pregnancy, no prior spontaneous PTB (sPTB) before 34 weeks' gestation, and an asymptomatic mid-trimester shortened cervix below 38 mm. This open-label, superiority, multi-centre randomised controlled trial was conducted in 20 hospitals in the Netherlands. Women with a healthy multiple pregnancy and an asymptomatic cervical length (CL) below 38 mm between 16 and 22 weeks' gestation were eligible, with a target sample size of 332. Following an interim analysis, the study was halted for futility. A total of 276 multiples, including seven triplet pregnancies, were randomised 1:1 to receive either an Arabin cervical pessary (N = 138) or vaginal progesterone 200 mg daily (N = 138) until 36 weeks' gestation or earlier if indicated. The primary outcome was a composite adverse perinatal outcome, with secondary outcomes including rates of (s)PTB before 24, 28, 32, 34, and 37 weeks. Predefined subgroup analyses were conducted based on CL, parity, chorionicity, and number of foetuses. Among 531 neonates (pessary N = 269, progesterone N = 262), the composite adverse perinatal outcome occurred in 19.7% of neonates in the pessary group versus 13.7% in the progesterone group (crude RR 1.43; 95% CI [0.85,2.4], p = 0.18). The rates of (s)PTB were not significantly different between groups. In the subgroup with a CL of ≤25 mm, no significant difference in the composite perinatal outcome was found (41.1% versus 34.7%, RR 1.18; 95% CI [0.60,2.33], interaction p = 0.63). However, among nulliparous women, the composite outcome was more frequent in the pessary group compared to progesterone (30.0% versus 15.9%, RR 1.88; 95% CI [1.03,3.43], interaction p = 0.93). The study's main limitations include the inability to blind interventions, potentially introducing bias, and low self-reported medication compliance in the progesterone group, which may have led to overestimated adherence and underestimated progesterone's preventive potential in the per-protocol analysis. In women with multiple pregnancies and a midtrimester short cervix below 38 mm, we found no superiority of a cervical pessary compared to vaginal progesterone the prevention of perinatal complications. While progesterone may have a modest effect, future studies should focus on other interventions in multiple pregnancies such as a cerclage, both ultrasound- and physical examination-indicated. This trial was registered at the International Clinical Trial Registry Platform (ICTRP, EUCTR2013-002884-24-NL, https://trialsearch.who.int/Trial2.aspx?TrialID=EUCTR2013-002884-24-NL).

Purpose Adverse pregnancy outcomes, including gestational diabetes mellitus (GDM), gestational hypertension (GHp), macrosomia, preterm birth, and low birth weight, pose significant risks to maternal and neonatal health. Pre-pregnancy overweight is a modifiable risk factor for these outcomes. However, comprehensive analyses of multiple adverse outcomes and their dose-response relationships with pre-pregnancy body mass index (BMI) remain limited. Methods This retrospective cohort study included 748 women with singleton pregnancies who delivered at Yuyao Maternal and Child Health Hospital from January 1, 2022, to December 31, 2022. Participants were categorized into normal-weight and overweight groups based on pre-pregnancy BMI. Logistic regression models were used to evaluate associations between overweight and adverse pregnancy outcomes, adjusting for confounding variables. Restricted cubic spline (RCS) regression was employed to investigate dose-response relationships between BMI and pregnancy outcomes. Results Pre-pregnancy overweight was significantly associated with higher risks of GDM (adjusted OR = 3.122, 95% CI [1.754–5.557], p < 0.001), GHp (adjusted OR = 2.864, 95% CI [1.566–5.239], p = 0.001), and macrosomia (adjusted OR = 2.119, 95% CI [1.076–4.173], p = 0.030). No significant associations were observed with preterm birth or low birth weight. RCS analysis showed no evidence of nonlinear relationships, indicating that the risk of adverse outcomes increased linearly with BMI. Conclusion Pre-pregnancy overweight is a significant modifiable risk factor for adverse maternal and neonatal outcomes, particularly GDM, GHp, and macrosomia. These findings underscore the importance of integrating BMI monitoring and personalized weight management strategies into pre-pregnancy care programs to mitigate risks and improve maternal and neonatal health outcomes.

Outside pregnancy, blood pressure variability (BPV) predicts cardiovascular events. We aimed to study associations (if any) between visit-to-visit BPV in pregnancy and (1) adverse maternal/perinatal outcomes, and (2) long-term maternal cardiovascular outcomes. We conducted a secondary analysis of data from ALSPAC (Avon Longitudinal Study of Parents and Children). Adjusted logistic regression assessed relationships between visit-to-visit BPV (by the measures of SD, average real variability, and variability independent of mean) and pregnancy outcomes (gestational/severe hypertension, preeclampsia, preterm birth, small-for-gestational-age infants, neonatal intensive care unit admission, stillbirth, and perinatal death). Adjusted Cox regression assessed relationships between visit-to-visit BPV measures and long-term maternal outcomes: hypertension (measured), diabetes (self-reported), and heart disease (self-reported) as a composite. Among 12 509 women in ALSPAC, 4956 answered a follow-up questionnaire and 4426 attended a follow-up clinic, an average of 22 years after the index pregnancy. Measures of variability in systolic and diastolic BP (by each of SD, average real variability, and variability independent of mean) were associated with adverse pregnancy outcomes, particularly severe hypertension and preeclampsia by SD and variability independent of mean (adjusted odds ratios, 1.30-2.11). BPV in pregnancy was not associated with hypertension, diabetes, or heart disease at follow-up in adjusted analyses. Our findings indicate that BP variation between antenatal visits is informative for identifying risk of short-term adverse pregnancy outcomes, but BPV provides no long-term utility in predicting cardiovascular risk.

Symptomatic biliary disease frequently prompts patients to seek medical care during pregnancy. Most guidelines now recommend prompt surgical intervention regardless of trimester for complicated biliary disease during pregnancy (i.e., acute cholecystitis, choledocholithiasis, cholangitis, and gallstone pancreatitis). We investigated our health system's experience with the care of this patient population in the context of current recommendations. The electronic medical record of a large, multi-hospital health system was queried from January 2017 to December 2024 for all patients with diagnoses of pregnancy and complicated biliary disease. Patients were divided into 4 groups based on trimester at time of procedural intervention or postpartum management. Patients in the postpartum group presented with symptomatic biliary disease during their pregnancy and progressed to complicated disease within three months after delivery, necessitating procedural intervention in that period of time. The search yielded 48 patients: 7 first trimester, 22 s, 5 third, and 14 postpartum. Procedural interventions included ERCPs and laparoscopic cholecystectomies. All cholecystectomies were completed without major surgical morbidity. Most interventions occurred in the second trimester or postpartum (75%). Surgical outcomes were similar across all groups; any variability in proportions was attributable to low sample sizes. Parental-fetal outcomes, including incidence of preeclampsia, pregnancy loss, and preterm delivery, were similar across groups. Our analysis confirms that procedural interventions for complicated biliary disease are safe to perform regardless of trimester. Our work also demonstrates the difficulties of studying this disease process as the prevalence is relatively low. This area of study could benefit from multi-institutional collaboration.