DHA (Pregnancy)

INTRODUCTION: Preterm prelabour rupture of membranes (PPRoM) is a significant cause of maternal and perinatal morbidity and mortality. The aim of this project was to identify interventions that reduce the prevalence of PPRoM. METHODS: Search strategy included a systematic literature search of MEDLINE, EMBASE, PubMed, and Cochrane Library. The selection criteria included randomized control studies that compared a therapy to standard care (no therapy or placebo) in pregnancy and included PPRoM as an outcome. Risk of bias was assessed according to the Cochrane risk-of-bias tool for randomized trials. Odds ratios with 95% confidence intervals were calculated using random-effects models. Quality of evidence was assessed using the GRADE methodology. RESULTS: Twenty-nine studies examining 10 interventions met the inclusion criteria. Therapies included docosahexaenoic acid (DHA), aspirin, rofecoxib, vitamin C alone and with vitamin E, folic acid (alone, with iron, with iron and zinc, within a multiple micronutrient supplement), zinc, calcium, copper, and treatment of bacterial vaginosis. There was no significant difference in the prevalence of PPRoM in the treatment groups compared to placebo, except for rofecoxib which showed an increased risk of PPRoM (RR 2.46, 95% CI 1.28-4.73; p = 0.007, 1 trial, 98 women; very low quality of evidence) and a multiple micronutrient supplement which showed a reduction in PPRoM (RR 0.40, 95% CI 0.19-0.84; p = 0.01, 1 trial, 1,671 women; very low quality of evidence). CONCLUSIONS: No interventions have been convincingly shown to reduce the prevalence of PPRoM. Given this is a common problem leading to significant morbidity and mortality, further research is required. © 2022 S. Karger AG, Basel.

2. Fetal Diagn Ther. 2022;49(5-6):273-278. doi: 10.1159/000525655. Epub 2022 Jun 30. Interventions for the Prevention of Preterm Premature Rupture of Membranes: A Systematic Review and Meta-Analysis. El-Achi V(1), Aggarwal S(2), Hyett J(3)(4). Author information: (1)Department of Maternal and F

BACKGROUND: Maternal omega-3 consumption during pregnancy has been positively linked with a positive impact on maternal health and fetal growth. However, the results of individual studies are inconsistent and conflicting. OBJECTIVE: Examine the effect of supplementation with DHA, and/or EPA, and/or ALA throughout pregnancy on offspring's growth and pregnancy outcomes. DESIGN: A systematic review and meta-analysis. POPULATION: Pregnant women. METHODS: According to (PRISMA) statement and the Cochrane Handbook guidelines. Human trials (RCT or quasi-RCT) which involved oral omega-3 supplementation at least twice a week during pregnancy were included and comparing it with control groups with no supplementation or placebo administration. Data were extracted and directed using RevMan software. Fifty-nine randomized controlled trials were eligible for inclusion in the meta-analysis. Performed in MEDLINE, PubMed, Scopus, Google Scholar, and the Cochrane Library comparing omega 3 with control groups, from 1990 to 2020. THE MAIN OUTCOME MEASURES: The primary outcome measures were pregnancy-induced hypertension, preeclampsia, gestational duration, preterm birth, early preterm birth, birth weight, low birth weight, neonatal length, and head circumference. The secondary outcomes were neonatal intensive care unit, infant death, prenatal death, and cesarean section. RESULTS: In 24 comparisons (21,919 women) n-3 fatty acids played a protective role against the risk of preeclampsia (RR = 0.84, 95% CI 0.74-0.96 p = 0.008; I2 = 24%). In 46 comparisons (16,254 women) n-3 fatty acids were associated with a significantly greater duration of pregnancy (MD = 1.35, 95% CI 0.65-2.05, p = 0.0002; I2 = 59%). 27 comparisons (15,510 women) was accompanied by a significant decrease in pre-term birth less than 37 weeks (RR = 0.86, 95% CI 0.77-0.95, p = 0.005; I2 = 0%). 12 comparisons (11,774 women) was accompanied by a significant decrease in early pre-term birth less than 34 weeks (RR = 0.77, 95% CI 0.63-0.95, p = 0.01; I2 = 40%). 38 comparisons (16,505 infants) had a significant increase in birth weight (MD = 49.19, 95% CI 28.47-69.91, p < 0.00001; I2 = 100%). Finally, 14 comparisons (8,449 i

BACKGROUND: Available interventions for preventing and treating perinatal depression remain unsatisfactory. AIMS: We examined the prophylactic and therapeutic effects, as well as adverse effects, of n-3 PUFA supplementation in reducing depressive symptoms during perinatal periods. METHODS: We included randomized, placebo-controlled trials that reported the changes of depression severity after the perinatal participants received n-3 PUFA supplementation. After the comprehensive searches in October 2019, we selected the trials, extracted the data, and assessed the quality of included trials. We compared the standardized mean differences (SMD) of depression score changes between groups using a random-effect model. RESULTS: We included 11 trials in the meta-analysis and one more trial for qualitative analysis (N = 3,181). The pooled standardized mean of decreased depression scores revealed no statistically significant difference between the n-3 PUFA and the placebo groups (N = 920, SMDs = -0.05, 95% CI -0.20 to 0.10, I2 = 21%). The pooled SMDs showed no statistically significant efficacy of n-3 PUFA supplementation for prevention (N = 779, SMDs = -0.03, 95% CI -0.20 to 0.13, I2 = 24%) and treatment (N = 141, SMDs = -0.14, 95% CI -0.55 to 0.27, I2 = 31%) of perinatal depression. The efficacy of n-3 PUFA supplementation was not associated with the daily doses of DHA, EPA, or DHA plus EPA. No trial reported any serious adverse effect of n-3 PUFA supplements. CONCLUSIONS: Although n-3 PUFA supplementation may improve maternal and infant outcomes, our meta-analysis found insufficient evidence to determine its benefit for perinatal depression.

OBJECTIVE: To explore whether omega-3 fatty acid supplementation is associated with lower risk of preterm delivery. METHODS: Searching the RCTs which were compared preterm birth between women with omega-3 fatty acid supplementation and without before December 2019 on Medline, EMBASE and Cochrane's Library, then performing a meta-analysis. RESULTS: 26 trials were identified, included 20124 women. There was almost no association between omega-3 fatty acid supplementation and lower risk of preterm delivery (risk ratio 0.92, 95% confidence interval 0.85 to 1.01, I2 = 9%), gestational duration (0.30, -0.05 to 0.64, I2 = 48%). In subgroup analyses, preterm delivery lower rate occurred in groups with mixed DHA and EPA supplementation not only DHA supplementation groups (P for interaction = 0.02); The dose of equivalent greater than 1 g made a higher reduction in preterm birth significantly. CONCLUSIONS: Omega-3 fatty acid supplementation was not associated with reduced risk of preterm delivery compared with placebo or no treatment during pregnancy. Relationship between Omega-3 fatty acid supplementation and other pregnant outcomes need more evidence and clinical studies.

INTRODUCTION: The omega-3 long-chain polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are important for brain development and cognitive performance. Because they are semi-essential fatty acids, they must be obtained from food. However, the dietary reference intakes of DHA and EPA have not yet been established. In women, a low DHA and/or EPA serum level during pregnancy or breastfeeding might negatively affect their children. For this study, we conducted a systematic review and meta-analysis of randomized control trials on the association between the consumption of fish oil supplements in pregnant and/or breastfeeding women and the cognitive performance of their children. METHODS: The PubMed, Embase, and Central literature databases were systematically searched. We included and extracted relevant studies in duplicate and assessed study quality. Cognitive outcomes were grouped according to published criteria and according to time elapsed after the intervention. We performed fixed-effects meta-analyses for each cognitive outcome and for birth weight. We assessed potential confounding with meta-regressions and sensitivity analyses. RESULTS: A total of 11 trials were included. No significant association was found between DHA/EPA supplementation and any of the assessed cognitive parameters or birth weight. DISCUSSION: Our results confirm previous reviews on the studied topic. Reasons for inconclusive results may be small sample sizes for each assessed category, questionable quality of included studies, and the difficulty of reliably measuring cognitive performance in small children. Blood levels of omega-3 long-chain polyunsaturated fatty acids were mostly not comparable. Furthermore, the influence of genetic and environmental factors could not be assessed. Studies in this field should address such shortcomings. © The Author(s) 2020. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: [email protected].

The efficacy of n-3 fatty acids supplementation on the prevention of pregnancy-induced hypertension or preeclampsia remains unclear. The aim of study was to examine the effect of supplementation with EPA, and/or DHA, and/or ALA during pregnancy on the pregnancy-induced hypertension or preeclampsia. A systematic search was performed on Scopus, PubMed, Web of Science (WoS), Cochrane Library, and Google scholar, which covered the period between 1991 and 2018. The clinical trials with any control groups (i.e. placebo or other supplementation) were selected. The whole process of meta-analysis and data analysis was done using Comprehensive Meta-Analysis (Version 2.0, Biostat). The searched keywords were: "Fatty Acids, Omega-3", "n-3 Polyunsaturated Fatty Acid" "Eicosapentaenoic Acid", "Docosahexaenoic Acids", "n-3 Polyunsaturated Fatty Acid", "n-3 PUFAs", "alpha-Linolenic Acid", "fish oil", "Nuts", "nutrient", or their synonyms "pregnancy induced hypertension" and preeclampsia. In addition, some key journals, according to Scopus report and the references of the original and review articles, were manually searched for possible related studies. The meta-analysis of the 14 comparisons demonstrated that n-3 fatty acids supplementation played a protective role against the risk of preeclampsia (RR, 0.82; 95% CI, 0.70-0.97; p = 0.024; I2 = 19.0%). The analysis of the 10 comparisons revealed that n-3 fatty acid supplements for pregnant women did not mitigate the risk of pregnancy-induced hypertension (RR, 0.98; 95% CI, 0.90-1.07; p = 0.652; I2 = 0%). The n-3 fatty acid supplements are an effective strategy to prevent the incidence of preeclampsia in women with low-risk pregnancies.

This meta-analysis and systematic review investigated evidence of the effect of oral micronutrient supplementation on male fertility. Following searches of PubMed, Ovid/Ovid Medline(r) and Embase, 18 randomized, double-blind, placebo-controlled trials were included in the meta-analysis (seven studies) and/or the systematic review (12 studies). The meta-analysis showed significant improvement in semen parameters for selenium (200µg/day and 100µg/day) (standard mean difference [SMD] 0.64 for oligozoospermia, 1.39 for asthenozoospermia), L-carnitine (2 g/day) and acetyl-L-carnitine (LAC; 1 g/day) combined (SMD 0.57 for asthenozoospermia), and co-enzyme Q10 (200 and 300 mg/day) (SMD 0.95 for oligozoospermia, 1.48 for asthenozoospermia, 0.63 for teratozoospermia). The systematic review identified promising data for supplementation with 66 mg/day zinc combined with folic acid (5 mg/day), and the polyunsaturated fatty acids eicosapentaenoic acid (EPA; 1.12 g/day) and docosahexaenoic acid (DHA; 0.72 g/day). Pregnancy rate was evaluated in a limited number of trials (four in the meta-analysis, three in the systematic review). This analysis suggests supplementation with selenium (alone or combined with N-acetylcysteine), co-enzyme Q10 and the combinations L-carnitine + acetyl-L-carnitine, folic acid + zinc and EPA + DHA is beneficial in the treatment of male infertility. Because of the small number of available studies and low number of participants, further well-designed clinical studies are needed to obtain a better overview of efficient methods of treating male infertility.

BACKGROUND: Higher intakes of foods containing omega-3 long-chain polyunsaturated fatty acids (LCPUFA), such as fish, during pregnancy have been associated with longer gestations and improved perinatal outcomes. This is an update of a review that was first published in 2006. OBJECTIVES: To assess the effects of omega-3 LCPUFA, as supplements or as dietary additions, during pregnancy on maternal, perinatal, and neonatal outcomes and longer-term outcomes for mother and child. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (16 August 2018), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing omega-3 fatty acids (as supplements or as foods, stand-alone interventions, or with a co-intervention) during pregnancy with placebo or no omega-3, and studies or study arms directly comparing omega-3 LCPUFA doses or types. Trials published in abstract form were eligible for inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed study eligibility, extracted data, assessed risk of bias in trials and assessed quality of evidence for prespecified birth/infant, maternal, child/adult and health service outcomes using the GRADE approach. MAIN RESULTS: In this update, we included 70 RCTs (involving 19,927 women at low, mixed or high risk of poor pregnancy outcomes) which compared omega-3 LCPUFA interventions (supplements and food) compared with placebo or no omega-3. Overall study-level risk of bias was mixed, with selection and performance bias mostly at low risk, but there was high risk of attrition bias in some trials. Most trials were conducted in upper-middle or high-income countries; and nearly half the trials included women at increased/high risk for factors which might increase the risk of adverse maternal and birth outcomes.Preterm birth < 37 weeks (13.4% versus 11.9%; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.81 to 0.97; 26 RCTs, 10,304 participants; high-quality evidence) and early preterm birth < 34 weeks (4.6% versus 2.7%; RR 0.58, 95% CI 0.44 to

BACKGROUND: The potential role of ω-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation during pregnancy on subsequent risk of obesity outcomes in the offspring is not clear and there is a need to synthesise this evidence. OBJECTIVE: A systematic review and meta-analysis of randomised controlled trials (RCTs), including the most recent studies, was conducted to assess the effectiveness of ω-3 LCPUFA interventions during pregnancy on obesity measures, e.g. BMI, body weight, fat mass in offspring. METHODS: Included RCTs had a minimum of 1-month follow-up post-partum. The search included CENTRAL, MEDLINE, SCOPUS, WHO's International Clinical Trials Reg., E-theses and Web of Science databases. Study quality was evaluated using the Cochrane Collaboration's risk of bias tool. RESULTS: Eleven RCTs, from ten unique trials, (3644 children) examined the effectiveness of ω-3 LCPUFA maternal supplementation during pregnancy on the development of obesity outcomes in offspring. There were heterogeneities between the trials in terms of their sample, type and duration of intervention and follow-up. Pooled estimates did not show an association between prenatal intake of fatty acids and obesity measures in offspring. CONCLUSION: These results indicate that maternal supplementation with ω-3 LCPUFA during pregnancy does not have a beneficial effect on obesity risk. Due to the high heterogeneity between studies along with small sample sizes and high rates of attrition, the effects of ω-3 LCPUFA supplementation during pregnancy for prevention of childhood obesity in the long-term remains unclear. Large high-quality RCTs are needed that are designed specifically to examine the effect of prenatal intake of fatty acids for prevention of childhood obesity. There is also a need to determine specific sub-groups in the population that might get a greater benefit and whether different ω-3 LCPUFA, i.e. eicosapentaenoic (EPA) vs. docosahexanoic (DHA) acids might potentially have different effects.

Despite well-documented benefits of omega-3 for maternal and child health, evidence on high-docosahexaenoic acid (DHA) supplementation in low-risk pregnant women is limited. A randomized, double-blind, placebo-controlled trial was conducted among low-risk pregnant women aged 20-40 years at 22-24 weeks of gestation to evaluate the effects of high-DHA omega-3 supplementation on maternal and neonatal health outcomes. The control group (CG, n = 30) received oral olive oil supplementation, and the intervention group (IG, n = 30) received omega-3 [1700 mg, 260 mg of eicosapentaenoic acid (EPA), and 1440 mg of DHA] for ∼16 weeks or until delivery. Maternal and neonatal health outcomes were collected by telephone 15 days after delivery. Forty-five pregnant women completed the study (IG: 20; CG: 25). Adherence to supplementation was above 90% and did not differ between groups (P > .05). There were no differences between groups in mean gestational age (CG: 39.3 ± 1.6; IG: 39.2 ± 1.6; P = .877), adequate gestational weight gain (CG: 24.0%; IG: 50.0%; P = .088), adequate gestational BMI before delivery (CG: 33.3%; IG: 27.8%; P = .261), vaginal delivery (CG: 72.0%; IG: 60.0%; P = .396), full-term birth (CG: 92%; IG: 90%; P = .815), adequate weight (CG: 91.3%; IG: 94.7%; P = .237), and adequate length for gestational age (CG: 82.6%; IG: 100%; P = .056). Omega-3 supplementation with a higher concentration of DHA had no effect on the maternal and neonatal health outcomes investigated in a Brazilian sample of low-risk pregnant women. Further studies are needed to evaluate this effect in pregnant women at higher nutritional risk and with low dietary intake of omega-3. © The Author(s) [2026]. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact [email protected].

AIM: This study aimed to evaluate whether docosahexaenoic acid (DHA) supplementation during pregnancy increases DHA concentrations in colostrum among Chinese women, and to determine whether continued postpartum supplementation is necessary to sustain DHA levels throughout lactation. Additionally, the study examined the impact of maternal DHA supplementation on the gut microbiota of both mothers and their infants. METHODS: 79 pregnant women were enrolled in this multicenter, double-blinded, randomized, placebo-controlled, parallel trial and were randomized to three groups (CC, control group; FC, DHA supplementation in the third trimester; FF, DHA supplementation from the third trimester to 42 days postpartum). Participants in the FF and FC groups were administered 100 mg/day DHA via milk powder and those in the CC group were administered milk powder without DHA fortification. Breast milk was collected - on days 3 and 42 postpartum. Fatty acid composition in breast milk was measured with gas chromatography and expressed as percentage of total fatty acids by weight. Fecal samples from mothers (at gestational week 28, 38 and 42 days postpartum) and infants (at 3 and 42 days of age) were collected, then analyzed using 16S rRNA sequencing. RESULTS: The FF group had significantly higher levels of DHA in colostrum than the other two groups (FF: 1.49%, FC: 1.27%, CC: 1.11, P-ANCOVA = 0.018) but not in early mature milk (FF: 0.94%, FC: 0.82%, CC: 0.85%, P-ANCOVA = 0.646). At 42 days postpartum, both mothers and infants in the FF group exhibited a higher abundance of the genus Lactobacillus in the fecal microbiome. CONCLUSION: In this cohort of Chinese women, maternal supplementation with 100 mg/day of DHA starting from the third trimester of pregnancy significantly increased DHA concentrations in colostrum. However, 100 mg/day may be insufficient to sustain DHA levels beyond colostrum. Additionally, maternal DHA supplementation was found to influence Lactobacillus abundance at 42 days postpartum of both mothers and their infants. Future studies should explore higher DHA doses for long-term lactation stability, and investigate dynamic changes in other gut microbiota taxa a

Prenatal supplementation with docosahexaenoic acid (DHA) has been reported to improve cognitive outcomes in infancy and early childhood in some studies. Existent studies have examined the effects of some dose of DHA against a true placebo; this report is the first to describe the effects of different doses of prenatal DHA on infant visual attention at 4 and 6 months of age. In a follow-up to a Phase III registered clinical trial (NCT02709239) designed to evaluate the effects of two prenatal doses of DHA supplementation (200 or 800 mg daily) on maternal physiology and fetal neurodevelopment, we assessed 215 infants delivered to these mothers at 4 and 6 months on a visual habituation task augmented with heart rate (HR) to assess visual stimulus processing, and a gap-overlap task to assess engagement and disengagement of attention. Infants of mothers supplemented with 800 mg/day of DHA had shorter look durations (indicative of more rapid visual learning) during habituation at both ages and a somewhat more mature pattern of HR-defined phases of attention. However, DHA dose did not affect infant HR, nor did it affect infant performance in the gap-overlap attention task. Results are consistent with positive effects of prenatal DHA supplementation on later outcomes, with higher benefit seen for a higher dose. © 2025 Wiley Periodicals LLC.

Neuroprotective nutrients including omega 3 fatty acid docosahexaenoic acid (DHA), choline, and carotenoids play an important role in infant brain structure and function; however, the effects of maternal nutrition on the infant brain are understudied. We leveraged data from our large randomized clinical trial among pregnant women to determine whether maternal nutrients including DHA, choline, lutein/zeaxanthin (L/Z) and egg intake (a food source of these nutrients) were related to infant brain function. Data from n = 241 maternal and infant dyads were included in this secondary analysis. Food frequency questionnaires (Diet History Questionnaire II) at 32 weeks' gestation were used to assess choline and carotenoid intake and a brief survey on egg consumption (# eggs consumed per week) was used to assess egg intake. Maternal red blood cell DHA status was measured at 32 weeks' gestation. Infant brain function was measured using high density electroencephalogram (EEG) to auditory (1 month of age) and visual (6 months of age) event-related potentials (ERP). At 1 month of age, maternal DHA status was associated with greater delta-band spectral power to the novel tone during the ERP. Choline, choline∗L/Z, L/Z∗DHA, and choline∗L/Z∗DHA were each related to power to the frequent tone during the ERP. At 6 months, choline, DHA status, and choline∗DHA were related to shorter latency to the novel visual stimulus. Choline∗L/Z and choline∗L/Z∗DHA were related to greater amplitude to the novel stimulus. Overall, maternal neuroprotective nutrients were related to several markers of infant brain function.

OBJECTIVE: To assess the impact of maternal supplementation with docosahexaenoic acid (DHA) during pregnancy and lactation on the immune and inflammatory functions in infants and specific infant morbidities. METHODS: A double-blinded, parallel-group, randomized, placebo-controlled trial was conducted among healthy pregnant women aged 18-35 years, from ≤ 20 weeks gestation through 6 months postpartum, to investigate the effectiveness of supplementation of 400 mg algal-derived DHA compared to placebo. Of 3379 women who were screened, 1171 were eligible, and 957 were randomized. Occurrences of 11 common morbidity symptoms including cough, nasal congestion, difficulty in breathing, cyanosis, convulsions, fever, vomiting, rash, ear discharge, excessive crying, and diarrhea were assessed for the offspring at 1, 6, and 12 months via maternal recall. RESULTS: Overall, there were 902 (out of 957) live births. Morbidity data were available for 871, 847, and 878 infants at 1, 6 and 12 months, respectively. The history of cough, difficulty in breathing, cyanosis, convulsions, fever, and vomiting at 1, 6, or 12 months were similar across DHA and placebo groups. At 1-month of age, fewer infants in the DHA group experienced any respiratory infection symptoms (cough, nasal congestion, and/or difficulty in breathing) as compared to placebo [29.3% vs 34.9%, P = 0.04; OR (95% CI) 0.74 (0.55, 0.98)]. At 6 months, there were fewer occurrences of 'other' symptoms like anemia, constipation, conjunctivitis, jaundice, and urinary tract infections in the DHA group [1.4% vs 4.8%, P = 0.005; OR (95% CI) 0.29 (0.11, 0.72)]. CONCLUSIONS: Pre- and postnatal maternal DHA supplementation did not show major differences in the incidence of common morbidity symptoms among infants at 1, 6, and 12 months. Meticulously planned and implemented studies on morbidity during infancy will be required to assess impact of maternal DHA supplementation on the morbidity during infancy. © 2025. The Author(s), under exclusive licence to Indian Academy of Pediatrics.

To explore whether prenatal conditions (i.e. chorioamnionitis, preeclampsia or small-for-gestational age (SGA)) affect the very preterm infant's response to docosahexaenoic acid (DHA) on bronchopulmonary dysplasia (BPD), according to mode of delivery, an independent factor shown to modulate this association. Secondary exploratory analysis of the MOBYDIck randomized controlled trial (NCT02371460) evaluating the effect of a neonatal high-dose DHA supplementation through maternal breastmilk compared to placebo. Population was preterm infants born before 29 weeks of gestation in sixteen Canadian neonatal intensive care units. Primary outcome was physiological BPD based on pulse oximetry assessment. Secondary outcomes included "death or BPD"; "moderate-or-severe" BPD; severe BPD; death from any causes. Heterogeneity in the effect of DHA on outcomes was assessed by prenatal conditions and mode of delivery using generalized estimating equation logistic regression models. The trial intended to enroll 800 mothers but was stopped early for safety, likely making subgroup analysis underpowered. 230 mothers (271 infants) were included in DHA group and 226 mothers (252 infants) in placebo group. The association between high-dose DHA and BPD differed by chorioamnionitis status (heterogeneity P=0.04). In infants exposed to chorioamnionitis and vaginal delivery, DHA supplementation was associated with a reduced risk of physiological BPD (adjusted odds ratio, 0.18 [95% CI, 0.05 to 0.62], P=0.007). No heterogeneity was found by maternal preeclampsia (heterogeneity P=0.44) nor SGA status (heterogeneity P=0.17). CONCLUSION: This secondary analysis generated hypotheses for a potential differential effect of neonatal enteral high-dose DHA supplementation on BPD in very preterm infants according to chorioamnionitis exposure. WHAT IS KNOWN: • The MOBYDIck trial reported a potential protective effect of docosahexaenoic acid (DHA) supplementation on bronchopulmonary dysplasia (BPD) in infants born vaginally, but not in those born via cesarean section. • Placenta pathologies are associated with inflammation in the infants and could affect the very preterm infant's response to a high-dose D

BACKGROUND & AIMS: Docosahexaenoic acid (DHA) is the most abundant omega-3 fatty acid in the brain and is accumulated by the fetal brain during the last trimester of pregnancy. Our objective was to determine whether high-dose DHA supplementation during the neonatal period, vs. placebo, improves behavioral functioning at 5 years in children born very preterm. METHODS: This is a follow-up at 5 years corrected age of a subset of children who participated in a multicenter randomized controlled trial. The participants received a high-dose DHA supplementation, or a placebo, through maternal breastmilk until 36 weeks' postmenstrual age. Primary outcome was child behavioral functioning, assessed by the Total Difficulties Score from the Strengths and Difficulties Questionnaire (SDQ). Secondary outcomes included behavioral scores from the SDQ, executive functions assessment and global developmental performance. Neurodevelopmental outcomes were assessed through interviews with parents. Mean differences between DHA and placebo groups were estimated using mixed linear models. Subgroup analyses were conducted for sex and gestational age (GA) at birth. RESULTS: Among 177 eligible children, 132 (74.6 %) completed neurodevelopmental assessment at 5 years (DHA, N = 64, placebo, N = 68). Total Difficulties Score did not differ between the DHA and placebo groups (mean differences, -0.9 [95 % confidence interval, -2.7 to 0.8], P = 0.30), nor any of the secondary outcomes. There was no significant interaction between treatment groups and sex, nor GA, for the primary outcome. However, significant interactions between treatment groups and sex or GA were found for some secondary outcomes. CONCLUSIONS: In very preterm infants, high-dose DHA supplementation did not improve behavioral functioning at 5 years. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02371460, https://clinicaltrials.gov/study/NCT02371460.

BACKGROUND: Previous studies of maternal docosahexaenoic acid (DHA) supplementation during pregnancy have controversial and contrasting results on the short and long-term effects on early child growth. The impact of this nutritional intervention on the postnatal growth patterns in the offspring of women with pregestational overweight/obesity (PGO) also remains controversial. OBJECTIVE: To analyze the postnatal growth patterns during the first 4 months of life in the offspring of women with PGO randomly supplemented with 800 mg/day (PGO-800) compared with normative doses of 200 mg/day (PGO-200) of DHA during pregnancy (<15 weeks of gestation until delivery). METHODS: This study evaluated the growth patterns during the first 4 months of life of 169 infants of the women that participated in the MIGHT study (NCT02574767). We included the infants of women from the PGO-200 (n = 81) and PGO-800 group (n = 88). The growth patterns (weight, length, and head circumference) and change in z-score (World health Organization charts) were evaluated. RESULTS: Throughout the first 4 months of life, the infants of the PGO-800 group had lower weight-for-length z-score (coef. -0.65, 95% confidence interval [CI] -1.07, -0.22, p = 0.003) and lower body mass index-for-age z-score (coef. -0.56, 95% CI -0.99, -0.12, p = 0.012) compared with the PGO-200 group adjusted by maternal body mass index, gestational weight gain, gestational age, insulin in cord blood and infant feeding (exclusive breastfed, not breastfed, and partially breastfed). CONCLUSIONS: Maternal supplementation with DHA during pregnancy could beneficially limit the offspring's postnatal weight gain during the first 4 months of life. © 2024 European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

77. Am J Obstet Gynecol MFM. 2024 May;6(5):101358. doi: 10.1016/j.ajogmf.2024.101358. Epub 2024 Mar 27. Racial disparity in efficacy of docosahexaenoic acid supplementation for prevention of preterm birth: secondary analysis from a randomized, double-blind trial. DeFranco EA(1), Valentine CJ(2), Carlson SE(3), Sands SA(3), Gajewski BJ(4). Author information: (1)Department of Obstetrics and Gynecology, University of Kentucky, 800 Rose St., C373, Lexington, KY 40536. Electronic address: [email protected]. (2)Banner University Medical Center, The University of Arizona, Tucson, AZ. (3)Department of Dietetics and Nutrition, University of Kansas Medical Center, Kansas City, MO. (4)Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, MO. DOI: 10.1016/j.ajogmf.2024.101358 PMCID: PMC11102282 PMID: 38552960 [Indexed for MEDLINE] Conflict of interest statement: Disclaimer: SEC, BJG and CJV were PIs and EAD a site-PI of the multisite trial conducted under R01HD083292; SEC has received honorariums for presentations about DHA in infancy and pregnancy; CJV was an employee of RB Nutrition, which produces infant formulas and supplements with DHA at the time the study was conducted, however, RB was not involved in the study execution or analysis. CJV conducted this study through her role as an Adjunct Professor at The University of Cincinnati. The other authors have no competing interests.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in fatty acid desaturase (FADS) genes may modify dietary fatty acid requirements and influence cardiometabolic health (CMH). OBJECTIVES: We evaluated the role of selected variants in maternal and offspring FADS genes on offspring CMH at the age of 11 y and assessed interactions of genotype with diet quality and prenatal docosahexaenoic acid (DHA) supplementation. METHODS: We used data from offspring (n = 203) born to females who participated in a randomized controlled trial of DHA supplementation (400 mg/d) from midgestation to delivery. We generated a metabolic syndrome (MetS) score from body mass index, high-density lipoprotein cholesterol, triglycerides, systolic blood pressure, and fasting glucose and identified 6 distinct haplotypes from 5 offspring FADS SNPs. Dietary n-6 (ω-6):n-3 fatty acid ratios were derived from 24-h recall data (n = 141). We used generalized linear models to test associations of offspring diet and FADS haplotypes with MetS score and interactions of maternal and offspring FADS SNP rs174602 with prenatal treatment group and dietary n-6:n-3 ratio on MetS score. RESULTS: Associations between FADS haplotypes and MetS score were null. Offspring SNP rs174602 did not modify the association of prenatal DHA supplementation with MetS score. Among children with TT or TC genotype for SNP rs174602 (n = 88), those in the highest n-6:n-3 ratio tertile (>8.61) had higher MetS score relative to the lowest tertile [<6.67) (Δ= 0.36; 95% confidence interval (CI): 0.03, 0.69]. Among children with CC genotype (n = 53), those in the highest n-6:n-3 ratio tertile had a lower MetS score relative to the lowest tertile (Δ= -0.23; 95% CI: -0.61, 0.16). CONCLUSIONS: There was evidence of an interaction of offspring FADS SNP rs174602 with current dietary polyunsaturated fatty acid intake, but not with prenatal DHA supplementation, on MetS score. Further studies may help to determine the utility of targeted supplementation strategies and dietary recommendations based on genetic profile.

BACKGROUND: The choice of malaria treatment for HIV-infected pregnant women receiving efavirenz-based antiretroviral therapy must consider the potential impact of drug interactions on antimalarial exposure and clinical response. The aim of this study was to investigate the effects of efavirenz on artemether-lumefantrine (AL) because no studies have isolated the impact of efavirenz for HIV-infected pregnant women. METHODS: A prospective clinical pharmacokinetic (PK) study compared HIV-infected, efavirenz-treated pregnant women with HIV-uninfected pregnant women in Tororo, Uganda. All women received the standard 6-dose AL treatment regimen for Plasmodium falciparum malaria with intensive PK samples collected over 21 days and 42-days of clinical follow-up. PK exposure parameters were calculated for artemether, its active metabolite dihydroartemisinin (DHA), and lumefantrine to determine the impact of efavirenz. RESULTS: Nine HIV-infected and 30 HIV-uninfected pregnant women completed intensive PK evaluations. Relative to controls, concomitant efavirenz therapy lowered the 8-hour artemether concentration by 76% (P = 0.013), DHA peak concentration by 46% (P = 0.033), and day 7 and 14 lumefantrine concentration by 61% and 81% (P = 0.046 and 0.023), respectively. In addition, there were nonsignificant reductions in DHA area under the concentration-time curve0-8hr (35%, P = 0.057) and lumefantrine area under the concentration-time curve0-∞ (34%, P = 0.063) with efavirenz therapy. CONCLUSIONS: Pregnant HIV-infected women receiving efavirenz-based antiretroviral therapy during malaria treatment with AL showed reduced exposure to both the artemisinin and lumefantrine. These data suggest that malaria and HIV coinfected pregnant women may require adjustments in AL dosage or treatment duration to achieve exposure comparable with HIV-uninfected pregnant women.

OBJECTIVE: This study was performed to evaluate the effects of vitamin D and omega-3 fatty acids co-supplementation on glucose metabolism and lipid concentrations in gestational diabetes (GDM) patients. METHODS: This randomized double-blind placebo-controlled clinical trial was done among 140 GDM patients. Participants were randomly divided into 4 groups to receive: (1) 1000 mg omega-3 fatty acids containing 360 mg eicosapentaenoic acid and 240 mg docosahexaenoic acid (DHA) twice a day + vitamin D placebo (n = 35); (2) 50,000 IU vitamin D every 2 weeks + omega-3 fatty acids placebo (n = 35); (3) 50,000 IU vitamin D every 2 weeks + 1000 mg omega-3 fatty acids twice a day (n = 35), and (4) vitamin D placebo + omega-3 fatty acids placebo (n = 35) for 6 weeks. RESULTS: After 6 weeks of intervention, patients who received combined vitamin D and omega-3 fatty acids supplements compared with vitamin D, omega-3 fatty acids, and placebo had significantly decreased fasting plasma glucose (-7.3 ± 7.8, -6.9 ± 6.6, -4.0 ± 2.5, and +1.0 ± 11.4 mg/dL, respectively, P < .001), serum insulin levels (-1.9 ± 1.9, -1.3 ± 6.3, -0.4 ± 6.3, and +2.6 ± 6.5 μIU/mL, respectively, P = .005), homeostatic model of assessment for insulin resistance (-0.7 ± 0.6, -0.5 ± 1.4, -0.2 ± 1.5, and +0.6 ± 1.5, respectively, P < .001) and increased quantitative insulin sensitivity check index (+0.01 ± 0.01, +0.008 ± 0.02, +0.002 ± 0.02, and -0.005 ± 0.02, respectively, P = .001). In addition, changes in serum triglycerides (-8.2 ± 41.0, +7.6 ± 31.5, +3.6 ± 29.9, and +20.1 ± 29.6 mg/dL, respectively, P = .006) and very low-density lipoprotein cholesterol (-1.6 ± 8.2, +1.5 ± 6.3, +0.8 ± 6.0, and +4.0 ± 5.9 mg/dL, respectively, P = .006) in the vitamin D plus omega-3 fatty acids group were significantly different from the changes in these indicators in the vitamin D, omega-3 fatty acids, and placebo groups. CONCLUSION: Overall, vitamin D and omega-3 fatty acids co-supplementation for 6 weeks among GDM patients had beneficial effects on fasting plasma glucose, serum insulin levels, homeostatic model of assessment for insulin resistance, quantitative insulin sensitivity check index, serum triglycerides, and

Comment in Clin Pharmacol Ther. 2018 Apr;103(4):571. doi: 10.1002/cpt.963. Clin Pharmacol Ther. 2018 Apr;103(4):570. doi: 10.1002/cpt.961. Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. We assessed the impacts of pregnancy and efavirenz-based antiretroviral therapy on exposure to DHA and piperaquine in pregnant Ugandan women. Intensive sampling was performed at 28 weeks gestation in 31 HIV-uninfected pregnant women, in 27 HIV-infected pregnant women receiving efavirenz, and in 30 HIV-uninfected nonpregnant women. DHA peak concentration and area under the concentration time curve (AUC0-8hr ) were 50% and 47% lower, respectively, and piperaquine AUC0-21d was 40% lower in pregnant women compared to nonpregnant women. DHA AUC0-8hr and piperaquine AUC0-21d were 27% and 38% lower, respectively, in pregnant women receiving efavirenz compared to HIV-uninfected pregnant women. Exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, suggesting a need for dose modifications. The study of modified dosing strategies for these populations is urgently needed. © 2017 American Society for Clinical Pharmacology and Therapeutics.

The tolerability, safety, and disposition of dihydroartemisinin (DHA) and piperaquine (PQ) were assessed in 32 pregnant (second/third trimester) and 33 nonpregnant Papua New Guinean women randomized to adult treatment courses of DHA-PQ (three daily doses) or sulfadoxine-pyrimethamine (SP)-PQ (three daily PQ doses, single dose of SP). All dose adminstrations were observed, and subjects fasted for 2 h postdose. Plasma PQ was assayed by using high-performance liquid chromatography, and DHA was assessed by using liquid chromatography-mass spectrometry. Compartmental pharmacokinetic models were developed using a population-based approach. Both regimens were well tolerated. There was an expected increase in the rate-corrected electrocardiographic QT interval which was independent of pregnancy and treatment. Two pregnant and two nonpregnant women had Plasmodium falciparum parasitemia which cleared within 48 h, and no other subject became slide positive for malaria during 42 days of follow-up. Of 30 pregnant women followed to delivery, 27 (90%) delivered healthy babies and 3 (10%) had stillbirths; these obstetric outcomes are consistent with those in the general population. The area under the plasma PQ concentration-time curve (AUC0-∞) was lower in the pregnant patients (median [interquartile range], 23,721 μg · h/liter [21,481 to 27,951 μg · h/liter] versus 35,644 μg · h/liter [29,546 to 39,541 μg · h/liter]; P < 0.001) in association with a greater clearance relative to bioavailability (73.5 liters/h [69.4 to 78.4] versus 53.8 liters/h [49.7 to 58.2]; P < 0.001), but pregnancy did not influence the pharmacokinetics of DHA. The apparent pharmacokinetic differences between the present study and results from other studies of women with uncomplicated malaria that showed no effect of pregnancy on the AUC0-∞ of PQ and greater bioavailability may reflect differences in postdose fat intake, proportions of women with malaria, and/or racial differences in drug disposition.

Prenatal and postnatal ethanol exposure induces abnormal cell death in the nervous system. We have previously reported that docosahexaenoic acid (DHA; 22:6n-3) prevents neuronal apoptosis through promoting phosphatidylserine (PS) accumulation. Previously, we have shown in C6 glioma cells that ethanol inhibits the accumulation of PS caused by DHA supplementation. In this report, we demonstrate that in vitro or in vivo exposure to ethanol inhibits DHA-dependent PS accumulation and neuronal survival. We found that Neuro 2A cells exposed to ethanol accumulated considerably less PS in response to the DHA enrichment and were less effective at phosphorylating Akt and suppressing caspase-3 activity under serum-starved or staurosporine-treated conditions. The in vivo paradigm correlated well with the in vitro findings. We found that the total PS and DHA contents in the fetal hippocampus were slightly but significantly lowered by the prenatal ethanol exposure. Fetal hippocampal cultures obtained at embryonic day 18 from ethanol-treated pregnant rats contained significantly higher apoptotic cells after 7 days in vitro under basal conditions and exhibited particular susceptibility to cell death induced by trophic factor removal in comparison with the pair-fed control group. The reduction of PS and the resulting neuronal cell death inappropriately enhanced during development may contribute to the defects in brain function often observed in fetal alcohol syndrome.

This study investigated the effects of varying dietary levels of very long-chain polyunsaturated fatty acids on growth, brain fatty acid composition and behavior in mice. Five groups of pregnant and lactating B6D2F1 mice were fed diets with either a very high (n-6):(n-3) ratio of 49 [(n-3) deficient)], a normal ratio of 4.0 or a low ratio of 0.32. The (n-6) fatty acids (FA) were provided either entirely as linoleic acid (LA) or as LA in combination with arachidonic acid (ARA), and the (n-6):(n-3) ratios were adjusted by partial replacement of the (n-6) FA with docosahexaenoic acid (DHA). Offspring were maintained on these diets after weaning. The diets with the low (n-6): (n-3) ratio had no effect on the birth weights of the pups, but after 15 d resulted in a significant 12% reduction in body weights. This effect persisted to adulthood and was apparent in both brain and body weights unless ARA was substituted partially for LA as the source of (n-6) FA. There were significant effects of diet on brain fatty acid composition. Increasing levels of DHA in the diet increased brain DHA and decreased ARA, and there was also retroconversion of DHA in EPA in the mice fed high levels of DHA. Addition of ARA to the diet increased brain ARA, and, at high levels only, decreased DHA. There were no effects of this wide variation in dietary (n-6):(n-3) ratio on the ability of the mice to learn the place of the hidden platform in the Morris water maze. However, in both the cued and the place learning, the mice fed the low (n-6):(n-3) diet swam more slowly, unless ARA substituted partially for LA as the source of (n-6) FA. There were no effects of diet on activity in the spatial open field. These findings show that the effects of a diet with a low (n-6):(n-3) ratio and (n-3) FA provided as DHA, can be overcome if LA is partially replaced by ARA as the source of (n-6) FA.

Dehydroepiandrosterone sulfate (DHA-S) is one of the successful drugs used to induce cervical ripening. There is growing evidence that interleukin-8 (IL-8) plays an essential role during cervical ripening. IL-8 was found to be hormonally controlled in the cervix. The aim of this research was to study the effect of DHA-S on the function of IL-8 on the cervix. Sixteen pregnant white New Zealand rabbits where tested either by placebo (adeps solidus, n = 4), DHA-S (10 mg, n = 4), IL-8 (100 ng, n = 4) or combination of DHA-S and IL-8 (n = 4). Collagen contents in the cervices were assessed histologically after staining with picrosirius red. The number of neutrophils in 5 random fields of the cervical tissue was counted in all groups. Collagenase, elastase and gelatinase were measured in those groups. The collagen content of the cervices was significantly decreased after treatment with DHA-S, IL-8 or a combination of both drugs compared to the control group (p < 0.004, 0.001 and 0.001, respectively). A maximal decrease in collagen content was found in the DHA-S + IL-8-treated group (71.5%). Neutrophil infiltration was significantly increased in the IL-8 and DHA-S + IL-8-treated groups (p < 0.0001). Neutrophil numbers in the DHA-S + IL-8-treated group were significantly higher than in the IL-8 group (p < 0.006). Collagenase activity was increased in the DHA-S, IL-8 and DHA-S + IL-8 groups compared to the control group (p < 0.02, 0.008 and 0.001, respectively). Elastase activity was also significantly increased in the same groups (p < 0.002, 0.005 and 0.001, respectively). A similar increment was found in gelatinase activity (p < 0.004, 0.0001 and 0.0001, respectively). DHA-S has a synergistic effect with IL-8 during cervical ripening.

BACKGROUND: Evidence has indicated that polyunsaturated fatty acids (PUFAs)-enriched diet could reduce inflammation because of thyroid autoimmunity in vivo, and therefore, enhance thyroid function. OBJECTIVES: We investigated whether early pregnancy plasma phospholipid PUFAs could benefit maternal thyroid function across pregnancy, which is critical to fetal brain development and growth in pregnancy. METHODS: Within the National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort, we collected plasma samples longitudinally from 214 subjects [107 with gestational diabetes mellitus (GDM) matched with 107 controls] with a singleton pregnancy. We measured 11 PUFAs at early pregnancy (10-14 wk) and 5 thyroid biomarkers at 10-14, 15-26, 23-31, and 33-39 wk, including free thyroxine (fT4), free triiodothyronine (fT3), thyroid-stimulating hormone, antithyroid peroxidase, and antithyroglobulin. Associations of PUFAs with thyroid function biomarkers and relative risk (RR) of gestational hypothyroidism (GHT) during pregnancy were assessed using generalized linear mixed models and modified Poisson regression, respectively. RESULTS: After sample weighting because of subjects with GDM over-representing in the analytic sample with biomarkers, eicosapentaenoic acid (EPA) at early pregnancy was associated with a reduction of 0.24 pmol/L (95% confidence intervals: -0.31, -0.16) in fT3 across gestation per standard deviation (SD) increment, whereas docosahexaenoic acid (DHA) at early pregnancy was associated with an increment of 0.04 ng/dL (0.02, 0.05) in fT4 across gestation per SD increment. Furthermore, EPA and docosatetraenoic acid (DTA) were associated with lower risks of persistent GHT (EPA-RR: 0.13; 0.06, 0.28; DTA-RR: 0.24; 0.13, 0.44) per SD increment. All significant associations remained robust in sensitivity analysis and multiple testing. CONCLUSIONS: Certain plasma phospholipid PUFAs were associated with optimal levels of thyroid biomarkers and even lower risk of GHT throughout pregnancy, which might be potentially targeted for maternal thyroid regulation in early pregnancy. CLINICAL TRIAL REGISTRY: This trial was registered at https:/

BACKGROUND: We aimed to investigate plasma phospholipid PUFA levels in early pregnancy and fetal growth trajectories throughout pregnancy. METHODS: Within the NICHD Fetal Growth Studies-Singleton Cohort, we enrolled 2,802 pregnant women at gestational weeks 8-13 and randomly assigned them to four ultrasonogram schedules to capture weekly fetal growth throughout pregnancy. Eleven plasma phospholipid PUFAs were measured at early pregnancy using blood samples collected from a subsample of 321 pregnant women. We modeled fetal growth trajectories across tertiles of PUFAs with cubic splines using linear mixed models after adjusting for major confounders. We then compared pairwise weekly fetal growth biometrics referencing the lowest tertile in each PUFA using the Wald test. FINDINGS: Among plasma n-3 PUFAs in early pregnancy, docosahexaenoic acid (DHA, 22:6n3) and alpha-linolenic acid (ALA, 18:3n3) showed positive associations with all fetal growth measurements. For instance, compared with the lowest tertile, the highest tertile of DHA had greater estimated fetal growth (EFW) and abdominal circumference (AC), starting at 13 weeks of gestation and throughout pregnancy (at gestational week 38: 3235.3 vs. 3089.0 g for EFW; 344.6 vs. 339.2 mm for AC). As for plasma n-6 PUFAs, some showed positive associations (e.g., linoleic acid [LA], 18:2n6) while others (e.g., docosatetraenoic acid [DTA], 22:4n6) showed inverse associations with fetal growth measures. INTERPRETATION: Our data suggested that higher plasma levels of DHA and ALA in the first trimester were associated with increased fetal size and weight throughout subsequent pregnancy. FUNDING: National Institute of Child Health and Human Development intramural funding.

Preeclampsia (PE) remains a major cause of maternal and fetal morbidity and mortality worldwide, with placental dysfunction and angiogenic imbalance playing central roles in disease pathogenesis. Emerging evidence highlights epigenetic regulation and angiogenic biomarkers, including placental growth factor (PlGF), as key contributors to disease heterogeneity and risk stratification. A systematic review of studies published between 2022 and 2025 was conducted in accordance with PRISMA 2020 guidelines to synthesize current evidence on epigenetic mechanisms and biomarker potential in PE. In addition, a supplementary exploratory analysis was performed using laboratory-derived PlGF data to assess analytical variability and biological associations. Non-parametric methods were applied, including Mann-Whitney U testing to compare PlGF distributions by analytical sample classification and Kendall's tau correlation to evaluate associations with gestational age and the sFlt-1/PlGF ratio. The systematic review identified consistent epigenetic alterations involving DNA methylation, histone modifications, and non-coding RNAs across maternal and placental tissues. Supplementary analysis demonstrated significantly higher and more variable PlGF concentrations in analytically classified measured samples compared with accepted samples (P = 0.03), suggesting an influence of analytical factors on biomarker distribution. PlGF levels showed a positive association with gestational age (τ = 0.32, P = 0.04) and an inverse association with the sFlt-1/PlGF ratio (τ = -0.41, P = 0.02). These findings support PlGF as a biologically relevant marker of gestational progression and angiogenic balance while underscoring the importance of rigorous analytical quality control. Integrating epigenetic insights with robust biomarker analysis may enhance personalized risk stratification in preeclampsia. © 2026 The Author(s).