By Ahizechukwu C. Eke, MD, PhD, MPH
Synopsis: Women with a history of recurrent pregnancy loss are at significantly increased risk of adverse outcomes, including preeclampsia, placental abruption, cesarean delivery, preterm birth, stillbirth, and perinatal mortality.
Source: Chen Y, Chu B, Chen Y. The effect of recurrent pregnancy loss on obstetric and neonatal outcomes: A systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2025;38(1):2505755.
Recurrent pregnancy loss (RPL) is characterized by the spontaneous loss of two or more pregnancies before fetal viability.1-3 Globally, it has been reported to affect approximately 1% to 5% of couples attempting to conceive, although the true prevalence remains uncertain because of variability in diagnostic criteria and definitions.1
The burden of RPL is multifactorial in etiology and complex in effect. Several recognized risk factors include advanced maternal age, parental chromosomal rearrangements, thrombophilia disorders (e.g., antiphospholipid syndrome), uterine anomalies, and hormonal dysregulation (uncontrolled diabetes, thyroid disorders).1,3,4 Environmental and lifestyle factors, such as smoking, obesity, and poor nutrition, may further increase the likelihood of pregnancy loss.5 Despite advancements in reproductive technologies and supportive care, the prognosis for women with prior RPL remains guarded. Importantly, although significant efforts have focused on identifying the causes of RPL, less attention has been given to understanding its implications for subsequent pregnancies. Yet, mounting evidence suggests that RPL is not just a marker of reproductive failure, but a predictor of adverse obstetric and neonatal outcomes.
Understanding the effect of prior RPL on future pregnancies is critical, since these women represent a high-risk obstetric group requiring tailored prenatal care. Emotional trauma and increased anxiety following RPL also can alter patient behaviors, including delayed care seeking and reduced engagement with healthcare services.6 Moreover, medical conditions often underlying RPL, such as autoimmune disorders, can reemerge or worsen during subsequent pregnancies, affecting maternal-fetal health.7 Prior miscarriage, particularly when recurrent, has been associated with an increased risk of preterm birth, preeclampsia, stillbirth, fetal growth restriction, and placental complications.1,5,7-9 These sequelae emphasize the need for clinicians to consider RPL not only as a fertility issue but as a harbinger of future obstetric morbidity. Thus, comprehensive data synthesis through meta-analysis is invaluable for clinical risk stratification and management.
In the systematic review and meta-analysis conducted by Chen et al, the authors aimed to evaluate the effect of RPL on obstetric and neonatal outcomes.10 A rigorous search strategy was applied across PubMed, Embase, and Scopus up to Sept. 15, 2024, including only observational cohort, case-control, and cross-sectional studies with more than 100 participants per group. Studies were excluded if they included fewer than 100 participants per group (women with and without prior pregnancy loss); were published before the year 2000; focused exclusively on patients undergoing assisted conception; were case reports, letters, reviews, or conference abstracts; or lacked a control group.10
Data were synthesized using random-effects models because of baseline heterogeneity, and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for each outcome. The risk of bias was assessed using the Newcastle-Ottawa Scale, and the certainty of evidence was graded using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Publication bias was assessed using the Egger’s test, with P < 0.05 being statistically significant.
Fourteen studies met eligibility criteria, encompassing diverse populations across China, Europe, the United States, Japan, and the Middle East. The results demonstrated that women with prior RPL had significantly increased risks of several maternal complications, including cesarean delivery (OR, 1.41; 95% CI, 1.21, 1.65), placental abruption (OR, 2.11; 95% CI, 1.31, 3.39), and preeclampsia (OR, 1.25; 95% CI, 1.04, 1.50). Regarding neonatal outcomes, prior RPL was associated with increased risk of preterm birth (OR, 1.58; 95% CI, 1.38, 1.81), small-for-gestational-age neonates (OR, 1.31; 95% CI, 1.11, 1.55), stillbirth (OR, 1.77; 95% CI, 1.19, 2.61), and perinatal mortality (OR, 2.02; 95% CI, 1.46, 2.81).
Although other outcomes, such as low birth weight, low Apgar scores, neonatal intensive care unit (NICU) admission, and birth defects, trended higher in the RPL group, these did not reach statistical significance. Notably, RPL was not associated with an increased risk of gestational diabetes (OR, 1.11; 95% CI, 0.91, 1.35). The authors highlighted that the certainty of evidence was rated as “low” to “very low” for most endpoints, except for perinatal mortality (graded “moderate”). No publication bias was reported for all outcomes.
Commentary
This comprehensive meta-analysis offers compelling evidence that RPL confers a significant and clinically meaningful risk for subsequent adverse obstetric and neonatal outcomes. The association with placental-mediated disorders (such as preeclampsia, placental abruption, fetal growth restriction, and stillbirth) points to a shared pathogenic mechanism, potentially involving defective placentation or chronic uterine hypoperfusion. Given that many women with RPL harbor undiagnosed prothrombotic states, autoimmune conditions, or uterine anomalies, these comorbidities may persist into viable pregnancies and predispose to complications. The finding of a doubled risk for placental abruption (OR, 2.11) and perinatal mortality (OR, 2.02) underscores the necessity for vigilant placental and fetal surveillance in pregnancies following RPL. These patients may benefit from early screening for hypertensive disorders during pregnancy.
The meta-analysis also demonstrated the higher incidence of cesarean deliveries in women with RPL, likely attributable to obstetric and labor-related complications (e.g., prior uterine surgery or non-reassuring fetal status) and perhaps a lower threshold for intervention by clinicians managing these emotionally high-stakes pregnancies. The increased likelihood of preterm birth (OR, 1.58) and small-for-gestational-age neonates (OR, 1.31) echoes the findings seen in other high-risk groups, such as women with antiphospholipid syndrome or thrombophilia.11,12 Although low Apgar scores and NICU admission did not reach statistical significance, the trends suggest increased neonatal compromise, which may reflect subclinical placental insufficiency or inflammation-mediated preterm labor mechanisms. These associations, even when modest, argue for closer intrapartum and postpartum monitoring of neonates born to women with prior RPL.
Psychosocial dimensions also must be considered. The emotional toll of previous pregnancy losses often leads to increased maternal stress, which independently contributes to adverse pregnancy outcomes via pathways such as the hypothalamic-pituitary-adrenal axis dysregulation and increased inflammatory markers.13,14 Anxiety-driven care delays, overuse of assisted reproductive technologies, and altered patient-provider communication dynamics all are downstream effects that may complicate management. Moreover, women with RPL may disproportionately pursue high-intervention models of care, including frequent monitoring, early interventions, and scheduled elective primary cesarean deliveries. This high-intervention approach, while often intended to provide reassurance or prevent complications, can increase the likelihood of admission of newborns to the NICU, further increasing maternal anxiety. Integrating mental health services into prenatal care pathways for these patients can help mitigate these risks and foster a more holistic care model.
Finally, although this meta-analysis provides valuable insights, the study is limited by the retrospective nature of most included data, heterogeneity in RPL definitions (≥ 2 vs. ≥ 3 losses), and variable control for confounders across studies. Additionally, critical effect measure modifiers, such as gestational age of prior losses, interpregnancy intervals, and use of supportive therapies (e.g., progesterone, aspirin, or low molecular weight heparin), were not uniformly reported across studies, precluding subgroup analyses. Future research should aim to stratify risk based on these granular variables, ideally through large, prospective cohort studies with standardized definitions and intervention protocols. Nevertheless, this study reinforces the view that women with RPL merit categorization as a distinct high-risk group requiring individualized, multidisciplinary, and anticipatory obstetric care.
Ahizechukwu C. Eke, MD, PhD, MPH, is Associate Professor in Maternal Fetal Medicine, Division of Maternal Fetal Medicine, Department of Gynecology & Obstetrics, Johns Hopkins University School of Medicine, Baltimore.
References
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