Journal Club Papers
Paper 1: Identifying novel prodromal symptoms of eclampsia: A two-country, case-control study
Hastie et al 2026,
PLOS Medicine
https://doi.org/10.1371/journal.pmed.1004994
Eclampsia remains one of the most serious complications of preeclampsia and is associated with maternal death, intracerebral haemorrhage, and persisting neurological morbidity. Magnesium sulphate halves the risk of eclampsia but identifying which women are at highest risk of seizure remains difficult. Current clinical warning symptoms -headache, visual disturbance, and epigastric pain - are widely used in practice, but have only modest predictive performance.
This study aimed to identify novel prodromal symptoms that may be more strongly associated with eclampsia than the symptoms currently used in clinical assessment.
The study: A multi-site, prospective case-control study conducted across three tertiary referral hospitals across Pakistan and South Africa.
The population: 2,085 pregnant or postpartum women, including:
341 women with eclampsia (!!)
1,355 women with preeclampsia without eclampsia
389 women with normotensive pregnancies
The exposure: Presence of neurological or prodromal symptoms. Women with eclampsia were asked about symptoms experienced in the 7 days before seizure onset. Women with preeclampsia and normotensive pregnancies were asked about symptoms experienced before enrolment.
The study assessed 20 neurological symptoms, including established symptoms such as headache, visual disturbance, epigastric pain, nausea and vomiting, as well as many neurological symptoms not thought to be associated with eclampsia (but associated with other neurological conditions).
The outcome: The primary analysis examined the likelihood of symptoms occurring before eclampsia, compared with their presence among women with preeclampsia who did not experience eclampsia. Symptoms were also assessed among women with normotensive pregnancies to determine how commonly they occurred outside hypertensive disease.
The findings: Established warning symptoms were associated with eclampsia. But the magnitude of association was very modest (Odds ratios ranging between just 2 to 6.)
- Headache: (Odds ratio) OR 2.56; 95% CI 1.81–3.62
- Visual disturbance: OR 5.73; 95% CI 4.44–7.39
- Epigastric pain: OR 2.25; 95% CI 1.76–2.89
In contrast, they study identified 10 symptoms with odds ratios between 10 to 43 for eclampsia, compared with preeclampsia:
Twitching or jerking limbs: OR 42.03
Affected hearing: OR 36.00
Affected mind state: OR 33.60
Impaired speech: OR 33.12
Feelings of doom: OR 23.71
Severe vertigo: OR 26.59
Confusion: OR 20.52
Jitters: OR 18.16
Difficulty concentrating: OR 15.18
Weakness or paralysis: OR 10.49
These symptoms were very rare among normotensive pregnancies, nor not reported at all.
Only 2.4% of women with eclampsia reported no prodromal symptoms screened meaning eclampsia occurring in the absence of any neurological symptoms is very uncommon.
Summary of findings: This two-country case-control study uncovered many novel prodromal symptoms that were far more strongly associated with eclampsia than headache, visual changes or epigastric pain. In fact, relying on these current symptoms may be misleading as they were commonly present in preeclampsia without eclampsia.
Symptoms such as twitching or jerking limbs, affected hearing, altered mind state, impaired speech, feelings of doom, severe vertigo, confusion, jitters, difficulty concentrating, and weakness or paralysis may be important additions to clinical history-taking among women with preeclampsia, or those with gestational hypertension.
These findings suggest that a broader neurological symptom screen may help identify women at higher risk of eclampsia and support more targeted use of magnesium sulphate prophylaxis.
Paper 2: Prenatal paracetamol exposure and child neurodevelopment: a systematic review and meta-analysis
D’Antonio,
The Lancet Obstetrics,
Gynaecology & Women’s Health, 2026,
DOI: 10.1016/s3050-5038(25)00211-0
Review contributed by Alexandra Roddy Mitchell
Paracetamol, or acetaminophen, is the most common analgesic and antipyretic used in pregnancy. Concerns have been recently raised in the US about potential adverse effects on child neurodevelopment, and in particular, autism spectrum disorder. This systematic review and meta-analysis aimed to rigorously assess available literature, to clarify the association between exposure to paracetamol during pregnancy and childhood neurodevelopment.
The study design: Systematic review and meta-analysis.
The trials included: Cohort studies comparing paracetamol exposure with no paracetamol exposure, where estimates were adjusted for confounding factors.
Importantly, this study prioritised sibling comparison analyses. Sibling analyses compare exposed and unexposed siblings, with the aim of reducing confounding by addressing shared familial factors, such as parental genetics, socioeconomic status and the home environment. It is a powerful epidemiological analysis approach.
The intervention: Exposure to paracetamol during pregnancy compared with no exposure.
The outcome: A diagnosis of autism spectrum disorder, ADHD, or intellectual disability, using a validated questionnaire or medical record.
The findings: 43 studies were included in the systematic review and 17 in the meta-analysis.
The study found no association between paracetamol exposure during pregnancy and autism spectrum disorder, ADHD, or intellectual disability.
Pooling results from sibling analyses, paracetamol exposure during pregnancy was not associated with an increased risk of:
1. Autism spectrum disorder (2 studies; N=262,852; OR 0.98, 95% CI 0.93 – 1.03),
2. ADHD (3 studies; N=335,255; OR 0.95, 95% CI 0.86 – 1.05),
3. Intellectual disability (2 studies; N=406,681; OR 0.93, 95% CI 0.69 – 1.24).
The null findings were consistent when the authors analysed the full set of studies that met the inclusion criteria, and also when they restricted the analysis to more rigorous subsets of studies, including those at low risk of bias and those with longer follow-up.
This systematic review and meta-analysis found no evidence that paracetamol exposure in pregnancy is associated with autism spectrum disorder, ADHD, or intellectual disability when analyses were restricted to studies that addressed confounding, particularly sibling-comparison designs. The consistency of null findings across sensitivity and secondary analyses suggests that earlier associations reported in conventional observational studies are more likely to reflect residual confounding by indication, maternal illness, familial/genetic susceptibility, or shared environmental factors, rather than a causal effect of paracetamol.
This study supports the safety of paracetamol use in pregnancy when taken as directed. It reaffirms the recommendations from RANZCOG, ACOG, RCOG, and the TGA which consider the use of paracetamol in pregnancy as safe (Category A medication).
Paper 3: Pregnancy outcomes in women at high risk of preterm birth receiving a vaginal cervical cerclage with, or without, progesterone: A retrospective, secondary analysis of the C-STITCH randomised controlled trial data
Hodgetts Morton et al,
PLOS Medicine, 2026
DOI: doi.org/10.1371/journal.pmed.1004513
Review contributed by Dr Hannah Gordon
Cervical cerclage and progesterone are commonly used interventions for women at risk of preterm birth. It is uncertain whether their combined use reduces the risk of pregnancy loss.
The trial: This study involved a secondary analysis of the C-STITCH trial, conducted across 75 maternity centres in the United Kingdom, where women at high risk of preterm birth were randomised to insertion of a braided or monofilament cervical cerclage. Using the C-STITCH data, this retrospective analysis compared obstetric outcomes for women who did and did not use progesterone in addition to cerclage.
The population: Adult women with singleton pregnancies who received an elective cervical cerclage (braided or monofilament) in the context of: (1) previous midtrimester losses or premature births (≤28 weeks’ gestation) with a cervix ≤25mm in the current pregnancy,* (2) three or more previous midtrimester losses or premature births, (3) insertion of cervical suture in a previous pregnancy, or (4) considered at risk of preterm birth due to history or ultrasound.
*The shortest cervix in the cohort was 23.1mm at time of cerclage placement.
The intervention: Cervical cerclage plus progesterone (any route; any dose) during pregnancy compared with cervical cerclage and no progesterone.
The outcome: Pregnancy loss, including miscarriage, stillbirth and neonatal death within 7 days of life.
The findings: This secondary analysis included 1,943 women (95% of C-STITCH cohort), including 1,109 (57.1%) with cerclage alone, and 834 (42.9%) with cerclage and progesterone. Progesterone was used vaginally in 200mg or 400mg doses 80.1% of the women, with intramuscular and ‘other’ progesterone doses and routes less common. There were some differences between those using progesterone and not, with progesterone more common among those without any prior live preterm births (70% vs 65%), non-black women (85% vs 78%), and where bladder dissection was required at time of cerclage (34% vs 17%). Cerclages were placed at a slightly earlier mean gestation in the progesterone group (15.9 vs 16.3 weeks’ gestation).
Pregnancy loss occurred in 49 (5.9%) women in the progesterone group, compared with 91 (8.3%) in the non-progesterone group (this included pregnancy losses due to termination of pregnancy). Following adjustment for confounders, progesterone was associated with a 30% lower risk of pregnancy loss compared with no progesterone (aRR 0.70 [95% CI: 0.50, 0.99]).
However, after excluding terminations due to fetal anomalies (1 in the progesterone group; 6 in the no progesterone group), the association did not remain statistically significant (aRR 0.74 [95% CI: 0.53, 1.05]).
Similarly, there was no difference in gestational age at birth between groups, nor did progesterone alter the risk of adverse perinatal outcomes, including maternal and neonatal sepsis, and PPROM.
Summary of findings: In the primary analysis, progesterone combined with cerclage was associated with a lower risk of pregnancy loss than cerclage alone. This finding should be interpreted with some caution, as important covariates such as BMI and smoking were not available for adjustment, and the reduction in pregnancy loss was no longer statistically significant once pregnancy terminations for fetal anomalies were excluded (likely due to small numbers).
The current evidence (including these data) may not be sufficient to conclude routinely adding progesterone to cerclage improves outcomes.
Paper 4: Hypertensive Disorders of Pregnancy Subtypes and Long-Term Cardiovascular Risk
Kwak et al 2026
JAMA Internal Medicine
DIO: https://doi.org/10.1001/jamainternmed.2025.7802
Review contributed by Dr Su Jen Chua
Hypertensive disorders of pregnancy affect approximately 5–10% of pregnancies and are known to increase the long-term risk of cardiovascular disease (CVD).
However, hypertensive disorders of pregnancy is not a single condition but a spectrum of subtypes, including:
Gestational hypertension
Chronic hypertension
Preeclampsia/eclampsia
Preeclampsia superimposed on chronic hypertension
It remains unclear if the risk of future cardiovascular disease is uniform across all these subtypes or if certain categories carry a higher risk. Furthermore, while these risks are well-documented in Western populations, there is a lack of data among Asian populations.
This study aimed to investigate the link between hypertensive disorders of pregnancy and long-term cardiovascular outcomes in a South Korean population, specifically examining whether the level of risk varies depending on the HDP subtype.
The study: Retrospective cohort study utilising the National Health Insurance Service database. This database contains demographics, ICD-10 codes, prescriptions and hospitalisation data from biennial national health screening programs covering the entire South Korean population from January 2010 to December 2018.
The population: 570 843 women (22,876 with hypertensive disoders of pregnancy; 547,967 without) aged 19-50 years old with at least one documented birth during the study period (most recent birth used as reference event). Women with end stage kidney disease, malignancy, prior cardiovascular events, missing data and events occurring within 1 year postpartum were excluded.
The exposure: Hypertensive disorders of pregnancy subtypes were defined using diagnostic codes and prescription records:
Gestational hypertension
Chronic hypertension
Preeclampsia or eclampsia (new onset during pregnancy)
Superimposed preeclampsia (preeclampsia developing in patients with pre-existing hypertension)
Unspecified hypertensive disorders of pregnancy (cases not meeting specific criteria for the other groups)
The outcome: The primary outcome included a composite of cardiovascular events (cardiovascular death, heart failure, myocardial infarction, stroke, and atrial fibrillation). Secondary outcomes were individual components, utilising specific hospital admission codes and claims for diagnostic imaging to ensure clinical accuracy.
The findings: After a median follow-up of 6.5 years, incidence rates of cardiovascular events were 4.39/1000 person-years in women who had hypertensive disorders of pregnancy, compared with 2.29/1000 person years in women without hypertensive disorders of pregnancy
Hypertensive disorders of pregnancy were associated with an increased risk of cardiovascular events even after adjustment for conventional risk factors (adjusted HR 1.62; 95% CI, 1.49-1.76)
This association was present across all subtypes of hypertensive disorders of pregnancy
Rates of all individual cardiovascular events were higher in women with hypertensive disorders of pregnancy
The levels of magnitude of increased incidence of composite cardiovascular events differed by hypertensive disorders of pregnancy subtype:
Preeclampsia superimposed on chronic hypertension: 9.83/1000 person years
Chronic hypertension: 5.51/1000 person years
Unspecified hypertension: 4.22/1000 person years
Pre-eclampsia / eclampsia: 4.01/1000 person years
Gestational hypertension: 3.94/1000 person years
(versus 2.20/1000 person years in women without any of these conditions)
Summary of findings: This large South Korean population-based cohort study confirms that hypertensive disorders of pregnancy are associated with an increased risk of later cardiovascular disease, extending evidence beyond predominantly Western populations. Importantly, the magnitude of risk was not uniform across hypertensive disorders of pregnancy subtypes. Women with preeclampsia superimposed on chronic hypertension had the highest subsequent cardiovascular event rate, followed by those with chronic hypertension. These findings support the need to consider hypertensive disorders of pregnancy subtype, rather than as a single exposure, when counselling women about long-term cardiovascular risk and planning postpartum cardiovascular prevention.