Journal Club Papers
Paper 1: Preterm prelabour rupture of membranes before 23 weeks’ gestation: prospective observational study.
Goodfellow and Care et al. BMJ Medicine. 17 November 2023. DOI: 10.1136/bmjmed-2023-000729.
Preterm prelabour rupture of membranes (PPROM) before 23 weeks’ gestation occurs in 0.1% of pregnancies and is associated with significant maternal and fetal morbidity and mortality. Counselling in these situations is difficult because of a lack of clinical outcome data from large studies.
This prospective observational study examined the maternal and neonatal outcomes of women with PPROM between 16+0 and 22+6 (from September 2019 to February 2021) across 194 obstetric hospitals in the UK.
- Of 364 women with PPROM prior to 23 weeks’ gestation.
- 69% (n=251) women were managed expectantly
- 31% (n=113) had a termination of pregnancy – most commonly because of evolving chorioamnionitis, others elected for this after counselling about likely prognosis
- Among 223 expectantly managed singleton pregnancies:
- Birth occurred a median of 13 days following rupture of membranes, with 27% (n=60) of women going into labour within the first 72 hours.
- Livebirths occurred in 44% (98/223), with 26%overall (54/207) surviving to hospital discharge.
- Among surviving neonates, 70% (38/54) were free from severe morbidity (grades III or IV intraventricular haemorrhage and/or need for supplemental oxygen at 36 weeks postmenstrual age).
- Overall, this means that 18% of infants survived to hospital discharge free of serious morbidity.
- The gestation of which PPROM happened impacted upon infant survival to hospital discharge:
- With PPROM between 16 – 17 weeks’ gestation, only 18% (7/40) of singleton infants survived
- With PPROM at 22 weeks’ gestation, 38% (10/26) survived.
- Importantly, maternal sepsis affected 12% of women with a singleton pregnancy (39/326), with no significant difference between the expectant management and termination of pregnancy groups (13% vs. 10% respectively). Rates of sepsis were higher among women with multiple pregnancy (29%). Five women (1.3%) developed sepsis requiring intensive care unit admission, with two (0.6%) subsequent maternal deaths.
The clinical outcome data from this paper may be useful to help clinicians make difficult management decisions with affected families
Paper 2: Efficacy of a single low dose of esketamine after childbirth for mothers with symptoms of prenatal depression: randomised clinical trial.
Wang et al. BMJ. 10 April 2024. DOI: 10.1136/bmj-2023-078218.
Postpartum depression is increasingly common, but treatment options are limited. Traditional antidepressants have unknown safety profiles for breastfeeding women and can take many weeks to have a therapeutic effect.
Esketamine (a potent form of ketamine) is a rapid-onset antidepressant and analgesic, which has shown promise in reducing postpartum depression and pain among women undergoing caesarean section.
This trial aimed to determine whether a single dose of esketamine after delivery may relieve symptoms of postpartum depression in this high-risk group.
- This was a randomised, double-blind, placebo-controlled trial conducted across five tertiary hospitals in China. Women with a score of ≥10 on the Edinburgh postnatal depression scale (indicating mild to severe depression) prior to giving birth (either vaginally or via caesarean section) were eligible.
- 364 women were randomised to either a single dose of esketamine (0.2mg/kg) or placebo (saline), which was given over a 40-minute period after umbilical cord clamping.
- Women were followed up for 42 days, with a primary endpoint of a major depressive episode (using the Mini-International Neuropsychiatric Interview). Other depression scales were assessed and reported as secondary outcomes. Other secondary outcomes included ratings of pain, exclusive breastfeeding, length of hospital stay, and maternal or neonatal complications.
Esketamine significantly reduced the risk of a major depressive episode.
- Women who received esketamine had a 74% reduction in their risk of a major depressive episode up to 42 days postpartum (6.7% vs 25.4%; RR 0.26, 95% CI 0.14 – 0.48; p<0.001).
- The number needed to treat to prevent one major depressive episode was only 5 (95% CI 4 – 9)!
- Women who received esketamine also showed reduced depression symptoms when assessed with the Edinburgh postnatal depression scale (MD -3, 95% CI -4 – -2; p<0.001) and the Hamilton depression rating scale (MD -4, 95% CI -6 – -3; p<0.001), as well as a 26% reduction in persistent pain at 42 days postpartum (RR 0.74, 95% CI 0.58 – 0.95; p=0.02).
- There were no differences in any other secondary outcomes (length of hospital stay following delivery, exclusive breastfeeding, or risk of maternal or neonatal complications).
Women who had been diagnosed with a mood disorder prior to pregnancy were excluded – only those with the onset of depressive symptoms in pregnancy were included. Most women likely had mild antenatal depression – the effect of esketamine for women with severe depression is unclear. Further research is needed into how long the effect of esketamine lasts beyond 42 days post-partum, given that postpartum depression can be ongoing.
Paper 3: Epidural analgesia during labour and severe maternal morbidity: population-based study.
Kearns et al. BMJ. May 2024. doi: https://doi.org/10.1136/bmj-2023-077190
This population-based cohort study of 567,216 births in Scotland aimed to determine whether epidural analgesia in labour reduces the risk of severe maternal morbidity.
Severe maternal morbidity encompasses conditions such as myocardial infraction, amniotic fluid embolism, cardiac arrest, disseminated intravascular coagulation, hysterectomy, and ventilation (ie. severe events that we want to avoid).
- All women between 24+0 – 42+6 weeks gestation from 2007 to 2019 were included (of 567,216 women, 125,024 (22%) had an epidural in labour)
- Those that had a planned caesarean delivery (and so wouldn’t have an epidural in labour) or missing mode of birth (5.5%) were excluded.
- Analyses were adjusted for maternal socioeconomic status and ethnicity, pre-existing maternal medical conditions and age – all things that might influence both severe maternal morbidity and epidural use. Multivariable regression methods were used to estimate risk ratios.
The primary outcome was severe maternal morbidity, (US Centers for Disease Control and Prevention definition) or admission to a critical care unit.
The secondary outcome was a composite of severe maternal morbidity AND a critical care admission, or severe respiratory morbidity.
- Severe maternal morbidity occurred in 2,412 women (4.3 per 1000 births)
- Epidural analgesia use was associated with a:
- 35% reduction in risk of severe maternal morbidity (RR 0.65, 95% CI 0.50-0.85)
- 53% reduction in risk of severe maternal morbidity AND critical care admission (RR 0.46, 95% CI 0.29 – 0.73) (composite secondary outcome).
- Severe respiratory morbidity was not significantly reduced (RR 0.42, 95% CI 0.16 – 1.15), yet was likely underpowered due to small numbers of women experiencing severe respiratory morbidity.
- The greatest benefit of epidural (50% risk reduction) was seen among those with higher risk of severe morbidity, ie. a preexisting medical indication for epidural (preeclampsia, breech, multiple pregnancy etc) (RR 0.50, 95% CI 0.34 -0.72). This risk was further reduced (64% reduction) among women with a medical indication for epidural and a preterm birth (RR 0.36, 95% CI 0.24 – 0.53).
Overall, epidural analgesia reduced severe maternal morbidity overall by 35%, and severe maternal morbidity associated with critical care admissions by 53%. However, there was only a benefit in pregnancies that were preterm, or where there was a medical indication for an epidural.
Paper 4: Neurodevelopmental Outcomes After Late Preterm Antenatal Corticosteroids: The ALPS Follow-Up Study.
Gyamfi-Bannerman et al. JAMA. April 2024. doi:10.1001/jama.2024.4303
The Antenatal Late Preterm Steroids (ALPS) trial, published in NEJM in 2016, found that antenatal steroids (Betamethasone) given between 34+0-36+6 weeks’ gestation significantly reduced severe neonatal respiratory morbidity – but increased neonatal hypoglycaemia. This study led to a change in practice in many parts of the world with increased use of steroids in the late preterm setting.
There have since been multiple publications raising concerns about the long-term neurodevelopmental impacts of antenatal steroid exposure.
This prospective follow-up study sought to examine long-term neurodevelopmental outcomes for the children in the ALPS cohort. The original cohort included 2,831 children. 949 (479 betamethasone, 470 placebo) completed the long-term follow-up assessment at a median age of 7 years.
The primary outcome was a General Conceptual Ability score less than 85 (1 SD below mean score) on the Differential Ability Scales – a US-developed assessment performed by psychologists to measure a child’s verbal ability, non-verbal reasoning skills and spatial ability. A high score indicates greater ability. Secondary outcomes were formally assessed and included gross motor function, social responsiveness and general child behaviour. Assessors remained blinded to the original treatment.
Parents of the children that participated in this follow-up study were generally older, less likely to have smoked during pregnancy, and more likely to be employed, have private health insurance and a college degree.
The primary outcome (a GCA score less than 85) was similar between groups: 82 of 479 (17.1%) in the betamethasone group and 87 of 470 (18.5%) in the placebo group (adjusted RR, 0.94; 95% CI 0.73-1.22). There were no differences in any of the secondary outcomes.
Sensitivity analyses were conducted to account for differences between the trial groups, lost to follow up and gestational age at birth. The primary outcome estimate did not change even after accounting for differences between parent characteristics, nor after assuming all high risk groups of children (those lost to follow-up, those born preterm or those with diagnosed with neuromotor/cognitive conditions) had the primary outcome.
In summary, no significant differences were found in neurodevelopment at age 6-7 years by antenatal steroid exposure in this ALPS follow-up study. However, only 949 of an intended sample size of 2000 were recruited. Multiple assumptions about the children not followed up were tested and the findings remained unchanged – no differences in the primary or secondary outcome by steroid exposure.