Journal Club Papers
Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial. Beardmore-Gray et al. Lancet. 29 June 2023. DOI: 10.1016/S0140-6736(23)00688-8
Timing of birth among women with late preterm preeclampsia (34 – 37 weeks’) requires careful balancing of maternal and neonatal risks and benefits. Studies from high income settings have shown that compared with expectant management, planned birth from 34 weeks’ reduces the risk of maternal morbidity, but increases NICU admissions (with no increase in neonatal morbidity) (Lancet 2019;394:1181-1190). However, the applicability of these findings to low resource settings, where the burden of disease is greatest, is unknown.
The CRADLE-4 team undertook a multicentre, open-label, randomised controlled trial evaluating planned birth at 34+0 – 36+6 weeks’ vs expectant management among women with preeclampsia across 9 sites in India and Zambia.
- 565 women were randomised: 284 to planned birth from 34 weeks’ (median gestation at birth 36+0) vs 281 to expectant management (median gestation at birth 36+3).
- The primary maternal outcome was a composite of multi-organ morbidity (including death, CNS, cardiorespiratory, hepatic, haematological and renal indices, placental abruption and systolic BP >160mmHg post randomisation).
- Planned birth was associated with a non-significant reduction in the composite maternal outcome; 154/282 (55%) planned birth vs 168/280 (60%) expectant management, adjusted risk ratio (aRR) 0.91 [95%CI 0.79 – 1.05].
- Among individual components of the composite, planned birth reduced the risk of severe hypertension; 123/282 vs 124/280; aRR 0.83 (95%CI 0.70-0.99).
- The primary perinatal outcome was a composite of neonatal death, antenatal or intrapartum stillbirth or neonatal unit admission >48hours.
- Planned birth was associated with a non-significant reduction in the primary perinatal outcome; 58/301 (19%) vs 67/300 (22%), aRR 0.88 (95%CI 0.64, 1.21).
- Among the individual components of the perinatal composite, planned birth significantly reduced the risk of stillbirth by 75%; 3/301 (1%) vs 12/300 (4%); aRR 0.25 [0.07, 0.87]. To prevent one antenatal stillbirth the number of planned births needed was only 33.
- There was no difference in the number of infants admitted to NICU for >48 hours (17% vs 18%)
- Birthweight percentile was significantly higher among those babies in the planned birth group; 22.8 vs 16.9 (p= 0.003).
These findings provide important information for women with late preterm preeclampsia in resource constrained settings. Planned delivery is safe. The maternal benefit does not come at the expense of increasing perinatal risk or increasing demands on finite neonatal resources. Prompt delivery in late preterm preeclampsia is thus an important intervention to reduce global maternal and perinatal morbidity. Importantly, stillbirths were significantly reduced (with a NNT of only 33) reinforcing that the safest place for the baby in late preterm preeclampsia is - in the cradle.
While run in a low-middle income setting, the findings are plausibly relevant to higher income populations. It suggests the drawback of expectant management may be that we leave the fetus in a hostile intrauterine environment where it struggles to thrive (where weight centiles slide and the fetus is exposed to a greater risk of stillbirth). Hence, for later preterm preeclampsia, simply aiming for a later gestation to birth the baby may not be clearly beneficial
The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptually or in the first trimester of pregnancy. An individual patient data meta-analysis. Chatzakis et al. AJOG. 18 July 2023. DOI: 10.1016/j.ajog.2023.07.022
Review contributed by Jess Atkinson.
Cytomegalovirus (CMV) is the most common congenital infection, affecting around 5 per 1000 livebirths in Australia. The risk of vertical transmission is greatest in cases of primary infection, that is, when the mother first becomes infected while she is pregnant. A 2020 randomised control trial found that valacyclovir, an antiviral drug, was effective at preventing fetal infection with CMV in cases of maternal primary infection (Lancet 2020;396(10253):779-785). Subsequent non-randomized studies have shown similar results. This individual patient data meta-analysis aimed to synthesise the results of these previous studies to assess the efficacy and safety of valacyclovir in preventing vertical transmission of CMV in cases of maternal primary infection. This included infection either periconceptually (3 months prior to conception) or during the first trimester.
- Three studies, reporting the results of 527 women with primary CMV infection were included.
- 218 women received valacyclovir (8g per day), and 309 received placebo or no intervention.
- The primary outcome was the rate of vertical transmission of CMV, assessed by amniocentesis. Secondary outcomes included positive CMV infection at birth; termination of pregnancy due to CMV associated effects; and maternal side-effects of valacyclovir.
Administration of valacyclovir was associated with a 76% reduction in the likelihood of vertical transmission of CMV (adjusted odds ratio [aOR] 0.34 [95% CI 0.18-0.61]).
- Only 24/217 (11%) of women in the valacyclovir group returned a positive CMV following amniocentesis, compared with 76/298 (25.5%) in the control group.
- Similar results were found after stratifying by timing of maternal infection – 76% reduction following infection during the periconceptual period (aOR 0.34 [95% CI 0.12-0.96]), and 75% reduction following infection during the first trimester (aOR 0.35 [95% CI 0.16-0.76]).
- Valacyclovir was also associated with a 70% reduced likelihood of neonatal infection (19.2% vs 41.1%; aOR 0.30 [95% CI 0.14-0.61]), and 77% reduced likelihood of termination of pregnancy (0.9% vs 4.5%, aOR 0.23 [95% CI 0.22-0.24]).
- Reported side effects of valacyclovir included nausea (20.8%), headache (20.8%), low platelet count (1.4%), and reversible acute kidney injury (2.1%).
This study demonstrates a significant protective effect of valacyclovir against vertical transmission of primary CMV infection, particularly when treatment was commenced early in pregnancy. Although termination of pregnancy due to CMV and congenital infection in live neonates are mutually exclusive outcomes, the reduction of both suggests an overall improvement in pregnancy outcomes with treatment. These results also provide impetus for improved screening of CMV during pregnancy to provide an opportunity for treatment.
At Mercy Perinatal, we super excited to announce we are launching a pilot study to investigate the feasibility and acceptability of routine CMV testing in the first trimester. Learn more about the ESE-CMV study here.
Treatment of gestational diabetes mellitus diagnosed early in pregnancy. Simmons et al. for the TOBOGM Research Group. NEJM. 8 June 2023. DOI: 10.1056/NEJMoa2214956
Review contributed by Dr Hannah Gordon.
Treatment of diabetes in pregnancy improves outcomes for mums and babies. However, it was unclear whether women at risk of hyperglycaemia may benefit from earlier treatment of diabetes in pregnancy. This multi-centre randomised controlled trial by Simmons et al aimed to determine this.
- Eligible women were those with a singleton pregnancy, at least one risk factor for hyperglycaemia and a subsequent early diagnosis of gestational diabetes on glucose tolerance test performed at a mean of 15.6 weeks’ gestation.
- 406 women were randomized to immediate treatment of diabetes and 396 to delayed or no treatment, depending on the result of their repeat 24–28-week glucose tolerance test.
- A group of women who tested negative for early gestational diabetes were included in the trial as “decoys” to blind group assignment from investigators and other participants.
- The primary outcome was a composite of neonatal adverse outcomes including perinatal death, prematurity (<37 weeks), birthweight ≥4.5kg, shoulder dystocia, neonatal respiratory distress, and need for phototherapy. Secondary outcomes included maternal pregnancy-related hypertension) and neonatal lean body mass as a marker for fetal undernutrition.
- Immediate treatment reduced the risk of adverse neonatal outcomes by 18%, (aRR 0.82 [95% CI: 0.68-0.98]; 94/378 vs 113/370), when compared with women in the control group.
- The number needed to treat to prevent one adverse neonatal outcome was 18.
- The reduction in adverse neonatal outcomes was predominantly driven by the reduction in neonatal respiratory distress; 37/376 (9.8%) of infants in the early treatment group vs 62/365 (17%) in the control group (aRR 0.57, (95% CI 0.41 to 0.79)).
- There was no significant difference between groups in mean gestational age at delivery (38.2 vs 38.3 weeks) or in rates of preterm birth (7.4% vs 8.4%, RR 0.89 [95% CI: 0.83-1.26]).
- There was no difference between the groups in rates of pregnancy-related hypertension and mean neonatal lean body mass.
- Treatment with insulin was more common in women in the immediate treatment group (58% compared with 41% control), and interestingly, 33% (n=117) of the control group tested negative on the repeat 24-28 week glucose tolerance test.
Among women with risk factors for hyperglycaemia, early treatment for diabetes has the potential to improve neonatal outcomes. The study included a predominantly Australian cohort, making these results particularly relevant to our Australian clinicians.
Also (for JCOTR who live in Australia) we are proud that a brilliant Aussie team did this trial which was published in NEJM.