Journal Club Papers
Cervical cerclage for prevention of preterm birth and adverse perinatal outcome in twin pregnancies with short cervical length or cervical dilatation: A systematic review and meta-analysis. D’Antonio et al. Plos Medicine. 3 August 2023. DOI: 10.1371/journal.pmed.1004266
Twin pregnancies are at high risk of preterm birth. The evidence for preventive strategies in the face of cervical shortening, such as vaginal progesterone or cervical cerclage, is uncertain. Prior studies on this subject have been limited by their small sample size. This updated systematic review assessed the role of cervical cerclage in preventing preterm birth and adverse perinatal outcomes in twin pregnancies with cervical shortening or dilatation. The review included 18 studies and 1,465 twin pregnancies:
- Fifteen observational studies assessing the risk of preterm birth among twin pregnancies undergoing cerclage vs no cerclage
- Four RCTs (74 pregnancies only) where twin pregnancies were allocated to cerclage for the prevention of preterm birth or to a control group (placebo or usual treatment)
All studies included patients that had either short cervical length on US or cervical dilatation on vaginal examination. The primary outcome was preterm birth <34 weeks gestation. Multiple secondary outcomes were examined; preterm birth <37, 32, 28 and 24 weeks, gestational age at birth and perinatal loss among them. The review found that cervical cerclage in women with a twin pregnancy and a short cervix at ultrasound or cervical dilatation was associated with a reduced risk of preterm birth:
- 27% reduced risk <34 weeks (RR: 0.73, 95% CI [0.59, 0.91], p = 0.005; difference in absolute risk (AR) 16%)
- 31% reduced risk <32 (RR: 0.69, 95% CI [0.57, 0.84], p < 0.001; AR difference: 16.92%)
- 46% reduced risk <28 (RR: 0.54, 95% [CI 0.43, 0.67], 0.001; AR difference: 18.29%)
- 52% reduced risk <24 (RR: 0.48, 95% CI [0.23, 0.97], p = 0.04; AR difference: 15.57%)
Cerclage was also associated with prolonged gestational age at birth (mean difference: 2.32 weeks, 95% [CI 0.99, 3.66], p < 0.001) and a 62% reduced risk of perinatal loss (RR: 0.38, 95% CI [0.25, 0.60], p < 0.001; AR difference 19.62%).
The reduction in preterm birth <34 weeks following cervical cerclage occurred in both women with cervical length <15 mm (RR: 0.74, 95% CI [0.58, 0.95], p = 0.02; AR: 29.17%) and in those with cervical dilatation (RR: 0.68, 95% CI [0.57, 0.80], p < 0.001; AR: 35.02%). There was no risk reduction noted for women with a shortened transvaginal cervical length between 15 and 25mm.
The authors concluded that emergency cerclage for cervical dilation or short cervical length <15 mm in twin pregnancies may reduce the risk of preterm birth and improve perinatal outcomes. However, most studies were observational, and the quality of evidence was rated low.
In summary, cerclage may be considered in twin pregnancies with severe cervical shortening: where cervical length is <15mm or where cervical dilation is present on physical examination. Yet the evidence underpinning these recommendations is limited, and the benefit of these interventions awaits confirmation in large and adequately powered RCTs.
Prenatal Intravenous Magnesium at 30-34 Weeks’ Gestation and Neurodevelopmental Outcomes in Offspring; The MAGENTA Randomized control trial. Crowther et al. JAMA. 15 August 2023. DOI: 10.1001/jama.2023.12357
Magnesium sulphate is given to reduce the risk of cerebral palsy among children born preterm. Its benefit among children born very preterm (<30 weeks’ gestation) is established. However, it is unclear whether children born at 30 - 34 weeks reap the same neurological benefits. To address this, Crowther et al. undertook a randomized clinical trial across 24 centres in Australia and New Zealand.
- 1,433 pregnant women at 30 – 34 weeks’ gestation with planned or expected birth within 24 hours were recruited. Women were randomized to 4 g of magnesium sulphate or placebo administered intravenously over 30 minutes.
- The primary outcome was a composite outcome of either death, or cerebral palsy before age 2 with children assessed by a paediatrician and assessor trained in administering the Bayley Scales of Infant Development (BSID-III). There were 36 secondary (or exploratory) outcomes spanning maternal, infant and child health.
- 1,660 children were available for 2-year follow up: 825/846 (97.5%) in the magnesium sulphate arm vs 789/814 (96.9%) in the placebo arm.
Magnesium sulphate did not alter the risk of death or cerebral palsy before age 2 when compared with placebo.
- Either death or cerebral palsy occurred in 3.3% (23/691) of children in the magnesium sulphate arm compared with 2.7% (18/674) of children in the placebo arm (adjusted relative risk [aRR] 1.19 [95% CI 0.65, 2.18], p=0.57).
- Investigating each separately, there was no difference in death alone (1.4% (12/837) magnesium sulphate vs 0.9% (7/796) placebo; aRR 1.50 [95% CI, 0.58 to 3.86], P = .40). And no difference in cerebral palsy alone (1.6% (11/679) vs 1.7% (11/667); aRR 0.98 [95% CI, 0.43 to 2.23], P = .96).
- For secondary outcomes at birth, neonatal respiratory distress syndrome was lower in the magnesium sulphate group; 34% (294/858) vs 41% (334/821); aRR, 0.85 [95% CI, 0.76 to 0.95], P = .01. Chronic lung disease was also reduced in the magnesium sulphate group; 5.6% (48/858) vs 8.2% (67/821); aRR, 0.69 [95% CI, 0.48 to 0.99], P = .04.
- For secondary outcomes at 2 years, there was no difference in developmental delay or child respiratory morbidity, asthma or hospital readmission. However, children in the magnesium sulphate group were more likely to have behavioural scores in the clinical problem range when come compared with placebo; 10% (40/389) vs 6% (24/379); aRR, 1.66 (95% CI, 1.03 to 2.68), P = .04. But, it is important to again note that these outcomes are exploratory and require further validation.
- For mothers, adverse events due to infusion were common in the magnesium sulphate group (77% vs 20%).
These findings suggest the neuroprotective benefits of magnesium sulphate are not seen after 30 weeks. However, there are some potential limitations. First, the trial may have been underpowered to detect a small but clinically meaningful difference, given a lower-than-expected prevalence of both death- and survival with cerebral palsy. The initial power calculation was based on an incidence of death or cerebral palsy of 9.6%, however in the trial the incidence was far lower, at 3.3% in intervention arm and 2.7% in placebo.
We also note that magnesium sulphate was given as a single bolus of 4g over 30 minutes, rather than the continuous infusion administered in the previous large trials. It is unclear whether a continuous infusion may have been beneficial. Given they compared 36 secondary outcomes, any significant differences among these secondary outcomes could have happened by chance. These differences in secondary outcomes require validation in future trials (!) before they can be accepted as evidence.
We remind readers that the national clinical guideline recommends magnesium sulphate for women with planned, expected or imminent birth before 30 weeks gestation to reduce the risk of cerebral palsy. These new findings do not support extending the gestational age window to 34 weeks’ gestation.
The proportions of term or late preterm births after exposure to early antenatal corticosteroids, and outcomes: systematic review and meta-analysis of 1.6 million infants. Ninan et al. BMJ. 2 August 2023. DOI: 10.1136/bmj-2023-076035
Review contributed by Alex Roddy Mitchell.
Antenatal corticosteroids reduce morbidity and mortality in babies born very preterm. The ALPS study (N Engl J Med 2016; 374:1311-1320) showed that given at 34 – 36 weeks’ gestation to women at high risk of late preterm birth betamethasone reduced the rate of neonatal respiratory complications. However, it is unclear whether these benefits are seen among those who receive corticosteroids before 34 weeks’ and then go on to birth at term or late preterm (34 – 36 weeks). The primary outcome of this systematic review and meta-analysis was the proportion of babies that received early antenatal corticosteroids (<34 weeks) and went on to be born at term or late preterm. Secondary outcomes included short- and long-term infant outcomes.
Babies born at term (≥37 weeks):
- In population-based studies, 45>#/strong### ([95% CI 44% – 46%]; 1 study; 14,868 babies) of babies exposed to early antenatal corticosteroid were born at term.
- In RCTs, 37>#/strong### ([30% – 44%]; 2 studies; 3,418 babies) of exposed babies were born at term.
- Early exposure to corticosteroids for babies born at term was associated with an increased likelihood of NICU admission (aOR 1.49 [1.19 – 1.86]; 1 study; 5,330 babies) and reduced head circumference (mean difference -0.21cm [-0.29 – -0.13]; 1 study; 183,325 babies).
- Babies exposed to early antenatal corticosteroids and born at term had an increased risk of long-term neurodevelopmental or behavioural disorder (aHR* 1.47 [1.36 – 1.60]); 1 study; 641,487 babies), compared with term babies not exposed to steroids. However, this is a secondary outcome, and the result was only from one study, which the authors rated as low certainty evidence.
Babies born late preterm (34 – 36 weeks):
- In population studies, 33% of babies exposed to early corticosteroids were born late preterm (95% CI 33 –3]; 1 study; 13,357 babies).
- In RCTs, 18>#/strong### ([17% – 20%]; 1 study; 3,178 babies) of exposed babies were born late preterm.
- Compared with no steroid exposure, babies exposed to early corticosteroids had a non-significant reduction in neonatal death (aOR 0.69 [0.47 – 1.01]; 1 study; 178,565 infants) but an increased risk of NICU admission (unadjusted RR 2.25 [1.37 – 3.71]; 2 studies; 204,233 babies).
- Among babies born late preterm, exposure to early antenatal corticosteroids was associated with an increased risk of neurocognitive disorders (aHR 1.12 [1.05 – 1.20]; 1 study; 25,668 babies). Again, this is a secondary outcome where the result is from a single study that the authors rated as low certainty evidence.
This review found that around 40% of babies exposed to early antenatal corticosteroids were born at term, and that exposure to early antenatal corticosteroids was associated with adverse short- and long-term outcomes among these babies. However, despite including RCTs and population-based studies only, the review rated most of the included evidence as low or very low. Also, many of the review findings were based on one study alone.
Antenatal corticosteroids remain an extremely important intervention for babies destined to be born before 34 weeks. However, this study raises the possibility that if antenatal corticosteroids are given early, but the baby is ultimately birthed late preterm or term, it may be harmful sometimes.