Journal Club Papers
There are increasing concerns that antenatal corticosteroids, whilst important for fetal lung maturation and reducing mortality and major morbidity for preterm infants, may also have potential for harm and be associated with poorer developmental and educational outcomes for children.
- This was a record-linkage study using population data from British Columbia, Canada.
- They included 5,562 singleton births from 31+0 – 36+6 weeks gestation from 2000-2013. Birth data were linked with routine early school age development testing data.
- The recommended upper gestational age for antenatal steroids in Canada is 33+6 weeks – educational outcomes were compared between infants admitted just before and after 34+0 weeks as surrogate for ‘steroid exposed’ (although it was not ascertained which infants <34 weeks had inadequate steroid cover, nor which infants >34 weeks may have had previous exposure).
- Using a regression discontinuity design, which estimates the change in risk at the point of treatment discontinuity (34+0 weeks), they found no association between antenatal corticosteroid administration and altered child development at early school age (score difference -0.5 (95%CI -2.2-1.7) p=0.65), nor developmental vulnerability (3.9 per 100 excess cases (95%CI -2.2-10.0) p=.24) or special needs designation (-0.5 per 100 excess cases (95%CI -4.2-3.1) p=0.96)
- The authors concluded that a policy for routine administration of antenatal corticosteroids does not have a negative impact on overall child developmental health
Considerations:
- Women excluded from the cohort due to missing/uncertain gestation data were more likely to be younger and smokers (statistically significant differences) – a large proportion of data pre-2008 were excluded (71%)
- Only one third of the total cohort of births between 31+0-36+6 weeks (15,741) had developmental metric data (due to 3-year testing waves), which is arguably the gestation of greatest interest
- An important concern is that birth data were not linked with medication/prescribing data – instead 34+0 weeks was used as a ‘line in the sand’ to determine assumed administration of steroids (before).
- there was no way of knowing if those babies admitted at 34-36 weeks actually received steroids earlier in the pregnancy
- there was no ability to demonstrate if the relationship between antenatal steroids and child development varies at different gestational ages
These findings (no impact from steroids) are in contrast to the large Finnish study we covered in Edition 6 of JCOTR, which found an increased risk of childhood mental or behavioural disorders among children exposed to antenatal corticosteroids. However, the effect in the Finnish study was largely seen among term born infants (and therefore doesn’t completely contradict these findings). The impact on educational outcomes in infants born preterm is likely to be attenuated because of the well-established benefits for survival.
Further large studies of long-term childhood health and development, stratified by gestational age at administration, gestational age at delivery, and adjusted for other confounding variables (particularly fetal growth restriction) following antenatal corticosteroid exposure are needed.
Maternal cardiovascular risk after hypertensive disorder of pregnancy. Arnott et al. Heart 2020.
- A retrospective cohort study using NSW data to investigate the risk of cardiovascular disease (CVD) following hypertensive disorders of pregnancy, with CVD defined as hospitalisation or death due to ischemic heart disease, stroke, or hypertensive disorder.
- Included 528,106 women whose first birth occurred between 2002 – 2016, with 10.3% (n=54,323) experiencing any hypertensive disorder of pregnancy (HDP); preeclampsia, eclampsia or gestational hypertension.
- The median follow-up was 7 years (IQR 3.4 – 10.8).
- 70% of women had follow up of ≥ 10 years, and among these the 10-year CVD risk was 5.5 per 1000 women for those with a HDP vs 2.1 per 1000 women (0.1% absolute risk) among those without.
- Early-onset HDP (<34 gestational weeks) was the greatest single risk factor for CVD, with an absolute risk of 1.1% at 10-years (15.9 per 1000 women) vs 0.4% (5.0 per 1000 women) for late-onset HDP.
- Maternal age, smoking, diabetes and SGA all further increased the risk of CVD among women with HPD.
- The strongest interaction was found between smoking and HDP; smokers with late-onset HDP had a 4-fold (RR 4.0; 95% CI 2.8 – 5.7) adjusted increased risk of CVD and smokers with early-onset HDP had a 23.5 (95% CI 13.5 – 40.8) adjusted increased risk compared to non-smokers without HDP.
These findings sound a strong word of caution, confirming previous reports of maternal CVD events which may occur reasonably soon following a pregnancy complicated by HDP. This study estimates a greater risk of CVD associated with HDP than that of smoking, and a strong interaction between HDP and smoking.
This highlights the urgent need for follow-up of CVD risk factors and patient education after hypertensive disorders of pregnancy, and particularly addressing modifiable risk factors, such as smoking.
BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. Dagan et al. NEJM 2021.
- A national wide study of Israel’s mass vaccination campaign against COVID-19 with the BNT162b2 vaccine (Pfizer mRNA vaccine).
- The authors performed a matched analysis of all people in Israel newly vaccinated between 20th Dec 2020 – 1st of Feb 2021.
- 596,618 vaccinated individuals were matched 1:1 to unvaccinated controls, matched on demographic and clinical characteristics. 1508 vaccinated pregnant women were included. The study was adjusted if an unvaccinated control was subsequently immunized.
- During the study period there were 10,561 infections, 5,996 symptomatic, 396 required hospitalisation, 229 severe cases and 41 deaths.
- Results following 1st dose at 14 – 20 days post vaccination: Vaccine effectiveness was 46% (95% CI 40-51) for any SARS-CoV-2 infection, 57% (95% CI 50-63) for symptomatic infection, 74% (95% CI 56 - 86) for hospitalization, 62% (39 – 80) for severe infection and 72% (95% CI 19 - 100) against death from COVID-19.
- Results following 2nd dose at ≥7 days: Effectiveness was 92% (95% CI 88 – 95) for any SARS-CoV-2 infection, 94% (95% CI 87 – 98) for symptomatic infection, 87% (95% CI 55 - 100) hospitalization, 92% (95% CI 75 – 100) for severe infection and there were too few deaths to calculate effectiveness against mortality (overall deaths: unvaccinated 39 vs 9 vaccinated).
- Comparable outcomes were found for sex and age but slightly lower effectiveness for those with multiple comorbidities. Effectiveness was not investigated among pregnant women alone or by ethnicity.
- Mean follow up was only 15 days. Further studies of long-term effectiveness are needed as well as investigation of pregnant women and minority groups.
These real-world findings echo those of the phase III trial of the Pfizer vaccine and provide evidence against asymptomatic infection. Importantly, during the trial infection of the B1.1.7 variant (UK variant) was on the rise in Israel, which suggest this vaccine may provide protection against the original virus and this newer strain.
This study will contribute to the evidence base for safety and effectiveness of vaccination in pregnant women. The immune response, vaccine effectiveness, optimal gestation and dosing, passage across the placenta and in breast milk are crucial research questions that can only be addressed by ensuring that pregnant and breast feeding women are safely included and followed up in COVID19 vaccination trials.