Journal club papers
- A systematic review of 77 observational studies investigating the effects of COVID-19 on pregnant and recently pregnant women.
- A total of 13,118 pregnant women and 83,486 non-pregnant women of reproductive age with confirmed COVID-19 infection were included. The majority of studies were from the USA (n=26 studies) and China (n=24 studies).
- The most common symptoms among pregnant women were fever (40%),and cough (39%). Among laboratory findings, lymphopaenia (35%) and raised C reactive protein levels (49%) were most common.
- Among 11,580 pregnant women with COVID-19, 73 died from any cause (0.1%; 95% CI 0.0% – 0.7%). 13% were diagnosed with severe COVID-19, 4% were admitted to ICU, 3% required invasive ventilation and 0.4% required extracorporeal membrane oxygenation.
- Compared to non-pregnant women with COVID-19, pregnant women were more likely to be admitted to ICU (odds ratio 1.96; 95% CI 1.33, 1.96) and require invasive ventilation (OR 1.88; 95% CI 1.36, 2.60).
- Maternal risk factors for severe COVID-19 were increasing age (OR 1.78; 95% CI 1.25, 2.55), a high BMI (OR 2.38; 95% CI 1.67, 3.39), chronic hypertension (OR 2.0; 95% CI 1.14, 3.38) and pre-existing diabetes (OR 2.51; 95% CI1.31, 4.80). Pre-existing comorbidities were also associated with ICU admission and invasive ventilation.
- The incidence of any preterm birth was 17% (95% CI 13% – 21%) and 6% (95% CI 3% - 9%) for spontaneous preterm birth. Among 2 studies comparing COVID-19 positive women to uninfected women, those with COVID-19 had a higher odds of any preterm birth (OR 3.0; 95% CI 1.15, 7.85).
- Neonates born to COVID-19 positive women were more likely to be admitted to the neonatal unit (OR 3.31; 95% CI 2.05, 4.78). However, these findings were from one study and it is unclear whether local policies on observation and quarantine influenced this finding.
- No association between stillbirth or neonatal death and COVID-19 infection were found.
This comprehensive living systematic review, which will be updated as new studies become available, highlights that while having co-morbidities (being older or overweight) increases the risk of severe pregnancy complications from COVID-19 infection, the absolute risk to pregnant women remains low. Additionally, although the incidence of preterm delivery was high among COVID-19 positive women, spontaneous preterm birth was not.
Paper 2: Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial
Shahar-Nissan et al. Lancet (09/2020)
- This randomised double blinded placebo-controlled trial investigated whether valaciclovir could prevent vertical transmission to the fetus if given to women with primary CMV infection in early pregnancy
- Women were enrolled over 3 years and included pregnant women over the age of 18 with serological evidence of primary CMV infection either periconceptually or in their first trimester
- Serological criteria were: seroconversion from IgG negative to IgG positive during first trimester, or positive IgM with low avidity IgG in early pregnancy, with a subsequent “substantial rise” in IgG titre.
- 45 patients were randomly allocated to each treatment arm – oral valaciclovir (8g per day, taken as two 4g doses) or placebo – until an amniocentesis at 21-22 weeks gestation
- Overall, valaciclovir significantly reduced the risk of vertical transmission; amniocentesis was positive in 5/45 (11%) in the valaciclovir arm vs 14/45 (30%) in the placebo arm (OR 0.29 (95%CI 0.09-0.90))
- Amongst participants with a primary first trimester infection, vertical transmission was also significantly less likely in the valaciclovir treatment group (2/19 (11%) vs 11/23 (48%); p=0.020)
- There were no clinically significant adverse events reported
- One fetus in the valaciclovir group developed severe CMV-related brain abnormalities; late termination of pregnancy was performed in this case
The gist of this study is that early treatment of primary CMV infection in pregnancy with valaciclovir may reduce the risk of vertical transmission. These findings are encouraging because they suggest valaciclovir may be effective in secondary prevention of the morbidity related to congenital CMV in women with confirmed early primary infection. This trial provides valuable information in managing this small sub-set of women.
Some discussion points
- This trial was undertaken in a setting where early routine screening for CMV is commonly undertaken (the first CMV serology was done at a median of 8 weeks’ gestation). This is important because the greatest effect was seen in those who commenced treatment early after infection (women who had a positive amniocentesis following valaciclovir began treatment significantly later). The benefits seen in this trial may not be realised where pregnancy screening or commencement of therapy occur later.
- Treatment with valaciclovir did not prevent all cases of severe fetal brain sequelae and thus valaciclovir cannot provide complete reassurance against fetal complications
- Some women made decisions to terminate their pregnancy before any evidence of fetal infection or injury. These outcomes should be considered when weighing up the benefits and harms of routine screening.
- Four infants in the treatment group were CMV-infected at birth despite a negative amniocentesis, suggesting that valaciclovir may postpone, rather than prevent, in utero transmission in some cases.
- The trial was limited by a relatively small sample size and was thus underpowered to assess neonatal outcomes.
- A couple of caveats when considering the place of routine screening
- laboratory assays for CMV IgG and IgM are not well standardised, so discordant results are common. Serological and clinical expertise is needed to assist with interpretation and maximise the benefits of screening.
- The majority of congenital CMV is caused by nonprimary infection, which is not addressed in this study.
In conclusion, this is a very significant trial in identifying a treatment that could feasibly reduce the burden of congenital CMV. However routine screening for CMV is perhaps still a step away from ‘prime time’. There remains unanswered questions about the feasibility, benefit and cost effectiveness of CMV screening in early pregnancy.