JCM | Free Full-Text | The Importance of Vaccination, Variants and Time Point of SARS-CoV-2 Infection in Pregnancy for Stillbirth and Preterm Birth Risk: An Analysis of the CRONOS Register Study
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4.1. Principal Findings
The rate of early preterm delivery and stillbirth was higher after infection before the third trimester and during the Alpha and Delta periods of SARS-CoV-2 infections. The rate of stillbirth and early PTB were lower in the vaccinated population. SARS-CoV-2 infection early in pregnancy and infection during the Alpha and Delta periods increased the risk for stillbirth and early preterm birth. Having symptoms independent of the severity reduced the risk for PTB, especially for early PTB. Hospital admission for COVID-19-related symptoms as a surrogate of a more severe course of COVID-19 disease increased the risks. Vaccination against SARS-CoV-2 significantly reduced the risks, especially for stillbirth. It is known that the risk of stillbirth after a SARS-CoV-2 infection in pregnancy is increased [26]. A recent meta-analysis estimated that the odds ratio of stillbirth in COVID-19 compared to non-COVID-19 pregnant women was 1.89 [27]. In 2022, we reported the increased risk especially after early infection in a smaller cohort based on our CRONOS register data [12]. Since the rate and risk of stillbirth is dependent on gestational age, it is not possible to exclude that not only the infection, but gestational age itself affected our results. Pregnant individuals may have presented in hospital due to the diagnosis of intrauterine demise and have had an early infection detected through hospital screening. In a retrospective study from 2010, the stillbirth rate was higher early in gestation, but the risk increased late in gestation, especially at 42 weeks [28]. The hypothesis is that the infection produced an inflammation in the maternal body affecting the fetus correlated with an adverse outcome increasing the risk of stillbirth and preterm birth.
Pregnant women with COVID-19 versus without COVID-19 are more likely to deliver preterm and could have an increased risk of maternal death and of being admitted to the intensive care unit [29]. Pregnant women especially early in the second trimester seem to be more susceptibly and tend to have a worse outcome after infection in this period [18]. In 2022, Piekos et al. [11] analyzed the risk of maternal and pregnancy complications depending on the time point of infection in 882 infected pregnant women compared with 889 matched control pregnant women. An infection in the first and second trimester increased the risk of stillbirth and early PTB. They also found that gestational week at infection could predict the week of gestation at delivery, but the severity of the infection was not correlated with gestational age at delivery. In our first analysis of a smaller cohort from CRONOS, which included 1149 pregnant women [12], and in this study including 8032 infections in pregnancy, the admission to hospital as a surrogate for the severity of infection increased the risk for stillbirth and preterm birth. In the case of admission to an ICU, the risk increase was even higher. Differently applied statistical models, but also the population size, could be explanations for the different results, since the number of infected women was lower in the cohort of Piekos and colleagues [11].
The prevalence of congenital malformations in SARS-CoV-2-infected women did not increase in the CRONOS register compared to the known European prevalence [30]. In countries where the Zika Virus is endemic, the clinical differentiation between the two entities with similar symptoms is difficult and represents an issue due to the late diagnosis of congenital Zika syndrome, which includes microcephaly and neurodevelopmental delay [31].
The Delta and the Alpha variants showed increased transmissibility shortly after being discovered compared to earlier variants. It soon became clear that the Delta variant was not only more transmissible but potentially more severe, leading to higher rates of hospitalization and complications in pregnant women, resulting in an increase in adverse maternal and fetal outcomes in affected pregnancies [32].
The study of Favre [17] examined the period before and after Delta. In this analysis, the higher risk for maternal health but also the increased risk for obstetrical complications especially preterm birth and stillbirth during Delta is evident. During the Delta period, the stillbirth rate was 2.8%, higher than the one observed in our study. The reason for this could be the smaller examined population with n = 1402, n = 262, and n = 391 for pre-Delta, Delta, and post-Delta, respectively.
Depending on different virus variants, different PTB rates were described at an academic center in New York (US) [18]: 9.9% during Omicron compared with a peak in PTB rate of 20.3% during the original period, which is of course much higher than the 11.06% PTB rate registered during the wild-type period in our study. The German preterm birth rate is 9%, stable in recent years [33] whereas the PTB birth rate in the US is higher, at 10.38% in 2022, with a higher rate among black non-Hispanic women (14.59%) [34]. The reason in this case could also be the different size of the studied populations, since in the study, 8983 women were analyzed but only 638 were infected.
Regarding vaccination, the main body of research evaluates the safety of vaccination against SARS-CoV-2 in pregnancy [35,36]. The role of vaccination and its effect on obstetrical outcomes has not yet been intensively examined. One recent study showed that the risk increase for PTB after infection was lower when the vaccination rate in the population was higher [19]. Our data support not only the safety of vaccination against SARS-CoV-2 in pregnancy, they underline the importance of vaccination by lowering the risk for adverse outcomes like stillbirth and preterm birth in the vaccinated population.
4.2. Clinical Implications
Our data provide a valid instrument for consulting pregnant women on the modulation of risk after SARS-CoV-2 infection during pregnancy and the role of vaccination. Overall, obstetrical complications seemed to be lower during the Omicron wave. However, an infection early in pregnancy has been shown to increase the risks of the analyzed obstetrical complications. Therefore, intensive obstetrical surveillance after an early pregnancy infection is still mandatory. Vaccination offers effective protection against the risk of stillbirth and preterm birth (PTB), and women should be encouraged to receive immunization against SARS-CoV-2 infection. Vaccination during pregnancy is a delicate topic that arouses a lot of skepticism in patients. The pandemic is a case in point. Since the results of the vaccination studies, including pregnant individuals, were available later than those regarding other populations, immunization in pregnancy started later. An earlier analysis of this important group could have prevented many complications making it a current and exemplary issue, an important lesson for the future.
4.4. Strengths and Limitations
We present one of the largest cohorts of infected women from high-income countries such as Germany and Austria, offering detailed insights into their symptoms, pregnancy outcomes, and medical histories. Our study meticulously examines the impact of vaccination, reaffirming its crucial role in preventing the elevated risks of stillbirth and early preterm birth. The recruited infected pregnant women primarily originated from obstetrical hospitals, predominantly tertiary care centers. As a result, most cases involved hospitalized and often high-risk individuals. We acknowledge that future studies should include an uninfected group for a comprehensive comparison. Additionally, we did not differentiate between spontaneous and medically indicated preterm deliveries, recognizing that both may be influenced by the infection. In the case of stillbirth, we did not categorize by specific causes, considering any delivery involving an unviable fetus as a stillbirth.
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