SARS-CoV-2 Infection During Pregnancy

An Analysis of Clinical Data From Germany and Austria From the CRONOS Registry

Background: Using data from the German CRONOS registry, we assessed the risk of a complicated course of COVID-19 in women with a SARS-CoV-2-infection during pregnancy, with particular consideration of gestational age, vaccination status, and pandemic dynamics.

Methods: Data acquired in two separate periods (March 2020 to August 2021; January to June 2022) for CRONOS, a prospective, hospital-based observational study (DRKS00021208), were studied with logistic regression models. Odds ratios comparing 32 with 22 weeks of gestation were calculated for relevant COVID-19-specific events occurring within 4 weeks of a positive test result.

Results: Data from 3481 women were evaluated. The risk of all of the defined COVID-19-specific events was low among women who became ill with COVID-19 during the first trimester and rose with increasing gestational age into the early third trimester. For example, the odds ratio for hospitalization because of a COVID-19 infection, comparing 32 versus 22 weeks of gestation, was 1.4 (95% confidence interval [1.2; 1.7]). This risk was lower in the second period of data acquisition than in the first (OR 0.66; 95% CI [0.50; 0.88]), and it was even lower if the pregnant patient had been vaccinated against COVID-19 (OR 0.27; 95% CI [0.18; 0.41]).

Conclusion: These findings can serve as a basis for counseling about prophylactic or therapeutic measures, such as the administration of monoclonal antibodies. They underscore the efficacy of vaccination for pregnant women even during the omicron phase of the pandemic.

COVID-19 is rarely severe in women of reproductive age. In pregnancy, however, infection with SARS-CoV-2 can lead to complications (1) and even to premature birth or stillbirth (2, 3). Starting in April 2020, the hospital-based registry CRONOS (COVID-19 Related Obstetric and Neonatal Outcome Study in Germany) of the German Society of Perinatal Medicine (Deutsche Gesellschaft für Perinatale Medizin, DGPM) records the data of women who test positive for SARS-CoV-2 during gestation (4), with the aim of improving our knowledge of the effects of infection with the virus on the pregnancy. Extracts of the information gained from CRONOS are published weekly (in German) at www.dgpm-online.org and used in the formulation of recommendations and guidelines on the care of pregnant women and their newborn children (5, 6, 7, 8).

This article answers questions as to how COVID-19 influences maternal and perinatal outcomes with regard to gestational age and the role played by the omicron variant of SARS-CoV-2 compared with earlier variants and in relation to vaccination status.

To this end, we analyzed the COVID-19-specific events experienced by pregnant women with COVID-19 within 4 weeks of the diagnosis of SARS-CoV-2 infection during two data collection periods. Period 1 included women whose infections occurred prior to 24 August 2021 (the period up to the first occurrence of the delta variant [9] and before the publication on 17 September 2021 of a general recommendation that pregnant women in Germany should be vaccinated [8]). Period 2 included data from women with infection detected between 17 January 2022 and 16 June 2022 (a period of > 95% omicron dominance [9]).

Method

CRONOS is a multicenter prospective observational study with data from 130 actively recruiting hospitals in Germany and Austria (as of 16 June 2022). The women included were those with acute or previous SARS-CoV-2 infection during pregnancy who, regardless of indication, were cared for in one of the participating obstetric departments. The study was approved by the ethics committees of the study center (UKSH Kiel, AZ: D 451/20) and the participating hospitals. Information about CRONOS has been published at the website www.dgpm-online.org and in the German Clinical Trials Registry (DRKS00021208). The registry’s methodology has been described elsewhere (4, 10, 11, 12). The data set from period 1 was analyzed with regard to the occurrence of unfavorable events depending on gestational age at the time of symptomatic infection (COVID-19). The impact of the omicron variant was estimated by comparing the data from period 1 with the data already available from period 2. To ensure comparability of the two periods, taking into account a considerable number of women not recruted timely to infection and with still ongoing pregnancy in period 2 we selected from both datasets patients who contracted COVID-19 after at least 22 weeks of gestation and came into contact with the hospital (as either outpatients or inpatients) within 4 weeks after infection. The evaluation was restricted to maternal COVID-19-related events.

The following maternal COVID-19-related events were defined:

• Hospital admission due to COVID-19 within 4 weeks after infection
• Pneumonia, defined by the findings of clinical examination or the need for oxygen therapy
• Intensive monitoring, invasive ventilation, or death of the pregnant woman
• Iatrogenic delivery due to COVID-19 within 4 weeks after infection

In addition, the following perinatal events were defined for period 1:

• The ending of pregnancy (miscarriage or premature birth at gestational age [GA] < 37 + 0 weeks) within 4 weeks after infection
• Delivery within 4 weeks after infection followed by transfer of the child to a neonatal intensive care unit (NICU) or by antenatal or postnatal death of the child

The findings were evaluated by means of logistic regression models and calculation of odds ratios to compare diagnosis of infection at GA 32 weeks versus 22 weeks, taking into account potential confounders such as maternal age, body mass index (BMI), comorbidities, and vaccination status.

Detailed description of the analysis strategy, the reason for building odds ratios, data processing, the exclusion criteria, and the rationale for exclusion of women with asymptomatic infections from model analyses can be found in the “Method,” “Prevention of bias,” and “Statistics” sections of the eMethods together with eTables 1 and 2 and eFigures 1–3.

eTable 1

Selected maternal characteristics and outcome parameters for pregnancy and SARS-CoV-2 infection in 2528 women from data collection period 1, comparing COVID-19 with asymptomatic infection

eFigure 1

Flowchart of the processing of the data from period 1, showing the underlying inclusion and exclusion criteria

eFigure 2

The number of SARS-CoV-2-positive pregnant women in the cohort from data collection period 1 by gestational age in weeks at the time of the positive test result

eFigure 3

Flowchart of the data selection, showing the underlying inclusion and exclusion criteria, for the comparison of periods 1 and 2 taking account of vaccination status

eTable 2

Selected perinatal and newborn characteristics and outcome parameters for 2161 women from data collection period 1, comparing COVID-19 with asymptomatic infection

Influence of gestational age at infection on the maternal and perinatal outcome

Data on 1827 cases of COVID-19 from period 1 were used for modeling. Of these women, 1773 (97%) were unvaccinated, while the vaccination status of the remaining 54 women (3%) was unknown. At the time of data extraction, pregnancy outcome and perinatal outcome data of 1497 women (82.0%) were available. The maternal and perinatal characteristics, together with the 701 asymptomatic women included in period 1, are described in the eMethods and listed in eTables 1 and 2.

Results

Maternal COVID-19-related outcomes in period 1

Seven hundred thirty-eight women (40.4%) were admitted to the hospital within 4 weeks after a positive test result, 318 (17.4%) of them due to COVID-19. The risk of admission due to COVID-19 rose from 5% (95% confidence interval [3; 10]) in the first trimester to around 22% [17; 26] in the early third trimester. Women diagnosed at GA 30 weeks had the highest risk (Figure 1a, Table 1). The risk of COVID-19 pneumonia went up from < 2% [1; 6] at GA 12 weeks to around 14% [11; 18] in the early third trimester. The highest risk was for women diagnosed at GA 30 weeks (Figure 1b, Table 1). The risk of transfer to an intensive care unit (ICU) or of invasive ventilation (IV) rose from < 0.3% (ICU; [0; 3]) and < 0.1% (IV; [0; 3]) respectively in the first trimester to around 7% [5; 11] for ICU (Figure 1c, Table 1) and around 4% [2; 8] for IV in the early third trimester, with the highest risk at GA 29 weeks (Figure 1d, Table 1). The odds ratios for all comparisons of the results at GA 32 versus 22 weeks are shown in Table 1. The probability of a pregnancy ending within 4 weeks after a positive COVID-19 test result rose between the early second trimester and the early third trimester, reaching 4% at GA 32 weeks (Figure 1e, Table 1). Besides increasing GA, higher BMI before pregnancy and higher maternal age have unfavorable effects on the outcome (Table 1). Four patients died, three of whom had become infected in the early third trimester (GA 29–30 weeks).

Figure 1

The probability of different COVID-19-related events after a positive SARS-CoV-2 test result at defined gestational ages among the group of 1827 patients with COVID-19 from period 1

Table 1

The risk of unfavorable COVID-19-related maternal and perinatal events

Perinatal outcomes in data collection period 1

Among the 1497 women with a documented outcome of pregnancy, 17 had a miscarriage before GA 24 weeks and 218 gave birth prematurely (GA 24 + 0 to 36 + 6 weeks). The proportion of the 1179 women with a positive COVID-19 test result before GA 37 + 0 was 18.5%. Eighteen pregnancies (1.2%) ended in a stillbirth; two of these children had lethal chromosomal anomalies. Four live-born children died of various causes during the postnatal period. The risk of experiencing miscarriage or premature birth within 4 weeks after a positive test result rose from < 2% for infection in the first trimester to around 11% in the early third trimester and > 16% at GA 31 weeks (Figure 2a, Table 1). In 602 (40.2%) of the 1497 women, pregnancy ended within 4 weeks of diagnosis of infection. The risk of delivery within 4 weeks followed by transfer of the child to a NICU or death of the child before or after birth increased from around 6% [4; 9] for infection at GA 22 weeks to around 12% [9; 15] at 32 weeks and stayed at that level up to the calculated delivery date (Figure 2b, Table 1). The odds ratios for comparisons of the risk at GA 32 versus 22 weeks are shown in Table 1. Other risk factors were higher BMI, higher maternal age, and pre-existing maternal diabetes (Table 1).

Figure 2

The probability of a perinatal event of a perinatal event after a positive SARS-CoV-2 test result at defined gestational ages among the group of 1497 symptomatic patients from period 1

Comparison of COVID-19-specific outcomes in data collection periods 1 and 2

During the 18 months of period 1, 953 women became ill with COVID-19 in or after the 22nd week of gestation and contacted a hospital within 4 weeks after infection; the corresponding figure for the 6 months of period 2 was 969 women (eFigure 3). While none of the women whose data were captured in period 1 had received vaccinations against COVID-19, 506 (51.2%) of those in period 2 were vaccinated (missing data in 75 cases). The proportion of pregnant women hospitalized for treatment of COVID-19 in period 2 was around a quarter less than in period 1. Moreover, fewer women had pneumonia, needed intensive care or invasive ventilation, or had mandatory delivery due to COVID-19 (Table 2). There were no deaths among the women from period 2. Comparison of vaccinated and unvaccinated women from period 2 showed that the former had lower rates of hospitalization and pneumonia and were less likely to undergo delivery due to COVID-19 (Table 2). The odds ratio of delivery because of COVID-19 between vaccinated and unvaccinated women was 0.30 ([0.10; 0.84]; p = 0.02) (Table 3). There was no difference between the rates—very low in both groups—of intensive care treatment or invasive ventilation (Table 2). The odds ratios for comparisons of other outcomes between unvaccinated and vaccinated women from periods 1 and 2 can be found in Table 3.

Table 2

The frequency of relevant COVID-19-specific events in period 1 and period 2 among women who became ill with COVID-19 after GA22 weeks and were entered in the registry via contact with a recruiting hospital within 4 weeks after infection

Table 3

The risk of relevant defined outcomes, calculated from the data of women who in data collection period 1 and data collection period 2 became ill with COVID-19 after GA 22 weeks and were entered in the registry via contact with a recruiting hospital within 4 weeks after infection

Discussion

Pregnant women constitute a group of patients that require particular consideration in the COVID-19 pandemic. Medications for COVID-19 have mostly not been tested in pregnancy, and great care must be taken to ensure they are indicated (6, 13), taking account of the actual COVID-19-specific risk. The study reported here, conducted at hospitals in Germany and at Linz, Austria, enables assessment of the risk of severe COVID-19 depending on the GA at the time of infection, the virus variant involved, and the woman’s vaccination status. For unvaccinated pregnant women with COVID-19, the risk of hospitalization and transfer to an ICU rises with increasing GA at the time of infection with SARS-CoV-2. In period 1, one of every five women infected at GA 30 weeks was hospitalized and one in 15 received intensive care treatment. The 4.0% rate of transfer to ICU among all women observed in the pre-omicron phase of the pandemic corresponds with findings from other countries. In a study of 2352 women with a positive SARS-CoV-2 test result from 17 hospitals in the USA, Metz et al. found a 3.7% rate of maternal transfer to ICU (14). In a Scottish prospective cohort study, 2.1% of 4950 women with confirmed SARS-CoV-2 infection had to be transferred to ICU. None of the women infected in the first trimester of pregnancy were involved, but 4.3% of those in the third trimester (15). Furthermore, modeling of the CRONOS data shows that the rate of ICU treatment goes down again for women infected later than GA 30 weeks. The reason for this may be that as fetal maturity increases, obstetricians are more generous in offering birth in severe COVID-19. One can theorize, with great caution, that delivery has a positive effect on the severity of COVID-19, for example through optimization of treatment options (e.g., the possibility of prone positioning of women on ventilation) (12). A noticeable consequence of these iatrogenic deliveries is an increasing proportion of premature births. In comparison with women not infected with SARS-CoV-2, Metz et al. describe a 3.7% higher rate of premature birth (14). In our sample, one in every seven women delivered prematurely—a rate somewhat lower than that stated by Metz et al. (17.7%) and slightly higher than found by Stock et al. (10.2%). The Scottish study showed an elevated rate of perinatal mortality (stillbirth or neonatal death), namely 8 per 1000 births versus the background rate of 5.6 per 1000 for all births during the same period. Stock et al. also evaluated in isolation the extended perinatal mortality among 5766 vaccinated women, finding a lower rate of 4.3 per 1000 births (15). However, their study also documented a lower vaccination rate in pregnant women: in October 2021, 32.3% of pregnant women were fully vaccinated compared with 77.4% for non-pregnant women of the same age. The finding that acceptance of vaccination is not high among pregnant women coincides with our own experience (16) and the results of the present study. In the 6 months of period 2, covering the omicron phase of the pandemic, almost half of the women in the CRONOS Registry were unvaccinated. Although the observed rate of severe illness in the omicron phase is very low, a protective effect of vaccination can be inferred from the data. With reference to the existing evidence on the safety of mRNA vaccines in pregnancy (8, 17, 18), the results presented here can be put to good use in informing pregnant women about the risks posed by infection of the unvaccinated.

This study evaluated data from 130 departments of obstetrics at hospitals providing different levels of care. Around one third of all births in Germany take place in these institutions. Almost all pregnant women in Germany sooner or later attend a hospital. Despite this distinct strength, the study also features limitations. Although complete documentation including the status of women after infection in early pregnancy is possible, it cannot be guaranteed for various reasons (e.g., bias in invitation for follow-up visits or in study inclusion). Furthermore, the number of undetected infections with SARS-CoV-2 among women in the early weeks of pregnancy is particularly high. Overestimation of the proportion of severe cases from the first trimester to the beginning of the third trimester can therefore be assumed and may explain the observed relative reduction in severe illness at the end of pregnancy. Asymptomatic cases are very often detected when the women concerned attend a hospital due to (pre-existing) complications of pregnancy or to give birth. In the early weeks of pregnancy these “incidental COVIDs” contribute to an elevation of the premature birth rate with COVID-19, not because of COVID-19. Owing to the over-representation in late pregnancy, however, asymptomatic women still distort the results regarding GA-related events even at this time. To counteract this bias, our study focused on COVID-19 patients who displayed symptoms. The core messages of the study, especially the elevated relative risk for women with COVID-19 as pregnancy progresses, can thus be considered valid. The quality of the data was guaranteed by monitoring, weekly assessment, and close communication with the individual hospitals regarding the documentation of severe events (serious maternal illness, death of child, infection of child).

Conclusion

Advanced pregnancy (GA > 22 weeks) at the time of infection, together with high BMI and high maternal age, is a major risk factor for a severe course of COVID-19. The virus variant also plays a part: in the omicron phase of the pandemic there were fewer cases of severe illness in pregnant women than was the case with earlier variants. In addition to the less virulent variant, accumulated experience in managing the disease and improved treatment strategies may have played a role. Furthermore, vaccinated women less often need COVID-19-related inpatient treatment or are delivered because of COVID-19 than unvaccinated women. The data underscore the recommendation of the German Standing Commission on Vaccination (STIKO) that pregnant women should (from the second trimester) be vaccinated against COVID-19 (8).

The data presented here may support physicians in their attempts to increase acceptance of vaccination for pregnant women or when considering drug treatments such as administration of monoclonal antibodies (13). Given the uncertainty regarding new variants of the virus and the possible occurrence of new waves of COVID-19 in fall 2022, the coming weeks and months should be used not only to offer vaccinations to women of reproductive age but also to make sure they understand the risks involved in contracting a SARS-CoV-2 infection in pregnancy, with considerable consequences for the unborn child.

The CRONOS Registry shows the feasibility of representative documentation of data from selected groups in Germany under the direction of professional associations. Continuation of this established registry infrastructure, also between pandemic phases, will—provided adequate funding of data acquisition and analysis is forthcoming—be of considerable medical benefit in the care of women who are pregnant, have recently given birth, or are breastfeeding (7). The membership of the CRONOS Network is shown in the eBox.

eBox

CRONOS Network

Conflict of interest statement
Prof. Pecks has received funding for parts of the CRONOS project from the Krumme Foundation (F379155) and the state of Schleswig-Holstein (K128002). Prof. Pecks has received fees for lectures on the topic of this article from Roche Diagnostics and Jenapharm. Prof. Pecks is research officer and board member of the German Society of Perinatal Medicine (Deutsche Gesellschaft für Perinatale Medizin, DGPM) and in this capacity manages the CRONOS Registry.

Prof. Rüdiger is an unpaid member of the board of the DGPM.

The remaining authors declare that no conflict of interest exists.

Manuscript received on 9 March 2022, revised version accepted on 30 June 2022

Translated from the original German by David Roseveare.

Corresponding author
Prof. Dr. med. Ulrich Pecks
Klinik für Gynäkologie und Geburtshilfe
Universitätsklinikum Schleswig-Holstein Campus Kiel
Arnold-Heller-Str. 3, 24105 Kiel, Germany

Cite this as
Pecks U, Mand N, Kolben T, Rüdiger M, Oppelt P, Zöllkau J, Dempfle A for the CRONOS Network: SARS-CoV-2 infection during pregnancy—an analysis of clinical data from Germany and Austria from the CRONOS Registry. Dtsch Arztebl Int 2022; 119: 588–94. DOI: 10.3238/arztebl.m2022.0266

►Supplementary material

eReferences, eMethods, eTables, eFigures, eBox:
www.aerzteblatt-international.de/m2022.0266

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