Pregnancy and SARS-CoV-2 Infection in Germany—the CRONOS Registry

When the COVID-19 pandemic took off in March 2020, the available data from China remained insufficient to estimate the risk of SARS-CoV-2 infection for pregnant women and neonates (1, 2). To be able to counsel and treat pregnant women on the basis of data generated in Germany, the research network of the German Society of Perinatal Medicine (DGPM) initiated the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS). Information on the study is available at www.dgpm-online.org und from the German Clinical Trials Register (DRKS00021208). On the background of case numbers of infections rising once again, we present the initial results of the registry, which has been in existence since 3 April 2020.

Method

All German maternity hospitals were invited to participate in the CRONOS registry. Obstetricians and neonatologists from 121 German hospitals and from Kepler University Hospital Linz, Austria, accepted this invitation. Ethics approval was obtained (University Hospital Schleswig-Holstein (UKSH) in Kiel, file number D 451/20). A reporting form was developed using the cloud-based electronic data capture platform of the service provider castoredc.com (Amsterdam, Netherlands). Women with confirmed SARS-CoV-2 infection during pregnancy were included. In addition to COVID-19 specific symptoms and treatments, pregnancy and birth specific events and neonatal outcomes were documented. The data were entered by each treating hospital. After patients had given informed consent, the further course of the pregnancy, the postpartum period, and the neonatal period were observed up to six week post partum. The data presented here were retrieved up to 1 October 2020. We used the software package Prism 8.3.0 (GraphPad Software, San Diego, USA) for our statistical analysis.

Results

98 of the 122 hospitals participated actively in the registry. These hospitals provided care during the preceding year for 185 787 patients, and thus >20% of births in Germany. Between 3 April 2020 and 1 October 2020, 247 cases were registered by 65 hospitals. The affected pregnant women were mostly (71%) younger than 35 and mostly (79%) had a body mass index (BMI) <30 kg/m². 38% of women were going through their first pregnancy. An underlying medical condition requiring long term medical treatment was documented in 11.8% of pregnant women. Important parameters of mother and child regarding SARS-CoV-2 infection and outcomes are shown in the Table 1. 14 (5.6%) women were treated in intensive care for COVID-19. Most of these patients did not have any particular risk factors. Five patients were either obese, presented with hypertension, or had a combination of these risk factors. 10 of the 14 women were infected during their third trimester. In 9 out of 14 cases, the SARS-CoV-2 infection affected the decision to affected the decision to deliver or the mode of delivery. 205 women have since recovered from SARS-CoV-2 infection. 185 have given birth. Four neonates (2.2%) tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) on their first or second day of life; all were discharged into their home environment. A follow-up survey after the neonatal period in 56 families did not yield any case of neonatal infection.

Table. Characteristics and outcomes of mothers and babies infected with SARS-CoV-2.

Variable	n	%	[95% CI]
Week of gestation when testing positive for SARS-CoV-2
< 22 + 0 22 + 0 to 27 + 6 28 + 0 to 31 + 6 32 + 0 to 36 + 6 ≥ 37 + 0 Not available	54 26 25 51 83 8	21.9 10.5 10.1 20.6 33.6 3.2	[17.2; 27.4] [7.3; 15.0] [7.0; 14.5] [16.1; 26.1] [28.0; 39.7] [1.7; 6.3]
Symptoms
None Cough Malaise, chills Fatigue Loss of or change to sense of smell or taste Temperature > 38 °C Sore throat Nasal congestion Headache Dyspnea Myalgia Chest pain Productive cough Diarrhea Nausea, vomiting Dizziness, drowsiness Not available	91 93 83 68 66 61 60 55 48 43 42 23 22 14 12 12 2	36.8 37.7 33.6 27.5 26.7 24.7 24.3 22.3 19.4 17.4 17.0 9.3 8.9 5.7 4.9 4.9 0.8	[31.1; 43.0] [31.8; 43.8] [28.0; 39.7] [22.3; 33.4] [21.6; 32.6] [19.7; 30.4] [19.4; 30.0] [17.5; 27.9] [15.0; 24.8] [13.2; 22.6] [12.8; 22.2] [6.3; 13.6] [6.0; 13.1] [3.4; 9.3] [2.8; 8.3] [2.8; 8.3] [0.1; 2.9]
Outcomes in pregnant women regarding SARS-CoV-2/COVID-19
Currently recovered Inpatient admission Of which intensive care (ICU) Of which invasively ventilated Of which critical (ECMO, etc) Of which deceased Ongoing or lost to follow-up	205 34 14 5 5 1 40	83.0 13.8 5.7 2.0 2.0 0.4 16.2	[77.8; 87.2] [10.0; 18.6] [3.4; 9.3] [0.9; 4.7] [0.9; 4.7] [0.0; 2.3] [12.1; 21.3]
Obstetric pregnancy outcome
Completed pregnancies Delivery of liveborn baby Delivery of stillborn baby Termination of pregnancy Ongoing or lost to follow-up	189 183 2 4 58	76.5 74.1 0.8 1.6 23.5	[70.9; 81.4] [68.3; 79.2] [0.1; 2.9] [0.6; 4.1] [18.6; 29.1]
Gestational age of liveborn babies (in weeks + days)*
22 + 0 to 27 + 6 28 + 0 to 31 + 6 32 + 0 to 36 + 6 ≥ 37 + 0 Not available	0 2 23 158 3	0.0 1.1 12.4 84.9 1.6	[0.0; 2.0] [0.2; 3.8] [8.4; 17.9] [79.1; 89.4] [0.4; 4.6]
Mode of delivery*
Spontaneous vaginal delivery Operative vaginal delivery Primary cesarean section Secondary cesarean section Emergency cesarean section Not available	94 11 44 29 2 3	51.4 6.0 24.0 15.8 1.1 1.6	[44.0; 59.0] [3.4; 10.0] [18.0; 31.0] [11.0; 22.0] [0.2; 3.9] [0.4; 4.7]
Neonatal outcome*
Referral to neonatal intensive care unit (NICU) CPAP non-invasive ventilation Intubation / invasive ventilation SARS-CoV-2-PCR positive	25 7 2 4	13.4 3.8 1.1 2.2	[9.3; 19.1] [1.8; 7.6] [0.2; 3.8] [0.8; 5.4]

The rates refer to the entire CRONOS cohort and (*) live births, respectively.

CPAP, continuous positive airway pressure; ECMO, extracorporeal membrane oxygenation;

ICU, intensive care unit; CI, confidence interval; NICU, neonatal intensive care unit;

PCR, polymerase chain reaction

Discussion

The CRONOS registry data imply a mostly favorable course of SARS-CoV-2 infection in those pregnant women in Germany who were included in the study. The high rate of asymptomatic patients in the CRONOS registry can be explained by the introduction of comprehensive screening in hospitals (3) and is reflected in the positive outcomes. That said, in the group under study, rates of premature births and cesarean deliveries seemed slightly higher than the German average in previous years—but lower than is reflected in international data (4). Although intrauterine transmission of the virus with neuronal involvement of the neonate has been reported recently (5), such an event seems very rare.

A limitation of this study is the fact that no conclusions can be drawn on the actual prevalence in pregnant women in Germany because of the cohort study design. Similarly, owing to the currently low case numbers, no final conclusions can be drawn regarding risk factors for severe maternal courses and neonatal infections. However, known risk factors such as diabetes, hypertension, and obesity should prompt special attention, especially in infections occurring during the third trimester. The CRONOS data provide important information for counseling and caring for pregnant women and their newborns. Further hospitals have been invited to participate, with the aim of documenting all SARS-CoV-2 positive pregnant women in the population of Germany.

CRONOS Network

Ulrich Pecks, Lars Mense, Bettina Kuschel, Peter Oppelt, Mario Rüdiger on behalf of the CRONOS network: Alexander Hein, Angela Lihs, Anja Leonhardt, Anke Reitter, Ann Carolin Longardt, Antonella Iannaccone, Asimina Kartsiouni, Babett Ramsauer, Barbara Filsinger, Bastian Riebe, Carla Maier, Carsten Hagenbeck, Carsten Lehment, Cathleen Heinemann, Charlotte Rohlwink, Christian Schindlbeck, Christine Morfeld, Christoph Scholz, Claudia Lässer, Claudia Roll, Constantin von Kaisenberg, Corinna Keil, Cosmin Paul Sarac, Dietmar Schlembach, Edith Reuschel, Elisa Mendez Martorell, Elsa Hollatz Galuschki, Franz Edler von Koch, Georgi Popivanov, Gunnar Schwennicke, Hendrik Veldink, Ines Erhardt, Ioannis Kyvernitakis, Iris Dressler-Steinbach, Irmgard Drost, Jacqueline Lammert, Janine Zöllkau, Jeannette Teeuwen-Mutter, Johannes Stubert, Katharina Weizsäcker, Katrina Kraft, Kerstin Regner, Kerstin Spranger, Lars Hellmeyer, Lisa Kaup, Loredana Delle Chiaie, Maike Manz, Marek Struck, Maria Delius, Markus Schmidt, Martin Berghäuser, Michael Abou-Dakn, Michael K. Bohlmann, Mirjam Kunze, Monika Palz-Fleige, Nadine Mand, Nadja Hirschfeld, Nina Axnick, Norman Doehring, Olaf Parchmann, Parnian Parvanta, Peter Jakubowski, Ralf Schild, Rolf F. Maier, Sabine Enengl, Sarah Fill Malfertheiner, Sebastian Häusler, Silvia Lobmaier, Sönke Ebert, Sven Seeger, Tamina Rawnaq, Tamme Goecke, Tanja Groten, Tanja Ruebelmann, Thomas Kolben, Ulrich Henning, Ute Schäfer-Graf, Uwe Herwig, Vanessa Hepp, Verena Bossung, Vincent Winkler, Zoltan Takacs, and others.