Vaccine Effectiveness in SARS-CoV-2-Infected Pregnant Women with Gestational Diabetes Mellitus: Results from a Multicenter Registry-Based Prospective Cohort Study in Germany

Abstract

Introduction COVID-19 in pregnancy is associated with increased maternal and neonatal morbidity and mortality. The aim of our study was to investigate the effectiveness of COVID-19 vaccination in SARS-CoV-2-infected pregnant women with focus on women with gestational diabetes mellitus on pregnancy outcomes.

Patients and Methods COVID-19 Obstetric and Neonatal Outcome study is a multicenter prospective observational study which registered SARS-CoV-2-infected pregnant women from April 2020 to December 2022. In March 2021, the study was complemented by the SATELLITES study which recruited vaccinated women until September 2023. Primary composite maternal and neonatal endpoints were defined. Multivariate adjusted logistic regression analysis was performed to evaluate the impact of vaccination on pregnancy outcomes. Vaccine effectiveness was defined as (1-adjusted odds ratio)*100.

Results We registered 10 386 pregnant women, 6112 of whom were analyzed. 30% of women were vaccinated against COVID-19. Vaccination in women with gestational diabetes mellitus was associated with a vaccine effectiveness of 75% (95% CI: 16 – 93), depending on the predominant virus variant, and of 67% in the total cohort (95% CI: 36 – 83). No statistically significant difference was found in vaccine effectiveness with regards to perinatal outcomes of women with gestational diabetes mellitus (16%; 95% CI −58 – 55) but there was an impact in the total cohort (26%; 95% CI 8 – 94).

Conclusion For pregnant women with gestational diabetes mellitus who were infected with SARS-CoV-2, at least one vaccination against COVID-19 before or during pregnancy was independently associated with a milder course of COVID-19 in mothers compared to no vaccination. We found no evidence of improved perinatal outcomes. The data emphasize the benefits of vaccination before or during pregnancy.

Zusammenfassung

Einleitung Eine COVID-19-Erkrankung in der Schwangerschaft ist mit höherer mütterlicher und fetaler Morbidität und Mortalität verbunden. Ziel dieser Studie war es, die Wirksamkeit einer COVID-19-Impfung bei mit SARS-CoV-2 infizierten schwangeren Frauen zu untersuchen mit besonderem Augenmerk auf die Schwangerschaft-Outcomes von Frauen mit Gestationsdiabetes.

Patientinnen und Methoden Die COVID-19 Obstetric and Neonatal Outcome Studie ist eine multizentrische prospektive Beobachtungsstudie, die von April 2020 bis Dezember 2022 mit COVID-19 infizierte schwangere Frauen registrierte. Im März 2021 wurde die Studie durch die SATELLITES-Studie ergänzt, die geimpfte Frauen bis September 2023 rekrutierte. Die primären zusammengefassten mütterlichen und neonatalen Endpunkten wurden definiert. Es wurde eine multivariate logistische Regressionsanalyse durchgeführt, um die Auswirkungen von Impfungen auf das Schwangerschafts-Outcome zu evaluieren. Die Imfpstoffwirksamkeit wurde als (1-adjusted Odds Ratio)*100 definiert.

Ergebnisse Insgesamt wurden 10 386 schwangere Frauen registriert, davon wurden 6112 in die Analyse eingeschlossen; 30% der Frauen waren gegen COVID-19 geimpft. Je nach vorherrschender Virusvariante betrug die Impfstoffwirksamkeit hinsichtlich des zusammengefassten mütterlichen Endpunkts 75% (95%-KI 16 – 93) bei Frauen mit Gestationsdiabetes und 67% (95%-KI 36 – 83) für die Gesamtkohorte. Hinsichtlich des perinatalen Outcomes gab es keinen statistisch signifikanten Unterschied zwischen geimpften und ungeimpften Frauen mit Gestationsdiabetes (16%; 95%-KI −58 – 55), wohl aber in der Gesamtkohorte (26%; 95%-KI 8 – 94).

Schlussfolgerung Bei schwangeren Frauen mit Gestationsdiabetes, die mit SARS-CoV-2 infiziert wurden, zeigte sich, dass mindestens eine Impfung gegen COVID-19 vor oder während der Schwangerschaft mit einem milderen Verlauf der COVID-19 Erkrankung assoziiert war, verglichen mit Frauen, die keine Impfung erhalten hatten. Es gab keine Hinweise auf ein besseres perinatales Outcome. Diese Daten unterstreichen die Vorteile einer Impfung vor oder während der Schwangerschaft.

Keywords

diabetes - SARS-CoV-2 - pregnancy - vaccination - impaired glucose tolerance

Schlüsselwörter

Diabetes - SARS-CoV-2 - Schwangerschaft - Impfung - Glukosetoleranzstörung

Introduction

Pregnancy, alongside pre-existing comorbidities such as diabetes, obesity, chronic respiratory or cardiovascular disease, is an independent risk factor for a severe course of COVID-19 [1]. During pregnancy, COVID-19 is associated with more admissions to an intensive care unit (ICU) and increased maternal and perinatal morbidity and mortality [2].

Virus transmission and disease progression changed over the five years of the global circulation of SARS-CoV-2. This is due to SARS-CoV-2 and its mutant variants which led to increased population immunity through SARS-CoV-2 infection and the rising availability of vaccines, the use of pharmacotherapy in the early stages of infection, and improvements in clinical care [3].

Vaccination against COVID-19 in pregnant women is effective in reducing the frequency of SARS-CoV-2 infection during pregnancy, leads to a less severe course of the disease, and decreases COVID-19 related adverse pregnancy outcomes [4]. Antenatal mRNA vaccination was not associated with an increased risk of pregnancy complications [5].

Gestational diabetes mellitus (GDM) is a common medical complication of pregnancy with a global prevalence of 14%. It is associated with adverse pregnancy outcomes, which depend on oral glucose tolerance test (OGTT) results [6], [7], [8], time of screening [9], and metabolic control until delivery [10]. We have previously reported that among non-vaccinated pregnant women with COVID-19, GDM, particularly in combination with periconceptional overweight and ongoing insulin therapy, was associated with adverse maternal outcomes [11]. We were also able to demonstrate that pregnancies of women with GDM and low vaccination rate against COVID-19 had worse perinatal outcomes compared to pregnant women with GDM before the pandemic [12].

It is unclear to what extent SARS-CoV-2-infected pregnant women with GDM benefit from vaccination. For the current study, data from nationwide German registries, the “COVID-19-Related Obstetric and Neonatal Outcome Study (CRONOS)” and the “CRONOS SATELLITES” study on infected pregnant women were combined. The aim of our current study was to evaluate the effect of COVID-19 vaccination before or during pregnancy on severe maternal and perinatal outcomes with focus on women with GDM.

Methods

CRONOS is a multicenter registry-based prospective observational study initiated by the German Society of Perinatal Medicine. It collects data from vaccinated and non-vaccinated inpatient pregnant women with confirmed SARS-CoV-2 infection or COVID-19. The methodology has been described elsewhere [13]. CRONOS SATELLITES was implemented following approval of COVID-19 vaccines in March 2021 and collected additional data from inpatient pregnant women vaccinated during pregnancy, either infected or not infected. Ethics approval was obtained from University Hospital Schleswig-Holstein, Kiel (D 451/20) on March 31, 2020 (CRONOS) and amended for vaccination (SATELLITES) on February 17, 2021.

This study is in accordance with the STROBE statement for cohort studies.

Data management

All women were prospectively enrolled at first presentation to a maternity hospital after informed consent was obtained or waived post partum if the woman was admitted in a critical condition. Basic maternal data and pregnancy outcome data were recorded cloud-based from every participating institution [13]. Frequent data monitoring was carried out by the central study center.

Study cohort

CRONOS collected data on a total of 8766 cases from April 2020 to December 2022; SATELLITES collected data from a total of 1620 cases from March 2021 to September 2023. Caregivers from 130 hospitals provided data. Double entries, implausible values, and cases with missing variables for any outcome parameters or confounders were removed. Both registries were stratified by vaccination status (vaccinated vs. non-vaccinated). For the present analysis only data from women with SARS-CoV-2 infection during pregnancy from both registries were considered. The merged data set consisted of 6112 infected pregnant women. Composite primary maternal and neonatal endpoints were defined. The final study cohort was composed of 593 and 6099 individuals for maternal endpoint analysis in the GDM cohort and the total cohort, respectively, and of 582 and 5950 participants for neonatal endpoint analysis in the GDM cohort and total cohort, respectively ([Fig. 1]).

Fig. 1 Flowchart showing the CRONOS and SATELLITES participants eligible for analysis. CRONOS, COVID-19-Related Obstetric and Neonatal Outcome Study; GDM, gestational diabetes mellitus.

Definition of GDM and GDM therapy

GDM was defined according to the International Diabetes in Pregnancy Study Groups criteria [14]. In Germany, a 2-step approach is required [15]. First, a 50-gram non-fasting 1-hour glucose screen is performed between 24 – 28 weeks of pregnancy. Women with a test result ≥ 135 mg/dL complete a fasting 75-gram OGTT. GDM is confirmed if any of the following venous plasma glucose values are met or exceeded: fasting 92 mg/dL, 1 hour 180 mg/dL, and 2 hours 153 mg/dL. Additionally, the diagnosis is confirmed without OGTT if the screening plasma glucose exceeds 200 mg/dL. GDM is treated according to German guidelines [15]. Insulin is indicated if basic measures for metabolic control, such as training in medical nutritional therapy and regular exercise at light or moderate intensity are not sufficient, i.e. 50% of intermittently self-monitored capillary blood glucose results within 1 – 2 weeks exceed 95 mg/dL fasting and 140 mg/dL at 1 hour or 120 mg/dL at 2 hours after a main meal. Metformin is not approved for GDM pharmacotherapy in Germany, but it is used off label for cases with severe insulin resistance and more than 1.5 – 2.0 U insulin/kg body weight per day. To detect fetal macrosomia, fetal growth is regularly monitored by ultrasound examination [15].

Treatment protocol of COVID-19

The care and treatment of pregnant women was carried out by local caregivers according to expert recommendations first published in March 2020 [16], updated in June 2020 [17], and finally summarized to the joint German, Austrian, and Swiss COVID-19 guidelines for pregnant women [18].

Definition of virus variants and vaccination status

SARS-CoV-2 infection during pregnancies of women studied refers to lab test-confirmed SARS-CoV-2 infection with or without symptoms. In Germany, the Robert Koch Institute defined dominant virus strains in each phase of the pandemic [19]. Based on the infection date, the pregnant women in the CRONOS registry were assigned dichotomized to pre-Omicron and Omicron periods. The German vaccination program started in January 2021. A woman was considered vaccinated if she had received at least one dose of a COVID-19 vaccine before her SARS-CoV-2 infection.

Outcomes

We conducted analysis comparing outcomes in vaccinated and non-vaccinated women with GDM and in all women independent of their metabolic status (total cohort). A primary composite maternal endpoint was defined as either

1. admission to ICU, including invasive ventilation, extracorporal membrane oxygenation, and death, or

2. need for oxygen supplementation outside the ICU.

A primary composite feto-neonatal endpoint was defined as

1. stillbirth ≥ 24^0/7 weeks of pregnancy,

2. neonatal death ≤ 7 days postnatally,

3. transfer to a neonatal intensive care unit (NICU), and

4. preterm birth < 37^0/7 weeks of gestation, if at least one of these is present.

We pre-specified secondary single maternal endpoints:

1. admission to ICU,

2. invasive ventilation,

3. need for oxygen supplementation outside the ICU,

4. virus-associated pneumonia,

5. caesarean delivery, and

6. death.

Secondary single feto-neonatal endpoints were defined as

1. stillbirth ≥ 24^0/7 weeks of pregnancy,

2. neonatal death ≤ 7 days postnatally,

3. transfer to a NICU,

4. preterm birth < 37^0/7weeks of pregnancy, and

5. small for gestational age status (< 10 percentile) or birth weight < 2500 g.

Covariates

Body mass index (BMI) was calculated based on maternity health record data at first presentation in pregnancy and used as a dichotomous variable for analysis with a cut-off value of 25 kg/m². Maternal age was recorded at hospital admission. Multiples (yes/no), parity (0/≥1), hypertensive medication (yes/no), and nicotine exposure by active or passive smoking during pregnancy (yes/no) were coded dichotomously. Language competence, i.e. communication possible without problems (yes/no), was used as a surrogate for socioeconomic status [20], [21], [22].

Statistical analysis

Statistical analyses were performed using R (R version 4.2.3 [2023-03-15 ucrt]) and RStudio (2023.12.1 Build 402). Power analysis was done based on previously published ICU admission rates of infected pregnant women with or without vaccination in a Scottish cohort [23] which estimated that 74 participants per group would be sufficient to detect a true difference between vaccinated and non-vaccinated women at a statistical power of 0.9 and a statistical significance of 0.05.

For 2-sided tests, statistical significance was considered at P ≤ 0.05. Group means were compared either using Welchʼs T-tests or Wilcoxon rank-sum tests. For categorical variables, Chi-square tests were conducted and Yateʼs continuity correction was applied when necessary.

Multivariate-adjusted logistic regression models were used to identify associations between vaccination status and the primary composite maternal or neonatal endpoint or the secondary endpoints, respectively. Based on published research data [4], [11], the following adjustments were performed: model 1 for maternal age (years) and BMI category (< 25 kg/m²/≥25 kg/m²), model 2 additionally for multiples (yes/no), parity (0/≥1), and hypertensive medication (yes/no), model 3 additionally for language competence (yes/no) and nicotine exposure during pregnancy (yes/no), model 4 additionally for virus variants (pre-Omicron/Omicron). In the GDM cohort, model 5 was additionally adjusted for insulin therapy (yes/no). Vaccine effectiveness (VE) was defined as VE = (1-adjusted odds ratio [aOR])*100.

Results

The final data set consisted of 6122 SARS-CoV-2-positive pregnant women. The GDM frequency in this group of women was 9.7%. The vaccination rate was 25.6% in the GDM cohort and 29.7% in the total cohort; 84.7% of women received an mRNA vaccine, while 9.4% of women were vaccinated with a non-mRNA vaccine (unknown vaccine type in 5.9% of women). Non-vaccinated compared to vaccinated pregnant women in both cohorts were about two years younger and had a lower language competence. Non-vaccinated women with GDM received their GDM diagnosis one week earlier compared to vaccinated women, and more of them were infected after GDM diagnosis. In both cohorts, medical treatment for COVID-19 was given more often to non-vaccinated women ([Table 1]).

Table 1 Characteristics of the study cohorts according to vaccination status.

	Infected	Infected	P	Infected	Infected	P
	vaccinated	non-vaccinated		vaccinated	non-vaccinated
Data are presented as number (percentage) or mean ± standard deviation, unless otherwise specified. P values indicate the comparison of vaccinated vs. non-vaccinated individuals. Data available for (GDM cohort/total cohort) 1 n = 570/5906 (only CRONOS), 2 n = 571/5914 (only CRONOS: glucocorticoids, antiviral agents, monoclonal antibodies), 3 n = 593/6098, 4 n = 570/5917, 5 n = 593/6094, 6 n = 571/5918, 7 n = 569/5879, 8 n = 592/6093, 9 n = 576/5914, 10 n = 582/5952 (combined from stillbirth and neonatal death), 11 n = 576/5910, 12 n = 544/5493, 13 n = 557/5726, 14 n = 570/5849. a Welchʼs T-test, b Wilcoxon rank-sum test, c Chi-square test, cy Chi-square test with Yates continuity correction. GDM, gestational diabetes mellitus; BMI, body mass index; PCR, polymerase chain reaction; ICU, intensive care unit; NICU, neonatal intensive care unit; SGA, small for gestational age, < 10 percentile; LGA, large for gestational age, > 90 percentile
Maternal data	GDM cohort (n = 593)			Total cohort (n = 6099)
	152 (25.6)	441 (74.4)		1810 (29.7)	4289 (70.3)
Maternal age [years]	33.4 ± 4.3	31.5 ± 5.3	< 0.001a	32.5 ± 4.7	30.6 ± 5.4	< 0.001a
Language competence (yes)	143 (94.1)	372 (84.4)	0.002c	1720 (95)	3622 (84.4)	< 0.001c
Nulliparous (yes)	43 (28.3)	136 (30.8)	0.55c	727 (40.2)	1636 (38.1)	0.14c
Continent of birth
Europe	106 (69.7)	233 (52.8)		1315 (72.7)	2658 (62)
North and South America	2 (1.3)	1 (0.2)		9 (0.5)	19 (0.4)
Africa	3 (2)	29 (6.6)		15 (0.8)	185 (4.3)
Asia	23 (15.1)	134 (30.4)		165 (9.1)	1039 (24.2)
Australia	0 (0)	0 (0)		0 (0)	1 (0)
Unknown	18 (11.8)	44 (10)		306 (16.9)	387 (9)
Active and passive smoking during pregnancy (yes)	12 (7.9)	42 (9.5)	0.55c	126 (7)	436 (10.2)	< 0.001c
Maternal BMI at the beginning of pregnancy [kg/m2]	28.6 ± 7	29.5 ± 6.9	0.15b	25.1 ± 5.5	25.8 ± 5.7	< 0.001b
BMI < 25 kg/m2	56 (36.8)	125 (28.3)	0.049c	1084 (59.9)	2306 (53.8)	< 0.001c
BMI ≥ 25 kg/m2	96 (63.2)	316 (71.7)		726 (40.1)	1983 (46.2)
Hypertensive disorders during pregnancy	23 (15.1)	45 (10.2)	0.10c	120 (6.6)	230 (5.4)	0.05c
Week of gestation of GDM diagnosis	24.7 ± 4.6	25.7 ± 4.4	0.037b
Week of gestation at COVID-19 diagnosis ≤ week of gestation at GDM diagnosis	32 (21.1)	110 (24.9)	< 0.001c
Week of gestation at COVID-19 diagnosis > week of gestation at GDM diagnosis	59 (38.8)	249 (56.5)
Unknown	61 (40.1)	82 (18.6)
GDM with insulin therapy	61 (40.1)	147 (33.3)	0.16c
SARS-CoV-2 assessment tool1	129	441		1623	4283
PCR	111 (86)	394 (89.3)		1323 (81.5)	3825 (89.3)
Antigen	8 (6.2)	14 (3.2)		143 (8.8)	125 (2.9)
Antibody	0 (0)	5 (1.1)		2 (0.1)	34 (0.8)
Test positive, unknown method	10 (7.8)	28 (6.3)		155 (9.6)	299 (7)
COVID-19 medical treatment2			< 0.001cy			< 0.001cy
Yes	9 (5.9)	69 (15.6)		51 (2.8)	473 (11)
No	121 (79.6)	372 (84.4)		1574 (87)	3816 (89)
Unknown	22 (14.5)	0 (0)		185 (10.2)	0 (0)
Virus variants2			< 0.001cy			< 0.001cy
Pre-Omicron	20 (13.2)	322 (73)		173 (9.6)	3299 (76.9)
Omicron	110 (72.4)	119 (27)		1452 (80.2)	990 (23.1)
Unknown	22 (14.5)	0 (0)		185 (10.2)	0 (0)
Any symptoms in CRONOS			< 0.001c			< 0.001c
Yes	112 (73.7)	347 (78.7)		1317 (72.8)	3221 (75.1)
No	11 (7.2)	78 (17.7)		127 (7)	863 (20.1)
Unknown	29 (19.1)	16 (3.6)		366 (20.2)	205 (4.8)
Most commonly reported COVID-19 related symptoms in CRONOS (%)
Cough	73.2	62.2		67.6	60.9
Malaise	51.8	52.4		45	54.6
Fatigue	51.8	45.8		58.5	47.6
Nasal obstructions	48.2	40.9		58.7	40.2
Sore throat	48.2	41.8		55.6	39.4
Headache	50.9	39.8		48	39.9
Myalgia	34.8	42.9		39.3	38.4
Changes in smell and taste	30.4	36.9		25.6	41
Preterm birth (< 370/7 wks)	14 (9.2)	54 (12.2)	0.31c	157 (8.7)	583 (13.6)	< 0.001c
Iatrogenic	7 (4.6)	35 (7.9)	0.24cy	82 (4.5)	360 (19.9)	0.09c
Non-iatrogenic	7 (4.6)	19 (4.3)		71 (3.9)	223 (12.3)
Unknown	1 (0.7)	1 (0.2)		9 (0.5)	12 (0.7)
Composite maternal endpoint	3 (2)	33 (7.5)	0.024cy	12 (0.7)	244 (5.7)	< 0.001c
ICU admission3	1 (0.7)	19 (4.3)	0.06cy	7 (0.4)	140 (3.3)	< 0.001c
Intubation4	0 (0)	9 (2)	0.16cy	2 (0.1)	69 (1.6)	< 0.001cy
Mother deceased5	0 (0)	0 (0)	–	0 (0)	8 (0.2)	< 0.001cy
Oxygen supplementation (not ICU)6	3 (2)	31 (7)	0.07cy	10 (0.6)	229 (5.3)	< 0.001c
Virus-related pneumonia7	2 (1.3)	26 (5.9)	0.038cy	3 (0.2)	184 (4.3)	< 0.001cy
Caesarean delivery8	48 (31.6)	187 (42.4)	0.013c	582 (32.2)	1561 (36.4)	0.002c
Primary	33 (21.7)	106 (24)		320 (17.7)	888 (20.7)
At request of woman	5 (3.3)	20 (4.5)		65 (3.6)	166 (3.9)
Secondary	14 (9.2)	67 (15.2)		243 (13.4)	601 (14)
Emergency	1 (0.7)	14 (3.2)		19 (1)	72 (1.7)
Neonatal data	GDM cohort (n = 582)			Total cohort (n = 5950)
	149 (25.6)	433 (74.4)		1777 (29.9)	4173 (70.1)
Composite neonatal endpoint	22 (14.8)	94 (21.7)	0.06c	218 (12.3)	792 (19)	< 0.001c
Stillbirth ≥ 240/7 wks gestation	3 (2)	3 (0.7)	0.37cy	8 (0.5)	27 (0.6)	0.47cy
Neonatal death within 7 days after live birth9	0 (0)	3 (0.7)	< 0.001cy	0 (0)	9 (0.2)	< 0.001cy
Perinatal mortality10	3 (2)	6 (1.4)	0.88cy	8 (0.5)	36 (0.9)	0.12cy
NICU transfer11	13 (8.7)	70 (16.2)	0.03c	150 (8.4)	569 (13.6)	< 0.001c
Preterm birth (week of gestation < 370/7)	13 (8.7)	53 (12.2)	0.23c	145 (8.2)	539 (12.9)	0.001c
SGA/birth weight < 2500 g12	13 (8.7)	31 (7.2)	0.49c	162 (9.1)	330 (7.9)	0.12c
LGA	19 (12.8)	57 (13.2)	0.95c	173 (9.7)	310 (7.4)	0.003c
Birth weight ≥ 4500 g	2 (1.3)	9 (2.1)	0.84cy	27 (1.5)	44 (1.1)	0.17cy
Apgar 5 < 713	7 (4.7)	30 (6.9)	< 0.001c	51 (2.9)	227 (5.4)	< 0.001c
Umbilical arterial cord pH < 7.114	4 (2.7)	18 (4.2)	0.11b	41 (2.3)	131 (3.1)	0.97b

When compared with vaccinated women, non-vaccinated women had a higher rate of preterm birth and were exposed more often to active or passive smoking. About 75% of SARS-CoV-2-positive women showed symptoms. The majority of vaccinated participants was infected with Omicron variants (80.2%), while pre-Omicron variants were more common in non-vaccinated pregnant women (76.9%, [Table 1]).

The composite maternal endpoint was reached by 0.7% (n = 12) of vaccinated women, of whom three were diagnosed with GDM. In contrast, the composite maternal endpoint was experienced by 5.7% (n = 244) of non-vaccinated women, of whom 33 were diagnosed with GDM. All deceased women had not been vaccinated against COVID-19 and had no GDM.

Newborns of vaccinated women with GDM and of the total cohort, respectively, reached the composite neonatal endpoint less often and were transferred to NICU less frequently. There was no statistically significant difference in stillbirth rates between newborns of vaccinated and non-vaccinated women. However, 0.2% (n = 9) of neonates of non-vaccinated mothers died, of whom three were born to mothers with GDM while there was no neonatal death in the vaccinated group ([Table 1]).

Associations between vaccination and composite endpoints

In the GDM cohort, VE was 75% (95% CI: 16 – 93) in model 3 ([Fig. 2]). However, the association between vaccination status and the composite maternal endpoint was attenuated after further adjustment for virus variants and insulin therapy, resulting in VE of 27% (95% CI: −187 – 81) (model 5, [Fig. 2]). Higher BMI was not independently associated with reduced vaccination probability, aOR: 0.98 (95% CI: 0.44 – 2.17).

Fig. 2 Associations between vaccination status and primary composite endpoints. Odds ratios with 95% CI for the composite maternal endpoint in the GDM (a) and the total cohort (b): (1) admission to intensive care unit (including invasive ventilation and death), (2) need for oxygen supplementation outside intensive care unit and the composite neonatal endpoint in the GDM (c) and the total cohort (d): (1) stillbirth ≥ 24^0/7 weeks of pregnancy, (2) neonatal death ≤ 7 days postnatally, (3) transfer to neonatal intensive care unit, (4) preterm birth < 37^0/7 weeks of gestation. Model 1 adjusted for maternal age (years) and the BMI category (< 25 kg/m²/>25 kg/m²). Model 2 additionally adjusted for multiple birth (yes, no), parity (nulliparous, multiparous), and hypertensive medication (yes, no). Model 3 additionally adjusted for language competence (yes, no) and nicotine exposure during pregnancy (yes, no). Model 4 additionally adjusted for virus variant (pre-Omicron, Omicron). Model 5 in the GDM cohort additionally adjusted for insulin therapy (yes, no). GDM, gestational diabetes mellitus; VE, vaccination effectiveness.

In the total cohort, the odds to reach the composite maternal endpoint were lower for vaccinated compared to non-vaccinated women with a VE of 67% (95% CI: 36 – 83; model 4, [Fig. 2]). Furthermore, in fully adjusted models, women with a BMI ≥ 25 kg/m² had a 25% decreased likelihood of being vaccinated (aOR: 1.25 [95% CI: 1.07 – 1.46], P = 0.004).

Neonates from vaccinated women with GDM experienced statistically non-significant lower odds of adverse perinatal outcomes compared to non-vaccinated women with a VE of 16% (95% CI −58 – 55; model 5, [Fig. 2]). In the total neonatal cohort, newborns of vaccinated women had lower odds for the composite neonatal endpoint compared to non-vaccinated women (model 4, [Fig. 2]), which corresponds to a VE of 26% (95% CI: 8; 40). VE was more pronounced in the maternal compared to the neonatal cohort.

Associations between vaccination status and secondary endpoints

Vaccinated pregnant women with GDM had lower odds for caesarean delivery; however, virus variants affected these results. Furthermore, lower odds for oxygen supplementation and virus-related pneumonia were found only in models adjusted for age and BMI. In fully adjusted models for the total cohort, vaccinated women showed lower odds for virus associated pneumonia, ICU admission, oxygen supplementation, and caesarean delivery compared to non-vaccinated pregnant women ([Table 2]).

Table 2 Associations between vaccination status (vaccinated vs. non-vaccinated) and secondary maternal endpoints.

Maternal secondary endpoints	Adjusted odds ratio [95% CI]	P value
Data are odds ratios with 95% CIs from logistic regression analyses with secondary endpoints (yes/no) as the dependent variable, respectively. Model 1 adjusted for maternal age (years) and the BMI category (< 25 kg/m2/> 25 kg/m2). Model 2 additionally adjusted for multiple birth (yes, no), parity (nulliparous, multiparous), and hypertensive medication (yes, no). Model 3 additionally adjusted for language competence (yes, no) and nicotine exposure during pregnancy (yes, no). Model 4 additionally adjusted for virus variant (pre-Omicron, Omicron). Model 5 in the GDM cohort additionally adjusted for insulin therapy (yes, no). 1 only CRONOS
GDM cohort
Virus associated pneumonia1
Model 1	0.22 [0.05; 0.95]	0.043
Model 2	0.23 [0.05; 0.99]	0.049
Model 3	0.23 [0.05; 1.01]	0.05
Model 4	0.57 [0.11; 2.88]	0.49
Model 5	0.57 [0.11; 2.89]	0.49
ICU transfer
Model 1	0.14 [0.02; 1.08]	0.06
Model 2	0.14 [0.02; 1.09]	0.06
Model 3	0.16 [0.02; 1.26]	0.08
Model 4	0.69 [0.08; 6.32]	0.74
Model 5	0.78 [0.09; 7.06]	0.83
Oxygen supplementation (not ICU)
Model 1	0.28 [0.08; 0.95]	0.041
Model 2	0.31 [0.09; 1.04]	0.06
Model 3	0.31 [0.09; 1.06]	0.06
Model 4	0.77 [0.2; 3.06]	0.72
Model 5	0.77 [0.19; 3.05]	0.71
Caesarean delivery
Model 1	0.6 [0.4; 0.9]	0.014
Model 2	0.57 [0.38; 0.85]	0.007
Model 3	0.61 [0.4; 0.92]	0.017
Model 4	0.63 [0.38; 1.03]	0.07
Model 5	0.61 [0.37; 1]	0.05
Total cohort
Virus-related pneumonia1
Model 1	0.04 [0.01; 0.13]	< 0.001
Model 2	0.04 [0.01; 0.14]	< 0.001
Model 3	0.05 [0.02; 0.15]	< 0.001
Model 4	0.13 [0.04; 0.43]	< 0.001
ICU transfer
Model 1	0.11 [0.05; 0.24]	< 0.001
Model 2	0.12 [0.06; 0.26]	< 0.001
Model 3	0.14 [0.07; 0.31]	< 0.001
Model 4	0.42 [0.18; 1.00]	0.049
Intubation
Model 1	0.07 [0.02; 0.30]	< 0.001
Model 2	0.08 [0.02; 0.33]	< 0.001
Model 3	0.10 [0.02; 0.42]	0.002
Model 4	0.43 [0.09; 2.00]	0.28
Oxygen supplementation (not ICU)
Model 1	0.11 [0.06; 0.20]	< 0.001
Model 2	0.12 [0.06; 0.22]	< 0.001
Model 3	0.13 [0.07; 0.24]	< 0.001
Model 4	0.33 [0.16; 0.67]	0.002
Caesarean delivery
Model 1	0.80 [0.71; 0.90]	< 0.001
Model 2	0.76 [0.68; 0.86]	< 0.001
Model 3	0.78 [0.69; 0.88]	< 0.001
Model 4	0.78 [0.67; 0.92]	0.003

Newborns of infected and vaccinated mothers with GDM had lower odds for NICU admission only in models 1 and 2. No other associations with secondary endpoints were found. Offspring of vaccinated women of the total cohort had lower odds for NICU transfer and preterm birth compared to non-vaccinated women ([Table 3]).

Table 3 Associations between vaccination status (vaccinated vs. non-vaccinated) and secondary neonatal endpoints.

Neonatal secondary endpoints	Adjusted odds ratio [95% CI]	P value
Data are odds ratios with 95% CIs from logistic regression analyses with secondary endpoints (yes/no) as the dependent variable. Model 1 adjusted for maternal age (years) and the BMI category (< 25 kg/m2/>25 kg/m2). Model 2 additionally adjusted for multiple birth (yes, no), parity (nulliparous, multiparous), and hypertensive medication (yes, no). Model 3 additionally adjusted for language competence (yes, no) and nicotine exposure during pregnancy (yes, no). Model 4 additionally adjusted for virus variant (pre-Omicron, Omicron). Model 5 in the GDM cohort additionally adjusted for insulin therapy (yes, no).
GDM cohort
NICU admission
Model 1	0.53 [0.28; 1]	0.049
Model 2	0.52 [0.27; 0.99]	0.045
Model 3	0.53 [0.28; 1.01]	0.05
Model 4	0.78 [0.37; 1.65]	0.52
Model 5	0.79 [0.37; 1.68]	0.54
Preterm birth
Model 1	0.66 [0.35; 1.27]	0.21
Model 2	0.71 [0.37; 1.37]	0.31
Model 3	0.77 [0.4; 1.51]	0.45
Model 4	0.85 [0.37; 1.92]	0.69
Model 5	0.92 [0.4; 2.11]	0.84
SGA
Model 1	1.13 [0.56; 2.26]	0.73
Model 2	1.03 [0.51; 2.07]	0.94
Model 3	1.09 [0.54; 2.23]	0.81
Model 4	0.92 [0.39; 2.19]	0.86
Model 5	0.96 [0.4; 2.28]	0.92
Stillbirth
Model 1	2.68 [0.52; 13.7]	0.24
Model 2	3.08 [0.58; 16.37]	0.19
Model 3	3.58 [0.64; 20.03]	0.15
Model 4	5.80 [0.34; 98.31]	0.22
Model 5	7.57 [0.43; 132]	0.17
Total cohort
NICU admission
Model 1	0.58 [0.48; 0.70]	< 0.001
Model 2	0.56 [0.46; 0.68]	< 0.001
Model 3	0.58 [0.48; 0.71]	< 0.001
Model 4	0.80 [0.62; 1.03]	0.049
Preterm birth
Model 1	0.60 [0.49; 0.73]	< 0.001
Model 2	0.55 [0.45; 0.68]	< 0.001
Model 3	0.57 [0.47; 0.71]	< 0.001
Model 4	0.75 [0.58; 0.97]	0.028
SGA
Model 1	1.13 [0.93; 1.39]	0.22
Model 2	1.05 [0.85; 1.28]	0.67
Model 3	1.07 [0.87; 1.31]	0.54
Model 4	0.96 [0.74; 1.25]	0.78
Stillbirth
Model 1	0.67 [0.30; 1.49]	0.32
Model 2	0.68 [0.30; 1.52]	0.35
Model 3	0.75 [0.33; 1.69]	0.49
Model 4	0.91 [0.27; 3.03]	0.88

Discussion

In this nationwide study, vaccination against COVID-19 before or during pregnancy reduced the odds for severe disease progression with a VE of 75% in pregnant women with GDM, depending on the predominant virus variants. However, no obvious vaccination effect was observed for perinatal outcomes. Vaccinated pregnant women from the total cohort had reduced odds for adverse maternal outcomes with a VE of 67% and for perinatal outcomes with a VE of 26%. A BMI ≥ 25 kg/m² was associated with lower odds for vaccination only in the total cohort. The overall vaccination rate was low.

SARS-CoV-2 binds to ACE2 receptors via spike proteins in the upper respiratory tract [24], is replicated there, enters the lower pulmonary segments and subsequently reaches target organs, including the endocrine pancreas and placenta [25], [26]. Subclinically elevated blood glucose levels, a hallmark of GDM, lead to increased glycation of SARS-CoV-2 spike proteins [27], which can facilitate binding to ACE2 receptors. ACE2 receptors are increasingly expressed in hyperinsulinemia [28], often combined with fasting hyperglycemia and obesity, a finding in the insulin-resistant GDM subtype [29] which may also facilitate virus entry. Here, with an obesity rate of 40% and 35% rate of women with GDM on insulin therapy, there was an increased risk of severe course of infection.

At least one vaccination against COVID-19 reduces severe maternal morbidity and mortality in pregnant women compared to non-vaccinated pregnant women [30]. This was additionally confirmed here for women with SARS-CoV-2 infection during pregnancy. Even vaccination within 12 months before pregnancy reduced preterm births and stillbirths [31]. In German studies, maternofetal antibody transfer was demonstrated after vaccination of pregnant women, suggesting that vaccination of the mother can likewise induce potential protection of the newborn against SARS-CoV-2 infection [32], [33]. Severe courses in infected pregnant women were associated with specific placentitis [26], which can lead to oxygen deficiency and subsequently increase the risk of premature birth or stillbirth. In the German obstetric background population of the 2020 – 2023 cohorts, a stillbirth rate of 0.43% was recorded [34]. We registered higher stillbirth rates in both the GDM cohort and the total cohort, suggesting metabolic and inflammatory factors. A study from Scotland found that all mothers of stillborn infants and newborns who died in the neonatal period were unvaccinated [23]. Here, we found that all maternal and neonatal deaths occurred exclusively in unvaccinated mothers. In a study from Israel, hybrid immunity of mothers reduced hospitalizations of their children, regardless of whether the infection occurred before or after vaccination [35].

Studies on pregnant women with GDM and COVID-19 are rare and usually do not report on vaccination coverage, and we could not find studies on vaccination effect in women with GDM [36]. A Swiss study showed that SARS-CoV-2 infection was an independent risk factor for GDM incidence but lacked information on vaccination uptake [37]. Moreover, the prevalence of GDM has changed in many countries due to a modification of the diagnostic criteria during the pandemic, e.g. by exclusively measuring fasting blood glucose. Therefore, a post-pandemic return to OGTT as the most effective test is supported [38]. Here, the guidelines for screening and diagnosis of GDM were not changed during the pandemic.

Women with GDM experience a 10-fold higher risk of developing type 2 diabetes after birth [39] and have an additionally increased risk of cardiovascular morbidity and mortality, depending on the duration of lactation [40]. These risks vary and depend on a number of factors, such as BMI, insulin therapy, and diagnostic criteria. A study from England recently showed that after COVID-19 unvaccinated individuals had a 5.3-fold increased risk of type 2 diabetes vs. vaccinated individuals [41]. Type 2 diabetes was more common in individuals ≤ 40 years of age, those with social deprivation, and after hospitalization for COVID-19. Future research should therefore evaluate the long-term impact of COVID-19 on type 2 diabetes risk in pregnant women with GDM, especially those with individual and social risk factors.

By November 2022, 85.5% of the German population had been vaccinated [3]. Vaccination hesitancy is common in pregnant women. The global vaccination prevalence against COVID-19 in pregnant women was low at just 27.5% until March 2022 [42]. An umbrella review based on 78 meta-analyses up to the end of 2023 showed a lower vaccination uptake among pregnant women at 48% compared to the total population which was 63% [43]. In an online cross-sectional study with selected pregnant women from Germany, a vaccination rate of 58.7% was found after the introduction of the official vaccination recommendations for COVID-19 in November 2021 [44]. The main reasons against vaccination were insufficient scientific data for vaccination during pregnancy, fear of pregnancy complications and fear of harm to the unborn child. Here, the vaccination rate was 25.6% of women with GDM and when only the period since vaccination was available was considered (i.e., from January 2021), the cumulative vaccination rate in the total cohort was 33.2%; we additionally found a vaccination rate for 2022 of 52.6%.

Even without further complications during pregnancy, women with GDM have an increased risk of experiencing unfavorable pregnancy outcomes. This particularly depends on the diagnostic criteria [8], the level of womenʼs overweight, and metabolic control from GDM diagnosis to delivery [10]. We found overweight and obesity in 71.7% of the non-vaccinated women with GDM and 33% of these women were being treated with insulin. Therefore, the lack of association of maternal vaccination against COVID-19 with improved perinatal outcomes in GDM is most likely due to the increased risk that GDM poses, independently from vaccination [45]. Pregnant women and their newborns are monitored more closely after GDM diagnosis so that abnormalities can be detected at an early stage. However, a higher vaccination rate should be achieved through comprehensive counseling and motivational strategies. This is essential because even with the persisting circulation of Omicron variants, unvaccinated and symptomatic pregnant women with SARS-CoV-2 infection had an increased risk of severe morbidity [46].

The strengths of our study include the large, multicenter, prospectively collected number of real-life cases with SARS-CoV-2 infection. The participating centers represent approximately 30% of all hospital deliveries in Germany. Through frequent data monitoring and confirmation of SARS-CoV-2 infections and GDM diagnoses using laboratory data, not ICD codes, we were able to exclude implausible cases such as misclassifications or cases with undiagnosed type 2 diabetes.

Some limitations should be considered. Firstly, many cases were registered in the pre-Omicron period when vaccination was not yet available. A study on vaccinated pregnant women from the USA found a VE of 100% in the pre-Omicron period compared to 51% in the Omicron period to avoid hospitalization [47]. Thus, we can assume that the vaccination effect is probably underestimated. Secondly, although the participating institutions represent 30% of all hospital deliveries in Germany, participation in the study was based on their own initiative. Consequently, a bias with regards to the underrepresentation of hospitals with few deliveries per year cannot be completely ruled out. Thirdly, no data were available on metabolic control of the GDM cohort after diagnosis; optimal GDM therapy may be associated with improved neonatal outcomes. Obstetricians, general practitioners, diabetologists, and neonatalogists are well trained according to the German guidelines to implement target-oriented management of women with GDM and their newborns; we therefore hypothesize that the quality of GDM therapy was comparably favorable in the unvaccinated and vaccinated cohorts. Fourthly, the interval between vaccination and delivery could not be determined. Immune competence following vaccination is not immediate, and outcomes may depend on this temporal relationship. Fifthly, in some analyses of the GDM cohort, the numbers were too small to obtain sufficient discriminatory power. Hence, the positive trending but statistically non-significant VE in the GDM cohort on perinatal outcomes should be investigated further. Lastly, the data were collected in a western industrialized country with high standards of obstetric, neonatal and diabetological care, therefore the results can only be generalized to a limited extent for countries with other socioeconomic conditions and different standards of medical care.

Conclusion

In SARS-CoV-2-infected pregnant women with GDM, at least one vaccination against COVID-19 before or during pregnancy was independently associated with a milder course of infection in the mothers, depending on the predominant virus variants. A vaccination effect on perinatal outcomes was not detectable. In the total cohort analyzed, vaccination was associated with improved maternal and perinatal outcomes. As pregnant women are at increased risk of adverse pregnancy outcomes related to COVID-19, and as this risk is even higher in women with GDM especially if they are overweight and treated with insulin, they should be encouraged to be vaccinated.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgements

The authors are grateful to the participating pregnant women, the contributing maternity hospitals, and Corinna Fruth and Lilly Bukowski for their assistance and coordination in the CRONOS study center. We especially thank Professor Wolfgang Lieb, MD, MSc, Kiel, Germany, for reviewing the manuscript and his helpful comments.

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Publication History

Received: 19 January 2025

Accepted after revision: 03 April 2025

Article published online:
29 April 2025