Discussion
In this study, our main observation was that neonates from women with GDM and SARS-CoV-2 infection were more likely to experience adverse perinatal outcomes (ie, NICU admission, neonatal death, and/or stillbirth) and to be born preterm compared with neonates born from women with GDM before the SARS-CoV-2 pandemic. In addition, SARS-CoV-2 infection in women with GDM resulted in a higher proportion of cesarean deliveries as compared with women with GDM before the pandemic. When comparing OGTT results, women’s fasting levels were higher in cases with SARS-CoV-2 infection and solely increased fasting plasma glucose—but not postchallenge levels—was associated with a higher risk of preterm birth. This association was only observed in women with GDM and SARS-CoV-2 infection, but not in women with GDM before the pandemic.
SARS-CoV-2 infection in GDM and risk of adverse neonatal outcomes
Some prior studies have reported an increased risk of preterm birth in neonates of mothers with COVID-19 during pregnancy,15 25–29 and we can confirm this association in women with GDM. There are several possible obstetrical reasons for preterm birth. Severe COVID-19 late in pregnancy could worsen the mother’s health condition, followed by multiorgan disease from viremia including placentitis in severe cases, and worsening of oxygen saturation. This, in turn, could lead to acute fetal distress, increasing the rate of emergency cesarean delivery and preterm birth due to fetal indication or more liberally general indication in the early period of the pandemic. Supporting the hypothesized underlying mechanism, here, increase in risk of preterm birth and the combined perinatal outcome particularly appeared in severe course of COVID-19, probably associated with metabolic imbalances and increasing blood glucose from GDM. Additionally, we observed an increased rate of LGA in the early waves of the pandemic compared with the Omicron period. More sedentary behavior, changed eating habits, and excessive gestational weight gain could contribute to higher blood glucose in the pregnant women, followed by increased transplacentary mother-to-fetus glucose transport, consecutive fetal hyperinsulinemia and insulin-mediated stimulation of fetal growth. Nevertheless, based on billing data of pregnant women covered by German statutory health insurance, it was possible to determine that prenatal care and GDM screening was also used intensively in the first year of the pandemic.30 With no data from the years 2021–2022, however, it cannot be ruled out that personal appointments may have been less frequent, possibly contributing to overlooked fetal growth acceleration.
OGTT results and risk for adverse neonatal outcomes
Levels of fasting plasma glucose were higher in women with GDM and SARS-CoV-2 infection compared with those with GDM before the pandemic; the majority of the infected women were symptomatic with COVID-19-related symptoms. Similar results were recently published by others.31 In our study, for most women the SARS-CoV-2 infection was diagnosed with or shortly after GDM was confirmed. Fasting hyperglycemia per se is associated with pronounced insulin resistance and consecutive hyperinsulinemia,32 which could facilitate virus entry and distribution. On the other hand, COVID-19 could contribute to increased blood glucose levels through systemic inflammation and oxidative stress. In the comparison of women with GDM with and without SARS-CoV-2 infection, fasting glucose results from OGTT were associated with adverse perinatal outcomes despite GDM therapy in accordance with the German guidelines. Associations of increasing glucose levels from OGTT with adverse perinatal outcomes are well known from pregnant women with GDM without treatment.5 In general, the risks of perinatal complications in treated women with GDM are associated with trajectories of glycemic control, depending on, for example, (1) how fast glucose control can be improved, (2) how long optimal control is maintained between GDM diagnosis and birth,33 and (3) the used glycemic targets.34
Vaccination status
In the CRONOS cohort 21.4% of women with GDM received at least one vaccination dose against COVID-19 since its availability in January 2021, which is far below the German population basic immunization rate of 85.4% up to November 2022,35 the time point of CRONOS data extraction. Vaccination against COVID-19 during pregnancy is safe and highly effective, not associated with higher than average rate of side effects, and reduces the risk of stillbirth, preterm birth, and NICU admission.36 37 Future research should evaluate the effect of vaccination against COVID-19 on maternal and neonatal outcomes in women with GDM. Many pregnant women are still reluctant to be vaccinated against COVID-19,38 so they should be counseled with support of more specific information on vaccination and be motivated to take part in the recommended vaccination program receiving benefits for themselves and their offspring. Under the recent Omicron variants maternal and neonatal risks are still of concern in symptomatic and unvaccinated women.39 Furthermore, there are currently no reliable findings on post-COVID-19 condition after GDM,40 whether COVID-19 during pregnancy accelerates the future risk of type 2 diabetes in the mother, and whether COVID-19 is associated with any long-term increase of risks in the exposed offspring.
Strengths and limitations
The strengths of our study are as follows: We used data from high-quality managed homogenous cohorts with frequent data monitoring. Additionally, in CRONOS, validation recalls with each local center concerning confirmation of SARS-CoV-2 infection, GDM diagnosis, insulin therapy, and pregnancy outcomes were carried out to detect and eliminate discrepancies. GDM was confirmed with OGTT results from both registries to avoid inaccuracy from International Classification of Diseases coding, hence cases with overt diabetes and misdiagnosis (no GDM) could certainly be excluded.
Some limitations merit consideration. First, data were collected in different time frames, each at least of 2 years’ duration. During these time periods, screening and management of GDM, treatment guidelines of SARS-CoV-2 infection or vaccination rates against COVID-19 may have changed, and the proportion of obesity, levels of stress and anxiety might have increased. In addition, before the pandemic, it had been extremely uncommon that women with GDM were transferred to ICU, received invasive ventilation or oxygen supply, so that these items were not included in the GestDiab dataset and could therefore not be included as covariates in our analyses. Second, the registry data were recruited in outpatient and hospital settings and therefore comparison has some residual restrictions. Third, in GestDiab, pregnancy outcome data were obtained in the diabetes outpatient offices either at the first postpartum visit or from discharge letters from maternity hospitals. Since only 38.2% of mothers attended the first postpartum visit,19 this might have accounted for the proportion of excluded participants. However, comparing the analyzed cohorts with the excluded women due to missing data, excluded women in CRONOS were earlier diagnosed with GDM and were more frequently managed with insulin. In contrast, excluded cases in GestDiab were younger and received less often insulin. From this observation, we can assume that the effect size of GDM combined with SARS-CoV-2 infection on the fetal and neonatal outcomes in our analysis may be underestimated. Fourth, because of different coding, chronic hypertension or pre-eclampsia could not be reliably differentiated in both registries and therefore were not included in the analysis. Lastly, data on the quality of diabetes management after GDM diagnosis were not available; targeting glucose control and duration of optimal control may be associated with improved outcomes.
In conclusion, neonates from women with GDM and SARS-CoV-2 infection were more likely to experience adverse perinatal outcomes, especially NICU transfer, stillbirth, and neonatal death, and were more frequently born preterm compared with neonates born to women with GDM before the SARS-CoV-2 pandemic. In addition, the higher fasting plasma glucose concentrations among women with SARS-CoV-2 infection appeared to be predictive for a worse perinatal outcome. Thus, with regard to the new phase of SARS-CoV-2 variants spread, fetuses and newborns of women with GDM and SARS-CoV-2 infection should still receive attention as a vulnerable group particularly if vaccination coverage is low.