Is the risk of still and preterm birth affected by the timing of symptomatic SARS-CoV-2 infection during pregnancy? Data from the COVID-19 Related Obstetrics and Neonatal Outcome Study Network, Germany

Objective

A SARS-CoV-2 infection during pregnancy increases the risk for preterm birth (PTB).¹ Recently, it has been shown that the gestational age at infection, but not the severity of the infection, has a significant impact on PTB rate.² This study aimed to analyze the association of the timing of symptomatic SARS-CoV-2 infection during pregnancy with PTB and stillbirth risk.

Study Design

From April 3, 2020 to August 24, 2021, the data of 2650 women with a confirmed SARS-CoV-2 infection during pregnancy from 113 hospitals in Germany and Austria (covering about 30% of all deliveries in Germany) were collected in the prospective register COVID-19 Related Obstetrics and Neonatal Outcome Study (CRONOS). The exclusion criteria were defined as follows: (1) asymptomatic infection, (2) SARS-CoV-2 infection after 37+0 weeks of gestation, (3) miscarriage before 20+0 weeks, and (4) incomplete data in terms of infection or delivery date, live birth, maternal age, admission for SARS-CoV-2 symptoms or for obstetrical reasons or a history of stillbirth or PTB in previous pregnancies. The timing of exposure was dichotomized into early (first or second trimester) and late (third trimester) infections. The primary endpoints were PTB (classified as early PTB ≤32 weeks’ gestation or late PTB >32 weeks’ gestation) and stillbirth. Association was assessed using log-binominal regression models for calculating adjusted relative risk (aRR) and 95% confidence intervals (95% CI). Secondary endpoints were defined as delivery within 4 weeks after SARS-CoV-2 infection and occurrence of other pregnancy complications. For categorical variables, chi-Square or Fisher exact tests (n<5) were used. All statistical analyses were performed using SPSS (version 27) for Windows (IBM Corp, Armond, NY).

Results

A total of 1149 patients were eligible for the final analysis. Of those, 1128 (98.2%) had a live birth and of those, 201 (17.8%) were preterm (Supplemental Figure). A total of 21 (1.8%) stillbirths occurred (Supplemental Table). More than half of the analyzed women acquired the infection in the third trimester and 45.5% acquired it earlier in pregnancy. Of the 1084 women with known immunization status, no one was vaccinated at the time of infection.

Supplemental Figure.

Flow diagram of recruitment process of the final study cohort

Iannaccone. Preterm birth risk after symptomatic SARS-CoV-2 in pregnancy. Am J Obstet Gynecol 2023.

Early symptomatic SARS-CoV-2 infection increased the risk for early PTB (aRR, 2.07; 95% CI, 1.10–3.91) and stillbirth (aRR, 2.76; 95% CI, 1.15–6.64) when compared with a late infection (Table ). The risk for PTB was higher within 4 weeks after infection (RR, 4.89; 95% CI, 3.86–6.19). Threatened PTB (RR, 1.80; 95% CI,1.07–3.01) and gestational cholestasis (RR, 3.18; 95% CI, 1.19–8.44) occurred more often in late infections.

Table.

Multivariate log-binominal model analysis of the risk for stillbirth and early and late preterm birth according to the time point of SARS-CoV-2 infections (early vs late infection)

Parameter	Stillbirth (all patients)			Early PTB (only live births)			Late PTB (only live births)
	RR	95% CI	P value	RR	95% CI	P value	RR	95% CI	P value
Maternal age (per year increase)	0.98	0.91–1.06	.618	1.05	0.99–1.12	.096	1.01	0.99–1.04	.266
History of miscarriage or preterm delivery	4.97	1.38–17.98	.014a	1.22	0.19–7.98	.837	1.76	1.06–2.91	.027a
In-patient care for SARS-COV-2 infection	16.62	3.34–82.54	.001a	12.97	5.37–31.33	<.001a	3.99	2.77–5.77	<.001a
In-patient care for other obstetrical complications	25.49	5.82–111.60	<.001a	7.63	3.09–18.83	<.001a	5.27	3.78–7.36	<.001a
Early (1st and 2nd trimester) vs late (3rd trimester) infection	2.76	1.15–6.64	.023a	2.07	1.10–3.91	.025a	0.60	0.44–0.81	.001a

RR adjusted for maternal age, SARS-CoV-2 infection needing in-patients’ treatment, obstetrical reasons urging in-patients’ treatment and history of miscarriage or preterm delivery.

CI, confidence interval; PTB, preterm birth; RR, risk ratio.

Iannaccone. Preterm birth risk after symptomatic SARS-CoV-2 in pregnancy. Am J Obstet Gynecol 2023.

^aIndicates significant P values.

Conclusion

A total of 17.8% of the women with symptomatic infections delivered preterm—more than double the rate when compared with the general German preterm birth rate of nearly 9%.³ Hospitalization for any reason was associated with PTB and stillbirth. However, although hospitalization for obstetrical complications mirrors a high-risk pregnancy possibly leading to PTB independently of COVID-19,⁴ hospitalization because of SARS-CoV-2 infection could be regarded as a surrogate marker for the severity of COVID-19. The impact of the hospitalization rate for SARS-CoV-2 on the risk for PTB and stillbirth suggests that the severity of infection is also contradictory to previous reports.²

Women with a symptomatic SARS-CoV-2 infection could profit most from intensive obstetrical surveillance. A symptomatic SARS-CoV-2 infection increased pregnancy complications and should be prevented by vaccination.

Appendix

Supplemental Table.

Baseline characteristics of the study cohort

Parameter	Number or mean	% or SD	Early infection (n=523, 45.5%) number or mean	% or SD	Late infection (n=626, 54.5%) number or mean	% or SD
Maternal age (y)	31	± 5	31.47	±4.879	31.2	±5.449
In-patient care for SARS-COV-2 infection	177	15.4%	42	8%	135	21.6%
In-patient care for obstetrical complications	207	18.0%	96	18.4%	129	20.6%
Vaccinateda	0	0%	—		—
History of miscarriage or preterm delivery	24	2.1%	11	2.1%	13	2.1%
Timing of infection
Gestational age at infection (wk, all patients)	26	± 9	18.65 (range, 1–27)	±6.599	33.0 (range, 38–37	±2.848
Gestational age at delivery (wk, all patients)	39	± 3	39.01	±3187	38.77	±2.486
Gestational age at delivery (wk, only live births; n=1128)	39	± 3	39.26	±2.696	38.80	2.487
Preterm ≤37+0 wk	201b	17.8%	77	14.7%	142	22.7%
Preterm early ≤32+0 wk	37	3.3%	28	5.4%	18	2.9
Preterm late 32+1 to 37+0 wk	164	14.5%	49	9.4%	124	19.8%
Pregnancy complications
Hypertensive pregnancy disorders	43	4.7%	17	3.3%	26	4.2%
HELLP syndrome	19	1.7%	6	1.1	13	2.1
Suspicious fetal heart rate pattern	58	5.0%	21	4.0%	37	5.9%
Premature rupture of membranes	115	10.0%	50	9.6%	65	10.4%
Premature labor with need of therapy	63	5.5%	20	3.8%	43	6.9%
Gestational cholestasis	24	2.1%	5	1.0%	19	3.0%

Data are presented for a sample of n=1149 patients.

HELLP, hemolysis, elevated liver enzymes, low platelet count; SD, standard deviation.

Iannaccone. Preterm birth risk after symptomatic SARS-CoV-2 in pregnancy. Am J Obstet Gynecol 2023.

^aData available for 1034 pregnant women, 3 vaccinations after infection

^bA total of 126 (62.7%) patients were iatrogenic. In 35 cases (17.4 %), COVID-19 was the reason for delivery. In 91 (45.3%) cases, delivery was for obstetrical reasons.