SARS‐CoV‐2 infection during pregnancy and perinatal outcomes in Estonia in 2020 and 2021: A register‐based study

Abstract

Introduction

Data from different countries show partly controversial impact of SARS‐CoV‐2 infection on pregnancy outcomes. A nationwide register‐based study was conducted in Estonia to assess the impact of SARS‐CoV‐2 infection at any time during pregnancy on stillbirth, perinatal mortality, Apgar score at 5 minutes, cesarean section rates, rates of preterm birth and preeclampsia.

Material and methods

Data on all newborns and their mothers were obtained from the Estonian Medical Birth Registry, and data on SARS‐CoV‐2 testing dates, test results and vaccination dates against SARS‐CoV‐2 from the Estonian Health Information System. Altogether, 26 211 births in 2020 and 2021 in Estonia were included. All analyses were performed per newborn. Odds ratios with 95% confidence intervals (CI) were analyzed for all outcomes, adjusted for mother's place of residence, body mass index, age of mother at delivery and hypertension and for all the aforementioned variables together with mother's vaccination status using data from 2021 when vaccinations against SARS‐CoV‐2 became available. For studying the effect of a positive SARS‐CoV‐2 test during pregnancy on preeclampsia, hypertension was omitted from the models to avoid overadjustment.

Results

SARS‐CoV‐2 infection during pregnancy was associated with an increased risk of stillbirth (adjusted odds ratio [aOR] 2.81; 95% CI 1.37–5.74) and perinatal mortality (aOR 2.34; 95% CI 1.20–4.56) but not with a lower Apgar score at 5 minutes, higher risk of cesarean section, preeclampsia or preterm birth. Vaccination slightly decreased the impact of SARS‐CoV‐2 infection during pregnancy on perinatal mortality.

Conclusions

A positive SARS‐CoV‐2 test during pregnancy was associated with higher rates of stillbirth and perinatal mortality in Estonia but was not associated with change in preeclampsia, cesarean section or preterm birth rates.

SARS‐CoV‐2 infection during pregnancy increased risk of stillbirth and perinatal mortality in Estonia but had no impact on preeclampsia, induction of labor, preterm birth, cesarean section or low Apgar score at 5 minutes.

Abbreviations

BMI

body mass index

CI

confidence interval

COVID‐19

Coronavirus Disease 2019

CS

cesarean section

GW

gestational week

SARS‐CoV‐2

severe acute respiratory syndrome coronavirus 2

Key message.

In Estonia, SARS‐CoV‐2 infection during pregnancy increased the rate of stillbirth nearly three times and perinatal mortality more than two times. There was no impact on preeclampsia, induction of labor, preterm birth, cesarean section or newborn's low Apgar scores at 5 minutes.

1. INTRODUCTION

In Estonia, the first case of SARS‐CoV‐2 was diagnosed on February 24, 2020. From March 12 to May 18, 2020, there was a strict lockdown in Estonia. Perinatal health care services continued during the lockdown, although distant counseling was encouraged under feasible circumstances. Extensive free‐of‐charge SARS‐CoV‐2 PCR testing was offered throughout the country, and results of all tests were recorded in a central electronic database. In January 2021, persons in high‐risk groups started to get vaccinations against SARS‐CoV‐2, and in April 2021, vaccinations against SARS‐CoV‐2 became available to everyone. Pregnant women and women planning pregnancy or infertility treatment were encouraged to get vaccinated. The impact of coronavirus type 2 infection on pregnancy outcomes was not known before the pandemic.

Data from different countries show partly controversial impact of COVID‐19 on pregnancy outcomes. A meta‐analysis of 37 studies showed that the COVID‐19 pandemic may be associated with a decrease in preterm birth and found no difference in stillbirths between the pandemic and pre‐pandemic period. ¹ An individual participant data meta‐analysis indicated that SARS‐CoV‐2 infection at any time during pregnancy increases the risk of maternal death, severe maternal morbidities and neonatal morbidity, but not stillbirth or intrauterine growth restriction. ² Another meta‐analysis of cohort studies reported higher rates of maternal mortality and stillbirth due to SARS‐CoV‐2 infection during pregnancy among lower‐/middle‐income countries. ³ A retrospective cohort study in the USA found increased odds of stillbirth among pregnant women with SARS‐CoV‐2 infection only in early pregnancy and midpregnancy. ⁴ A meta‐analysis of observational studies showed higher odds for preeclampsia/hypertensive disorders of pregnancy, neonatal intensive care unit admissions, stillbirths and perinatal mortality among SARS‐CoV‐2‐positive women. ⁵ A big cohort study from Italy found no association of COVID‐19 on preterm birth or stillbirth rates. ⁶ The findings from UK and US registries showed increased risk of preterm delivery and maternal mortality, whereas stillbirth, low birthweight and early neonatal death rates were not affected. ⁷ Reduction in preterm birth rates and elective cesarean section (CS) was observed in Iceland with no change in induction of labor. ⁸

The secondary analysis of the prospective UK cohort showed that the severity of maternal symptoms may have an impact on maternal and neonatal outcomes, and that COVID‐19 was more severe if the mother was ≥30 years of age, overweight or obese, or had gestational diabetes. ⁹ Danish data showed an increased risk of hospital admission due to severe SARS‐CoV‐2 infection related to obesity, smoking, asthma and infection after 22 gestational weeks (GW). ¹⁰

To assess the impact of SARS‐CoV‐2 infection at any time during pregnancy on stillbirth, perinatal mortality, Apgar score at 5 minutes, CS rates, rates of preterm birth and preeclampsia, a nationwide register‐based study was conducted in Estonia.

2. MATERIAL AND METHODS

2.1. Data sources and data definitions

Data of all children born in Estonia in 2020 and 2021 (n = 26 219) were retrieved from the Estonian Medical Birth Registry (EMBR). EMBR is a central digital registry that collects data on all births in Estonia. ¹¹ From EMBR, the following information was obtained: mother's personal identification code, mother's place of residence, self‐defined nationality, education, height, weight before pregnancy, smoking status during pregnancy, diagnoses of mother during pregnancy, during and after delivery according to ICD‐10, ¹² baby's birthdate, gestational age at birth, induction of labor, mode of delivery, baby's gender, live birth/stillbirth, number of babies born, birthweight, Apgar score at 1, 5 and 10 minutes, pH and base excess of umbilical blood, newborn's status at 7th day of life. In Estonia, stillbirth is defined as antenatal death of a fetus weighing >500 g or after 22 weeks (154 days) of pregnancy; perinatal mortality is defined as stillbirth or early neonatal death up to 7 days after birth. Any newborn with vital signs regardless gestational age is defined as live birth.

Personal identification codes of all mothers were then linked with the Estonian Health Information System (EHIS) database to retrieve information about their SARS‐CoV‐2 test dates and test results during 2020 and 2021. In addition, data on vaccinations against SARS‐CoV‐2 together with respective dates were retrieved from EHIS. EHIS is a central digital database integrating medical records from different healthcare providers. ¹³ A positive SARS‐CoV‐2 test during pregnancy was defined as at least one positive result at any time during pregnancy. The date of conception was estimated from gestational age at birth to define whether the SARS‐CoV‐2 testing occurred during pregnancy. All tests carried out 7 days before the estimated date of conception and before date of delivery were considered to have possibly affected the perinatal outcome if positive and were categorized as done during pregnancy.

All analyses were performed per newborn. Newborns with missing gestational age (n = 8) were excluded from the final sample (n = 26 211) because in these cases we were not able to verify whether the mother received the positive SARS‐CoV‐2 test during pregnancy.

Mother's age at the time of delivery was categorized as ≤35 and >35 years. Based on mother's height and weight before pregnancy, body mass index (BMI) was calculated. BMI was categorized as ≤30 and >30 kg/m². Place of residence was grouped into five regions according to NUTS‐3 (Nomenclature of territorial units for statistics). ¹⁴ Mother's nationality was categorized as Estonian, Russian and other foreign. Education was categorized as higher (university), secondary (including secondary vocational) and basic.

Mother's medical conditions during pregnancy were defined as follows, based on information reported on the birth card: diabetes (ICD‐10 codes E10–E14), gestational diabetes (O24), hypertension (I10–I15 and O10) and pulmonary disease (J43‐J45). Smoking during pregnancy was divided into two categories: (1) no or (2) yes or stopped during the 1st trimester. All women with unknown characteristics were categorized as unknown.

All women who had been vaccinated against SARS‐CoV‐2 at any time before delivery were considered vaccinated regardless of the timing of vaccination and the number of vaccine doses. Women with a positive SARS‐CoV‐2 test during pregnancy before vaccination were considered non‐vaccinated.

Pregnancy outcome was defined as stillbirth or live birth and perinatal mortality as number of stillbirths and neonatal deaths up to the 7th day of life. Eclampsia and preeclampsia during pregnancy or childbirth were categorized together as preeclampsia and defined as No or Yes. Induction of labor was categorized as No or Yes, regardless the method of induction. For the analysis, mode of delivery was categorized as (1) CS, including elective, emergency (non‐elective) and urgent CS (emergency CS within 20 minutes); (2) Other, including vaginal delivery, vacuum extraction or forceps. Preterm birth was defined as date of birth up to a gestational age of 36+6 weeks. Births before GW 28 were categorized as extremely preterm, GW 28–32 as very preterm and GW 32–37 as moderate to late preterm births. Apgar score at 5 minutes was used to describe newborn's adaptation to the environment and was categorized as ≤6, 7–10 and unknown, with the score <7 indicating complications of the baby. ¹⁵

2.2. Statistical analyses

STATA 17.0 was used for data analysis. ¹⁶ Chi‐square test was used for comparison of descriptive background characteristics, and logistic regression to calculate odds ratios (OR) with 95% confidence intervals (CI) for main outcome measures. First, all outcomes were analyzed in univariate models. The factors selected for multivariate models included those of a priori interest (SARS‐CoV‐2 test result during pregnancy) and those showing significant associations with all outcomes in univariate analyses (mother's age at delivery, BMI, place of residence and hypertension during pregnancy).

To assess the association of vaccination against SARS‐CoV‐2 with studied outcomes, a second set of models was constructed using only data for 2021, as no women were vaccinated in 2020. The second set of models included all variables included in the first set plus the vaccination variable. To avoid overadjustment, hypertension was omitted from the models studying the effect of a positive SARS‐CoV‐2 test during pregnancy on preeclampsia.

For both set of models, preterm birth was included as a binary variable and categorized as preterm (<37 GW) and non‐preterm (≥37 GW). Maternal age was included as a continuous variable in all models. Births with unknown characteristics were excluded from the analysis. Stillbirths were excluded from the analysis of Apgar score at 5 minutes. Interactions were tested but none were detected.

3. RESULTS

For the 26 219 babies born in Estonia in 2020 and 2021, gestational age was missing for eight cases, which were therefore excluded from the analysis. Of the 26 211 remaining births, 25 280 (96.5%) were singleton deliveries, 458 (3.5%) twin deliveries and five were triplet deliveries (0.06%). All results are presented per newborn. The total number of women giving birth was 25 282, of which 461 delivered twice during the study period. From these 461 deliveries, 459 (99.1%) were singleton and two (0.9%) were twin deliveries. If a woman had given birth twice during the study period, mother's background characteristics were analyzed according to the relevant pregnancy for each newborn. The mean age of mothers was 31.1 (SD 5.3) years. The proportion of babies born from vaccinated mothers was 0% in 2020 and 14.2% in 2021.

The proportion of newborns whose mother had had a positive SARS‐CoV‐2 test during pregnancy was 6.0% (0.4% in 2020 and 11.6% in 2021) (Table 1). There were no significant differences in age, BMI or education level between women with no or at least one positive SARS‐CoV‐2 test result during pregnancy. There were more newborns from mothers having had a positive SARS‐CoV‐2 test result during pregnancy who were living in Northern and North‐Eastern Estonia and with a Russian nationality. There were also more babies from mothers with a positive test result who did not smoke during pregnancy. There was no difference in the proportion of newborns from mothers with no or at least one positive SARS‐CoV‐2 test result diagnosed with gestational diabetes and diabetes before pregnancy, hypertension, pulmonary diseases, preeclampsia and eclampsia, or induction of labor. The proportion of women with an absolute or relative indication for CS (defined as placental abruption, placenta previa, uterine rupture, cephalopelvic disproportion or breech presentation) was the same (5.7%) among parturients with no or at least one positive SARS‐CoV‐2 test result during pregnancy.

TABLE 1.

Characteristics of pregnancies and SARS‐CoV‐2 test result during pregnancy, Estonia 2020–2021.

Characteristic	Total		Positive SARS‐CoV‐2 test during pregnancy				P‐value
			None		At least one
	n	col%	n	row%	n	row%
Total	26 211	100	24 639	94.0	1572	6.0
Year of delivery
2020	13 067	49.8	13 018	99.6	49	0.4	<0.001
2021	13 144	50.2	11 621	88.4	1523	11.6
Mother's age, years
≤35	19 354	73.8	18 213	94.1	1141	5.9	0.242
35+	6857	26.2	6426	93.7	431	6.3
BMI*, kg/m2
≤30	23 026	87.8	21 651	94.0	1375	6.0	0.661
>30	3131	12.0	2936	93.8	195	6.2
Unknown	54	0.2	52	96.3	2	3.7
Smoking during pregnancy
No	23 961	91.4	22 495	93.9	1466	6.1	0.018
Yes, or stopped during the 1st trimester	1788	6.8	1708	95.5	80	4.5
Unknown	462	1.8	436	94.4	26	5.6
Place of residence
Northern Estonia	13 154	50.2	12 257	93.2	897	6.8	<0.001
Central Estonia	2239	8.5	2124	94.9	115	5.1
North‐Eastern Estonia	1679	6.4	1556	92.7	123	7.3
Western Estonia	2561	9.8	2408	94.0	153	6.0
Southern Estonia	6524	24.9	6241	95.7	283	4.3
Outside of Estonia	54	0.2	53	98.1	1	1.9
Nationality
Estonian	19 785	75.5	18 768	94.9	1017	5.1	<0.001
Russian	5277	20.1	4799	90.9	478	9.1
Other foreign	1148	4.4	1071	93.3	77	6.7
Unknown	1	0.0	1	100.0	0	0.0
Education
Higher	13 086	49.9	12 302	94.0	784	6.0	0.030
Secondary	10 270	39.2	9630	93.8	640	6.2
Basic	2795	10.7	2654	95.0	141	5.0
Unknown	60	0.2	53	88.3	7	11.7
Preeclampsia, eclampsia
No	25 881	98.7	24 328	94.0	1553	6.0	0.853
Yes	330	1.3	311	94.2	19	5.8
GDM or diabetes before pregnancy
No	22 569	86.1	21 212	94.0	1357	6.0	0.797
Yes	3642	13.9	3427	94.1	215	5.9
Hypertension
No	25 888	98.8	24 336	94.0	1552	6.0	0.882
Yes	323	1.2	303	93.8	20	6.2
Pulmonary disease
No	26 192	99.9	24 622	94.0	1570	6.0	0.406
Yes	19	0.1	17	89.5	2	10.5

Abbreviations: BMI, body mass index; GDM, gestational diabetes mellitus.

^*Body mass index before pregnancy.

From the total of 26 211 births included in the analysis, 73.6% were spontaneous vaginal deliveries (Table 2). The proportion of preterm births was 6.1%. For mode of delivery, there were more urgent CS‐born babies among SARS‐CoV‐2‐positive pregnancies. There were no differences in preterm birth rates between babies from mothers with no or at least one positive SARS‐CoV‐2 test result during pregnancy (Table 2).

TABLE 2.

Characteristics of newborns and deliveries and perinatal outcomes, Estonia, 2020–2021.

Characteristic	Total		Mother's positive SARS‐CoV‐2 test result during pregnancy				P‐value
			None		At least one
	n	%	No	%	n	%
Year of delivery
2020	13 067	49.8	13 018	99.6	49	0.4	<0.001
2021	13 144	50.2	11 621	88.4	1523	11.6
Baby's gender
Male	13 415	51.2	12 612	51.2	803	51.1	0.935
Female	12 796	48.8	12 027	48.8	769	48.9
Pregnancy outcome
Livebirth	26 146	99.8	24 583	99.8	1563	99.4	0.008
Stillbirth	65	0.2	56	0.2	9	0.6
Newborn on 7th day of life
Alive	26 127	99.7	24 565	99.7	1562	99.4	0.022
Dead	84	0.3	74	0.3	10	0.6
Induction of labor
No	19 558	74.6	18 410	74.7	1148	73.0	0.135
Yes	6653	25.4	6229	25.3	424	27.0
Mode of delivery
Vaginal delivery	19 296	73.6	18 156	73.7	1140	72.5	0.024
VE or forceps	1386	5.3	1306	5.3	80	5.1
Elective CS	1646	6.3	1544	6.3	102	6.5
Emergency CS	3744	14.3	3512	14.2	232	14.8
Urgent CS	139	0.5	121	0.5	18	1.1
Preterm birth
Extremely preterm birth	91	0.4	86	0.3	5	0.3	0.410
Very preterm birth	138	0.5	125	0.5	13	0.8
Moderately preterm birth	1353	5.2	1279	5.2	74	4.7
Term birth	24 623	93.9	23 143	93.9	1480	94.1
Unknown	6	0.0	6	0.0	0	0.0
Apgar score at 5 min a
≤6	273	1.0	250	1.0	23	1.5	0.229
7–10	25 841	98.6	24 303	98.9	1538	98.4
Unknown	32	0.1	30	0.1	2	0.1

Abbreviations: CS, cesarean section; VE, vacuum extraction.

^a Among live births.

Having a positive SARS‐CoV‐2 test result during pregnancy increased the risk of stillbirth (adjusted odds ratio [aOR] 2.81, 95% CI 1.37–5.74) and perinatal mortality (aOR 2.34, 95% CI 1.20–4.56) but there was no association with preeclampsia, induction of labor, preterm birth, CS rate or low Apgar score (Table 3). Including the vaccination variable in the model did not change the observed associations significantly; the OR for perinatal mortality, however, decreased slightly.

TABLE 3.

Impact of positive SARS‐CoV‐2 test during pregnancy on selected perinatal outcomes, Estonia 2020–2021.

Outcome	Crude OR (95% CI)	Adjusted OR a (95% CI)	Adjusted OR b (95% CI)
Preeclampsia	0.96 (0.60–1.53)	0.96 (0.60–1.54)†	1.00 (0.61–1.65)†
Induction of labor	1.09 (0.97–1.22)	1.11 (0.99–1.25)	1.09 (0.96–1.23)
Preterm birth	0.97 (0.78–1.20)	0.94 (0.75–1.17)	0.89 (0.70–1.13)
Cesarean section	1.08 (0.96–1.23)	1.07 (0.94–1.21)	1.08 (0.95–1.23)
Stillbirth	2.53 (1.25–5.12)	2.81 (1.37–5.74)	2.82 (1.29–6.18)
Apgar score ≤6 at 5 min	0.69 (0.45–1.06)	0.71 (0.46–1.10)	0.65 (0.41–1.04)
Perinatal death c	2.13 (1.10–4.12)	2.34 (1.20–4.56)	2.10 (1.03–4.27)

Statistically significant results are presented in bold.

^a Adjusted for place of residence, BMI, age of mother at delivery and hypertension (†for preeclampsia, hypertension omitted from the model).

^b Adjusted for place of residence, BMI, age of mother at delivery, hypertension and vaccination using only 2021 data (†for preeclampsia, hypertension omitted from the model).

^c Defined as number of stillbirths and neonatal deaths up to the 7th day of life.

4. DISCUSSION

The analysis of data from population‐based registries showed that 6% of Estonian newborns in 2020 and 2021 were born to women who had a positive SARS‐CoV‐2 test during their pregnancy. After lifting the strict lockdown measures in 2021, the proportion of SARS‐CoV‐2 positive test results among pregnant women was higher than in 2020. A positive SARS‐CoV‐2 test during pregnancy increased the risk of stillbirth and perinatal mortality but was not associated with preeclampsia, CS or preterm birth rates.

The strength of this analysis was the use of central databases of good quality covering the whole country and the possibility to include vaccination data. Unlike many reports that compared aggregated data before and during the pandemic ¹ , ⁷ or analyzed cohort data, ⁶ , ⁹ , ¹⁰ we had the advantage of using personalized data and analyzing the impact of SARS‐CoV‐2 infection on an individual level.

As maternal vascular malperfusion causing stillbirth and low Agar scores has been described during SARS‐CoV‐2 infections, ¹⁷ all positive SARS‐CoV‐2 test results during pregnancy regardless of gestational age at the time of confirmed infection were included. Since extensive free‐of‐charge SARS‐CoV‐2 testing was offered in Estonia during the pandemic to all persons with cold symptoms or having been in contact with a person with a positive SARS‐CoV‐2 test result, we believe the testing data to be comprehensive. The limitation was that no distinction between mild and severe COVID‐19 cases could be made. Also, it was not possible to distinguish between different subtypes of SARS‐CoV‐2. The small number of vaccinated women hindered the analysis of vaccination impact, as we were not able to study the timing of vaccination against SARS‐CoV‐2 and the used regimen and number of vaccine doses. Further analysis of 2022 data in Estonia is being planned.

Our finding of increased risk of perinatal mortality associated with SARS‐CoV‐2 infection during pregnancy is consistent with national data showing increased perinatal mortality rate during the pandemic. According to the Estonian Causes of Death Registry data, the perinatal mortality rate per 1000 births was 2.37 in 2019, 2.58 in 2020, 3.58 in 2021 and 2.91 in 2022; the stillbirth rate per 1000 births in the same years was 2.01, 2.20, 2.44 and 2.14, respectively. ¹⁸ As the perinatal mortality rate in Estonia is very low, the relatively small increase in absolute numbers resulted in a statistically significant change in stillbirth and perinatal mortality rates. Globally, stillbirth is varyingly defined; in addition to that, the evidence of SARS‐CoV‐2 association with stillbirth and perinatal mortality may vary due to heterogeneity of study designs, methods of determining SARS‐CoV‐2 infection, baseline risk of study populations and health care settings during the pandemic.

SARS‐CoV‐2 infection was not associated with increased CS rate or preterm birth rate in Estonia. EBMR long‐term data support this finding, showing a stable CS and preterm birth rate over decades. ¹⁹ Further analyses are needed to check whether the negative impact of SARS‐CoV‐2 infection on perinatal outcomes will persist once the virus becomes endemic.

Background characteristics of women giving birth (eg their age, BMI, smoking status) differ across countries and may influence the severity of SARS‐CoV‐2 infection together with concurrent maternal diseases. A recent study from Canada showed that the impact of COVID‐19 on stillbirths and preterm birth was also dependent on the mother's socioeconomic status. ²⁰

In addition, the healthcare settings and clinical guidelines have an impact on follow‐up of women during pregnancy as well as the severity of lockdown restrictions in countries. Together with mothers’ characteristics, this may explain the heterogeneity of reports from different countries on the impact of COVID‐19 on pregnancy outcomes.

A recent systematic review showed that the rate of SARS CoV‐2 infections among vaccinated vs unvaccinated pregnant women is significantly reduced by 43%. ²¹ Considering the different risks of SARS‐CoV‐2 infection during pregnancy on perinatal outcomes, it is important to ensure vaccination for women planning a pregnancy or infertility treatment.

5. CONCLUSION

In Estonia, higher rates of stillbirth and perinatal mortality were observed among babies whose mothers had a positive SARS‐CoV‐2 test at any time during pregnancy. Such patients might benefit from a more vigorous follow‐up during pregnancy. Every effort should be made to fight disparities in healthcare. Most experts believe that SARS‐CoV‐2 is likely to become endemic. Thus, the continued collection of data on the impact of SARS‐CoV‐2 infection during pregnancy and the follow‐up of children born from mothers having had COVID‐19 during pregnancy is needed. Vaccination against COVID‐19 is a priority for pregnant women and women planning pregnancy.

AUTHOR CONTRIBUTIONS

PV planned the study and obtained the data from registries. ON analyzed the data. PV and ON wrote the first draft ad all authors contributed to the final draft and data interpretation. All authors have red and approved the article.

CONFLICT OF INTEREST STATEMENT

The authors have stated explicitly that there are no conflicts of interest in connection with this article.

6. Ethics statement

The study design was approved by Research Ethics Committee of the National Institute for Health Development in Estonia (TAIEK decision No. 1054) on March 23, 2022, and the Estonian Committee on Bioethics and Human Research (EBIN decision No 1.1‐12/193) on April 12, 2022.

Veerus P, Nõmm O, Innos K, Allvee K, Karro H. SARS‐CoV‐2 infection during pregnancy and perinatal outcomes in Estonia in 2020 and 2021: A register‐based study. Acta Obstet Gynecol Scand. 2024;103:250‐256. doi: 10.1111/aogs.14721