Vol 94, No 9 (2023)
Research paper
Published online: 2022-09-21

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Does asymptomatic/uncomplicated SARS-CoV-2 infection during pregnancy increase the risk of spontaneous preterm birth?

Pınar Kumru1, Seyhan Hidiroglu2, Ebru Cogendez1, Habibe Ayvaci1, Betül Yilmazer1, Hümeyra Erol3, Oya Demirci1, Pınar Ay2
Pubmed: 36134763
Ginekol Pol 2023;94(9):704-713.

Abstract

Objectives: The aim of this study was to analyze the perinatal outcomes of asymptomatic/uncomplicated SARS-CoV-2 infection during pregnancy and the relationship between gestational age at the time of infection and spontaneous preterm birth (PTB). Material and methods: This was a retrospective cohort study. The study population included pregnant women who were 19–45 years old and who had been admitted to a Research and Training Hospital for singleton birth delivery. Women who had contracted SARS-CoV-2 during their pregnancy (n = 102) were compared to those who were not infected (n = 378) for the development of spontaneous PTB and other perinatal outcomes. The factors associated with spontaneous PTB were analyzed through univariate and multivariate methods. Results: Spontaneous PTB developed in 22.5% of the pregnant women with a history of SARS-CoV-2 infection and in 5.3% without a history of the infection (p < 0.001). The multivariate model determined that compared to the non-infected women, the OR of spontaneous PTB among those who had contracted the virus in the first, second, and the third trimesters were 9.13 (p < 0.001), 1.85 (p = 0.292) and 7.09 (p < 0.001), respectively. Pregnancy cholestasis (3.9% vs 0.5%; p = 0.020) and placental abruption (3.9% vs 0.5%; p = 0.040) were significantly higher in cases with a history of SARS-CoV-2 infection compared to the non-infected women. Conclusions: Asymptomatic or uncomplicated SARS-CoV-2 infection during pregnancy increases the risk of spontaneous PTB. This risk is higher particularly among pregnant women who develop the infection in the first and the third trimesters.

ORIGINAL PAPER / OBSTETRICS

Ginekologia Polska

2023, vol. 94, no. 9, 704–713

Copyright © 2023 PTGiP

ISSN 0017–0011, e-ISSN 2543–6767

DOI: 10.5603/GP.a2022.0084

Does asymptomatic/uncomplicated SARS-CoV-2 infection during pregnancy increase the risk of spontaneous preterm birth?

Pınar Kumru1Seyhan Hidiroglu2Ebru Cogendez1Habibe Ayvaci1Betül Yilmazer1Hümeyra Erol3Oya Demirci1Pınar Ay2
1Department of Obstetrics and Gynecology, University of Health Sciences, Zeynep Kamil Women and Children’s Disease Training and Research Hospital, Zeynep Kamil, Dr. Burhanettin Üstünel Sokağı, Üsküdar/İstanbul, Turkiye
2Department of Public Health, Marmara University Faculty of Medicine, Istanbul, Turkiye
3Division on Nursing, University of Health Sciences, Zeynep Kamil Women and Childrens Diesease Training and Research Hospital, Department of Obstetrics and Gynecology, İstanbul, Turkiye
ABSTRACT
Objectives: The aim of this study was to analyze the perinatal outcomes of asymptomatic/uncomplicated SARS-CoV-2 infection during pregnancy and the relationship between gestational age at the time of infection and spontaneous preterm birth (PTB).
Material and methods: This was a retrospective cohort study. The study population included pregnant women who were 1945 years old and who had been admitted to a Research and Training Hospital for singleton birth delivery. Women who had contracted SARS-CoV-2 during their pregnancy (n = 102) were compared to those who were not infected (n = 378) for the development of spontaneous PTB and other perinatal outcomes. The factors associated with spontaneous PTB were analyzed through univariate and multivariate methods.
Results: Spontaneous PTB developed in 22.5% of the pregnant women with a history of SARS-CoV-2 infection and in 5.3% without a history of the infection (p < 0.001). The multivariate model determined that compared to the non-infected women, the OR of spontaneous PTB among those who had contracted the virus in the first, second, and the third trimesters were 9.13 (p < 0.001), 1.85 (p = 0.292) and 7.09 (p < 0.001), respectively. Pregnancy cholestasis (3.9% vs 0.5%; p = 0.020) and placental abruption (3.9% vs 0.5%; p = 0.040) were significantly higher in cases with a history of SARS-CoV-2 infection compared to the non-infected women.
Conclusions: Asymptomatic or uncomplicated SARS-CoV-2 infection during pregnancy increases the risk of spontaneous PTB. This risk is higher particularly among pregnant women who develop the infection in the first and the third trimesters.
Keywords: SARS-CoV-2; COVID-19 pandemic; pregnancy; preterm birth; perinatal outcome
Ginekologia Polska 2023; 94, 9: 704713

Corresponding author:

Pınar Kumru

Department of Obstetrics and Gynecology, University of Health Sciences, Zeynep Kamil Women and Children’s Disease Training and Research Hospital, Zeynep Kamil, Dr. Burhanettin Üstünel Sokağı No:10, 34668 Üsküdar/İstanbul, Turkiye

e-mail: pkumru@gmail.com

Received: 10.01.2022 Accepted: 14.08.2022 Early publication date: 21.09.2022

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

INTRODUCTION

The 2019 Coronavirus Disease (COVID-19) pandemic is an ongoing major global health crisis in our time. To date, close to 233 million cases infected with SARS-CoV-2 have been confirmed, and 4.8 million deaths have been reported [1]. A multicenter prospective study from Spain, one of the countries most affected by the pandemic, reported that SARS-CoV-2 screening of 16,308 pregnant women who were admitted for delivery and had no suspected infection or symptoms showed a 2.07% positivity rate [2]. Indeed, the current literature highlights the prevalence of asymptomatic infections and recommends that all pregnant women be routinely screened for SARS-CoV-2 infection during their hospital stay [3].

According to the data of centers in London and New York that routinely order SARS-CoV-2 testing for patients admitted to the labor floor, 88% of infected women remain asymptomatic [4]. It has been determined that SARS-CoV-2 infection causes changes in systemic immune response and an increase in the pro-immune inflammatory response in pregnancy, as well as in non-pregnant women. In addition, histopathological examinations have shown that the virus causes pathologic changes of the placenta [5]. The World Association of Perinatal Medicine (WAPM) has reported that COVID-19 infection may increase the risk of hypoxemia in pregnant women, thereby increasing maternal morbidity and mortality compared to the general population [6]. Recent studies have shown that pregnant women infected with SARS-CoV-2 are more at risk of adverse perinatal outcomes such as maternal death, need for maternal intensive care, preterm birth (PTB), premature rupture of membranes (PROM), venous thrombosis, and neonatal intensive care need compared to the general population [7, 8].

However, most of the studies conducted so far have reported maternal and neonatal outcomes of pregnant women who had complicated SARS-CoV-2 infection during pregnancy or were infected with SARS-CoV-2 peripartum. The effect of COVID-19 on pregnancy outcomes in women who had asymptomatic or uncomplicated SARS-CoV-2 infection during pregnancy has not been adequately demonstrated. In addition, the relationship between gestational age at SARS-CoV-2 infection and pregnancy outcomes remains unclear.

Objectives

The aim of this study is to analyze the perinatal outcomes of asymptomatic/uncomplicated SARS-CoV-2 infection during pregnancy and the relationship between gestational age at the time of infection and spontaneous PTB.

MATERIAL AND METHODS

Setting and study participants

Designed as a retrospective cohort study, this study was carried out between March 2021 and June 2021 in Zeynep Kamil Women and Children’s Diseases Training and Research Hospital. The study population is women admitted for delivery and followed up during the postpartum period in clinic.

Pregnant women aged between 1945 years, between 22 and 42 weeks of gestation, and who had a negative SARS-CoV-2 polymerase chain reaction (PCR) test at admission to the delivery room were included in the study. SARS-CoV-2 PCR test includes real-time PCR (qPCR)(RT-qPCR) that targets the RdRp gene fragment. All pregnant women who presented to our hospital for delivery, regardless of the presence of symptoms, underwent screening for SARS-CoV-2. The laboratory has been authorized by the Republic of Turkiye Ministry of Health, General Directorate of Public Health, Microbiology Reference Laboratory. For PCR analysis, swab samples from the oropharynx and nasopharynx were used. Women who gave birth at ≤ 22 weeks of gestation, stillbirths and termination of pregnancy cases, multiple pregnancies, and positive SARS-CoV-2 PCR test at the time of admission were excluded from the study.

Sample size calculation

The sample size was calculated using OpenEpi (Version 3). The primary outcome was PTB rate, which was reported to be approximately 23% in women with COVID-19 in a systematic review by Capobianco et al. [9]. In Turkiye, among the general population without a history of COVID-19, the PTB rate is approximately 10%. Considering the relatively limited number of people with COVID-19, we thought that it was appropriate to include a positive history of COVID-19 and non-exposed group in a 1:3 ratio; therefore, we planned to include at least 79 postpartum women in the positive history of SARS-CoV-2 group and at least 235 postpartum women in the negative history of SARS-CoV-2 group for a 5% alpha error and 80% power.

Definition of the variables

Outcome variable: In the study, the primary outcome was spontaneous PTB, which was defined as spontaneous (spontaneous rupture of membranes or spontaneous onset of contractions and onset of labor) or iatrogenic [planned cesarean section or induction of labor due to maternal (severe preeclampsia, abruptio placentae) or fetal (FGR and fetal distress) reasons] delivery before 37 weeks of gestation. Exposure variable: The exposure group consisted of women who were diagnosed with COVID-19 by PCR test at any time during pregnancy. Some of the women were tested due to symptoms, while others were tested because they had been in contact with a COVID-19 patient. PCR results were obtained from electronic patient records, and the time of infection was recorded to determine the trimester of the exposure. Clinical symptoms of the disease (fever, shortness of breath, air hunger, weakness, cough, headache, inability to taste and smell), the need for hospitalization due to COVID-19, and the need for medication or intensive care were questioned.

The COVID-19 clinical disease spectrum of the participants was determined according to the criteria of the NIH and the Turkish Ministry of Health. According to this spectrum, all cases were asymptomatic or met the criteria for mild disease [10]. Two out of 104 women with a positive history of COVID-19 infection were excluded because they did not meet the inclusion criteria, and 102 women were included in the study. The non-exposure group consisted of pregnant women who were not diagnosed with COVID-19 by PCR test during their pregnancy. Considering that there may be those without a positive PCR test even though they had COVID-19, symptoms of upper and lower respiratory tract diseases during pregnancy were questioned, and those with possible suspected COVID-19 were excluded from the study.

Cases without exposure were determined by the systematic sampling method. The 3rd, 6th, 9th, and 12th women, starting from the 3rd woman in the registry on the day of admission to the postpartum service of the participant included in the exposure group, constituted the non-exposure group. Three hundred seventy-eight pregnant women were included in the group without exposure. The participants’ sociodemographic characteristics, medical history, obstetric history [spontaneous PTB, preeclampsia, gestational diabetes mellitus (GDM), intrahepatic cholestasis of pregnancy], and current obstetric characteristics (antenatal period, birth, and neonatal period information) were evaluated. The definitions of perinatal outcomes (GDM, preeclampsia, small for gestational age (SGA), low birth weight (LBW), and intrahepatic cholestasis of pregnancy) were determined according to international criteria [11–15].

Data collection tools

Gestational age was calculated by using the first day of the last menstrual period and was confirmed by first trimester crown-rump length (CRL). Socio-demographic, personal health, antenatal period, birth, and postnatal characteristics of the participants and clinical characteristics of COVID-19 were obtained from the electronic database of our institution. Missing data were obtained by phone interviews with patients.

Ethical approval

The study was approved by the local ethics committee (decision number 65, dated 03/2021). All procedures in our study were carried out per the 1964 Declaration of Helsinki and subsequent amendments.

Data analysis

The conformity of the variables to the normal distribution was examined using visual (histogram and probability graphs) and analytical methods (Kolmogorov-Smirnov). Descriptive statistics are presented as median [interquartile ranges (IQR)] for the numerical variables and as ratios for the categorical variables. The median differences between groups were compared using the Mann-Whitney U test. The Kruskal-Wallis test was used to compare the quantitative data of three groups that did not show normal distribution. In the comparison of qualitative data, Chi-Square test or Fisher’s Exact Chi-Square test was used when test conditions could not be met. For multivariate analyses, logistic regression backward stepwise method was used. Variables with p < 0.1 and those found to be associated in the literature were included in the multivariate model. The strength of the relationship was defined by the OR (95% confidence interval). p < 0.05 was evaluated as statistically significant.

RESULTS

Between March and June 2021, a total of 1387 pregnant women gave birth at Zeynep Kamil Women and Children’s Diseases Training and Research Hospital. All patients were screened for SARS-CoV-2 infection at the time of admission to the maternity ward, and 15 (1.08%) women were excluded due to SARS-CoV-2 PCR positivity. The study population is shown in the flowchart (Fig. 1).

Figure 1. Flow chart of the study population; aCases without exposure were determined by the systematic sampling method; PCR polymerase chain reaction

The demographic characteristics of the participants are presented in Table 1. Univariate analysis evaluating the relationship between perinatal and neonatal outcomes of the participants with SARS-CoV-2 infection history are presented in Table 2. Spontaneous PTB was detected in 22.5% of cases with a history of SARS-CoV-2 infection and 5.3% of cases without a history of infection; the difference was statistically significant (p < 0.001). In our study, iatrogenic preterm birth rates were found to be statistically similar in the group with and without a history of COVID-19 (p = 0.058). In the group with a history of COVID-19, pregnant women had iatrogenic preterm deliveries due to severe preeclampsia (n = 4, 3.9%) and abruptio placentae (n = 4, 3.9%). Among the pregnant women without a history of COVID-19, pregnant women had iatrogenic preterm deliveries due severe preeclampsia (n = 34, 9%), abruptio placentae (n = 3, 0.8%), and FGR and fetal distress (n = 20, 5.3%).

Table 1. Socio-demographic and health characteristics of participants (n: 480)

Exposure groupa

n: 102

Nonexposure groupb

n: 378

p value

Maternal Characteristics and Maternal Comorbidities

BMI [kg/m2], median (IQR)

31.2 (27.334.1)

30.4 (27.333.3)

0.352

n (%)

n (%)

Age Range [years]

1924

14 (13.7)

67 (17.7)

0.462

2534

66 (64.7)

220 (58.2)

3545

22 (21.6)

91 (24.1)

Educational status

Primary school

26 (25.2)

80 (21.2)

0.215

Secondary school

19 (18.6)

101 (26.7)

High school

30 (29.4)

121 (32.0)

University

27 (26.5)

76 (20.1)

Family income

Low

17 (16.7)

56 (14.8)

0.896

Medium

76 (74.5)

287 (75.9)

High

9 (8.8)

35 (9.3)

Employed

27 (26.5)

76 (20.1)

0.165

Social security

86 (84.3)

317 (83.9)

0.912

Nulliparous

31 (30.4)

110 (29.1)

0.799

In vitro fertilization

5 (4.9)

3 (0.8)

0.013*

History of smokingc

22 (21.6)

73 (19.3)

0.612

Husband’s history of smoking

54 (52.9)

225 (59.5)

0.232

Chronic diseases

30 (29.4)

108 (29.1)

0.953

aWomen with a history of PCR + SARS-CoV-2 Infection; bWomen with no history of SARS-CoV-2 Infection; ccurrent smoker or ex-smoker; IQR interquartile range; BMI body mass index; *Statistically significant difference

Table 2. Pregnancy, birth, postpartum period, and neonatal outcomes of the participants (n: 480)

Exposure groupa

n: 102

Nonexposure groupb

n: 378

p value

Obstetric Outcomes of the Participants

Gestational age at delivery

median [weeks] (IQR)

38 (3739)

39 (3739)

0.271

n (%)

n (%)

Mode of birth

C/S

68 (66.7)

241 (63.8)

0.586

Vaginal delivery

34 (33.3)

137 (36.2)

Spontan. preterm delivery (< 37 weeks)

23 (22.5)

20 (5.3)

< 0.001*

Iatrogenic preterm labor (< 37 weeks)

8 (7.8)

57 (15.1)

0.058

Spontan. early preterm delivery (< 34 weeks)

6 (5.9)

16 (4.2)

0.435

Spontaneous PPROM

6 (5.9)

15 (4.0)

0.415

Hypertensive disease

12 (11.8)

43 (11.4)

0.913

Type of hypertensive disease

Chronic HT

1 (0.3)

0.663

Gestational HT

4 (3.9)

8 (2.1)

Preeclampsia/Eclampsia

8 (7.8)

30 (7.9)

Superimposed Preeclampsia

-

4 (1.1)

No hypertensive disease

90 (88.2)

335 (88.6)

GDM

24 (23.5)

61 (16.1)

0.083

Cholestasis

4 (3.9)

2 (0.5)

0.020*

Abruptio Placenta

4 (3.9)

3 (0.8)

0.040*

Neonatal Outcomes

Newborn birth weight [grams],

median (IQR)

3305.0 (27403580.0)

3230.0 (2880.03580.0)

0.999

n (%)

n (%)

Fetal gender

Male

Female

43 (42.2)

201 (53.2)

0.048*

59 (57.8)

177 (46.8)

Admitted in NICU

31 (30.4)

95 (25.1)

0.284

Apgar 5 score < 7

5 (4.9)

6 (1.6)

0.061

SGA

10 (9.8)

35 (9.3)

0.867

LGA

19 (18.6)

81 (21.4)

0.536

Birthweight < 2500 gm

15 (14.7)

50 (13.2)

0.699

Birthweight > 4000 gm

5 (4.9)

18 (4.8)

1.0

Neonatal Death

1 (1.0)

4 (1.1)

1.0

Fetal anomaly

9 (8.8)

21 (5.6)

0.226

Cardiac anomaly

2 (2.0)

4 (1.1)

0.612

CNS anomaly

4 (3.9)

4 (1.1)

0.067

aWomen with a history of PCR + SARS-CoV-2 Infection; bWomen with no history of SARS-CoV-2 Infection; IQR interquartile range; C/S Cesarean section; PPROM Preterm premature rupture of membranes; GDM Gestational diabetes mellitus; HT Hypertension; NICU Neonatal İntensive Care Unit; SGA Small for gestational age (Intergrowth 21); LGA large-for-gestational-age; CNS Central nervous system; *Statistically significant difference

The relationship between the gestational week of COVID-19 exposure and fetal anomaly was examined and no statistically significant difference was found (p = 0.9). However, fetal CNS anomalies were detected in three (10.3%) out of 29 women with a history of COVID-19 in the first trimester, and all these patients were symptomatic (all of them had fever, respiratory distress, headache, and malaise) (Tab. 3). The median (IQR) gestational week at which the participants were infected with SARS-CoV-2 was 22.0 weeks (13.029.0); 29 (28.4%) were infected in the first trimester, 41 (40.2%) were infected in the second trimester, and 32 (31.4%) were infected in the third trimester. When the groups were compared according to the trimester of infection, no significant differences were found in terms of maternal age, BMI, and mode of delivery (p > 0.05). However, the gestational age at birth of the pregnant women who were infected in the first trimester was lower than in pregnant women who were infected in the second and third trimesters (p = 0.005). Birth weight was also found to be lower if the infection was contracted in the first trimester compared to the second trimester (p = 0.018). The rates of spontaneous PTB were found to be higher in pregnant women who were infected in the first (34.5%) and third (28.1%) trimesters than in pregnant women who were infected in the second trimester (9.8%) (p = 0.034).

Table 3. The relationship between trimester during SARS-CoV-2 infection and maternal, current obstetric, postpartum, and neonatal period characteristics (n: 102)

Infection in 1st trimester

n: 29

Infection in 2nd trimester

n: 41

Infection in 3rd trimester

n: 32

p value

Maternal and Current Obstetric Outcomes of the Participants

BMI [kg/m2], median (IQR)

31.2 (27.634.0)

31.6 (29.634.9)

30.2 (26.533.6)

0.408

Gestational age at delivery [weeks], median (IQR)

37.0 (36.039.0)

39.0 (38.039.0)

38.0 (37.039.5)

0.005*

Newborn birth weight [grams], median (IQR)

2940.0 (2490.03440.0)

3400.0 (3210.03600.0)

3125.0 (2650.03595.0)

0.018*

N (%)

N (%)

N (%)

Age Range [years]

2534

3545

19-24

4 (13.8)

4 (9.8)

6 (18.8)

0.752

19 (65.8)

29 (70.7)

18 (56.2)

6 (20.7)

8 (19.5)

8 (25.0)

Symptomatic SARS-CoV-2

22 (75.9)

17 (41.5)

21 (65.6)

0.010*

Mode of birth

Vaginal delivery

C/S

20 (69.0)

29 (70.7)

19 (59.4)

0.566

9 (31.0)

12 (29.3)

13 (40.6)

Spontan. preterm delivery (< 37 weeks)

10 (34.5)

4 (9.8)

9 (28.1)

0.034*

İatrogenic preterm labor (< 37 weeks)

6 (20.7)

1 (2.4)

1 (3.1)

0.010*

Spontaneous PPROM

4 (13.8)

1 (2.4)

1 (3.1)

0.100

Hypertensive disease

6 (20.7)

4 (9.8)

2 (6.2)

0.190

Type of hypertensive disease

Chronic HT

0.469

Gestational HT

2 (6.9)

1 (2.4)

1 (3.1)

Preeclampsia/Eclampsia

4 (13.8)

3 (7.3)

1 (3.1)

Superimposed Preeclampsia

No hypertensive disease

23 (79.3)

38 (90.5)

30 (93.8)

GDM

6 (20.7)

10 (24.4)

8 (25.0)

0.912

Cholestasis

4 (12.5)

0.011*

Abruptio placenta

3 (10.3)

1 (3.1)

0.086

Neonatal Outcomes

Admitted to NICU

10 (34.5)

10 (24.4)

11 (34.4)

0.558

Apgar 5 score < 7

1 (3.4)

2 (4.9)

2 (6.2)

0.880

SGA

4 (13.8)

4 (9.8)

2 (6.2)

0.613

LGA

4 (13.8)

9 (22.0)

6 (18.8)

0.689

Birthweight < 2500 gr

7 (24.1)

2 (4.9)

6 (18.8)

0.060

Birthweight > 4000 gr

1 (3.4)

1 (2.4)

3 (9.4)

0.361

Fetal anomaly

3 (10.3)

3 (7.3)

3 (9.4)

0.900

Neonatal death

1 (3.4)

0.281

BMI body Mass Index; IQR interquartile range; C/S cesarean section; PPROM preterm premature rupture of membranes; GDM gestational diabetes mellitus; HT hypertension; NICU neonatal Intensive Care Unit; SGA small for gestational age (Intergrowth 21); LGA large-for-gestational-age; CNS central nervous system; *Statistically significant difference

All cases diagnosed with intrahepatic cholestasis of pregnancy were women who had the infection in the third trimester. Although not statistically significant, placental abruption was detected in 10.3% of the cases infected with SARS-CoV-2 in the first trimester (p = 0.086). Birth weight of < 2500 g was more common among those who had the infection during the first and third trimesters, but this result was not statistically significant (p = 0.060). Neonatal complications did not differ between groups (p > 0.05) (Tab. 3).

Models were created using multivariate logistic regression (Backward LR) analysis to evaluate the independent effects of variables associated with spontaneous PTB. The model included maternal age groups, BMI, smoking, mode of conception (spontaneous/in vitro fertilization), fetal sex, and history of COVID-19 during pregnancy.

In multivariate logistic regression analysis, when the status of not having COVID-19 infection during pregnancy is taken as a reference, we calculated that the risk of spontaneous PTB was 9.13 times higher (95% CI 3.6822.66; p < 0.001) in those who were infected in the first trimester, and 7.09 times higher (95% CI 2.8517.62; p < 0.001) in those infected in the third trimester. If the infection occurred in the second trimester, the risk of spontaneous PTB birth was 1.85 times higher (95% CI 0.595.79; p = 0.292); this result was not statistically significant (Tab. 4).

Table 4. Characteristics associated with spontaneous preterm birth, univariate and multivariate analyses

Spontaneous preterm delivery

OR (95% CI)

Univariate analysis (OR)

Multivariate analysis (aOR)

p value

aOR (95% CI)

p value

SARSCoV2 positive status in pregnancy

SARSCoV2 negative

1.0

1.0

1st Trimester

9.42 (3.8822.90)

< 0.001*

9.13 (3.6822.66)

< 0.001*

2nd Trimester

1.94 (0.635.96)

0.250

1.85 (0.595.79)

0.292

3rd Trimester

7.00 (2.8717.10)

< 0.001*

7.09 (2.8517.62)

< 0.001*

Age [years]

1924

1.0

2534

1.78 (0.674.75)

0.249

3445

1.16 (0.373.68)

0.803

BMI [kg/m2]

0.95 (0.891.01)

0.117

0.94 (0.881.01)

0.096

Educational status

Primary school

0.52 (0.171.60)

0.252

Secondary school

1.38 (0.573.33)

0.475

High school

1.15 (0.482.74)

0.749

University

1.0

Income of family

Low

0.56 (0.181.72)

0.312

Medium

0.46 (0.191.12))

0.087

High

1.0

Working Status

Yes

0.90 (0.732.98)

0.168

No

1.0

Fetal gender

Female

1.0

0.014*

1.0

0.023*

Male

2.30 (1.184.48)

2.25 (1.124.53)

IVF pregnancy

No

1.0

0.013*

Yes

6.48 (1.4928.11)

Smoking habita

No

1.0

0.165

Yes

1.65(0.813.35)

Chronic diseases

No

1.0

0.587

Yes

0.82 (0.401.68)

Hypertensive diseases during pregnancy

No

1.0

0.340

Yes

0.56 (0.171.86)

BMI Body Mass Index; IVF In vitro fertilization; acurrent smoker or exsmoker; OR Odds ratio; CI confidence interval; Adjusted odds ratio (aOR) multiple imputation model adjusted for age groups, BMI, smoking habit, IVF pregnancy and SARS-CoV-2 positive status in pregnancy; 1.0 = as a reference; *Statistically significant difference

DISCUSSION

It is known that various viral infections increase the risk of fetal anomalies, fetal growth restriction (FGR), and PTB by negatively affecting fetal health [16]. When the first data on COVID-19 and pregnancy began to emerge, it was reported that almost all PTB were iatrogenic, due to deteriorating maternal status of COVID-19 or because of obstetric complications not related to COVID-19 [17]. Recent studies have reported that SARS-CoV-2 infection leads to an increased risk of PTB and LBW [9, 18–21].

Two systematic reviews from studies conducted in the early period of the pandemic reported an increased incidence of PTB, LBW, cesarean section, and Neonatal İntensive Care Unit (NICU) admissions in pregnant women infected with SARS-CoV-2 [18, 22]. Most of these studies were laboratory-confirmed, admitted to the intensive care unit, and nearly all had positive findings on thoracic computed tomography (CT) scans. Therefore, these studies have undeniable limitations such as that most of the cases were in critical condition, sample sizes were small, and there was a lack of information about pre-pregnancy medical conditions. SARS-CoV-2positive pregnant women with comorbidities are more likely to develop complications [23]. From this point of view, we analyzed the perinatal outcomes of asymptomatic and uncomplicated women and, by this, to reveal what kind of damage COVID-19 actually causes in pregnancy. The reason why we have chosen asymptomatic/uncomplicated pregnant women as the study population is that the most common form of COVID-19 is mild and moderate disease, and the literature data on this subject is limited.

The WAPM COVID-19 Working Group retrospectively analyzed the data of 266 women who had a singleton pregnancy, had laboratory-confirmed SARS-CoV-2 infection, and gave birth between February and April 2020. It was reported that 94.4% of women had a live birth, 26.3% had PTB before 37 weeks of gestation, 27.5% of newborns were admitted to the NICU, and 2.0% neonatal deaths were reported. What draws our attention is that approximately 70% of the pregnant women included in the study were in the third trimester [6]. In the meta-analysis by Capobianco et al. [9], consisting of 13 publications and 114 cases, the authors reported a high rate of maternal and neonatal complications in infected individuals. Elshafeey et al. [24] analyzed the results of 385 SARS-CoV-2positive pregnant women. In that study, 95.6% of the cases were mild infections, similar to the case group we selected in our study. However, in the study of Elshafeey et al., SARS-CoV-2positive pregnant women were not compared to uninfected pregnant women. The authors reported PTB (< 37 weeks of gestation) in 39 pregnant women, LBW (< 2500 g) in 20 newborns, fetal distress in 20, and need for NICU admission in 8 newborns. In our study, 23 cases had spontaneous PTB (< 37 weeks of gestation), 15 cases had LBW (< 2500 g), and 31 newborns required NICU admission in the asymptomatic or uncomplicated SARS-CoV-2 infection group. The rate of spontaneous PTB in pregnant women with a history of COVID-19 was significantly higher than in pregnant women without exposure to COVID-19.

Maternal SARS CoV-2 infection causes maternal immune activation resulting in pro-inflammatory cytokine release. This leads to the disturbance of placental perfusion and ultimately to placental dysfunction. Vascular malperfusion, fetal vascular thrombosis, infection with widespread inflammation, fibrin deposition, and intervillous thrombosis have been demonstrated in placenta samples of pregnant women infected with SARS-CoV-2 [5]. Smithgall et al. [25] collected placenta samples from 51 women with SARS-CoV-2 positive at delivery, and pathological examination was performed. Interestingly, it was reported that the frequency of placental histopathological findings was independent of the clinical status, and there was no difference between symptomatic and asymptomatic cases in terms of histopathological findings. This information suggests that asymptomatic or uncomplicated COVID-19 may also increase the risk of obstetric complications such as PTB, FGR, and LBW.

Another important issue that remains unknown is whether perinatal outcomes change according to the timing of infection (in which trimester). Although the WAPM COVID-19 Working Group reports that the incidence of combined adverse fetal outcomes increases significantly if infection occurs in the first trimester, we observed that spontaneous PTB occurred 9.13 and 7.09 times more often in women who were infected during the first and third trimesters, respectively, independent of other risk factors. Although we found that second trimester infection did not independently affect the risk of spontaneous PTB, we think that a possible type 2 error should not be ignored, and this issue should be re-examined with prospective studies in larger samples.

Preterm birth is an important public health problem that may adversely affect the health of the newborn and has short- and long-term effects [26]. The global prevalence of PTB has been reported as 10.6% [27]. As information from studies cumulates, countries may need to reconsider their healthcare policies regarding COVID-19. Determining vaccination strategies in pregnant women will be important in preventing COVID-19 and associated obstetric complications, especially PTB.

In our study, with its retrospective cohort design, SARS-CoV-2 infection during pregnancy was confirmed by PCR test positivity, and the gestational age at the time of the infection was correctly determined; these are the strengths of our research. Until now, most studies have evaluated PTB cases without distinguishing them as spontaneous and iatrogenic. However, in our study, we evaluated iatrogenic PTB cases of obstetric or maternal origin separately from spontaneous PTB cases. Therefore, our findings will help to explain the relationship between spontaneous PTB and COVID-19, for which there is not yet enough information in the literature.

Our study has some limitations. A significant number of COVID-19 infected individuals survive the disease without any symptoms or are not diagnosed by PCR. The diagnostic value of the PCR test is limited to 50-60%, and it may result in missed diagnosis. This may cause misclassification bias between the groups that had and did not have the infection. Since our research was conducted in a single center, the generalizability of the results to the general population is limited.

CONCLUSIONS

In conclusion, asymptomatic or uncomplicated pregnant women infected with SARS CoV-2 during the first and third trimesters should be followed up carefully and closely for spontaneous PTB, at least as much as pregnant women with complicated disease. In addition, one should keep in mind placental abruption and intrahepatic cholestasis of pregnancy during the course of follow-up. The fact that SARS CoV-2 infection has been associated with the risk of PTB in all spectrums, regardless of the severity of the disease, may reveal the importance of the COVID-19 vaccine in pregnancy, although data on its safety are limited. In this context, it seems reasonable to offer the vaccine option to pregnant women after proper counseling.

Article information and declarations
Author contribution

P Kumru: Project development, data collection, data analysis

S Hıdıroğlu: Project development, methodology, editing, supervision

E Cogendez: Manuscript writing / editing

H Ayvacı: Data collection

B Yılmazer: Data collection

H Erol: Data collection

O Demirci: Supervison

P Ay: Project development, methodology, supervision

Acknowledgments

We are grateful to all participants who spent their precious time and participated in this research program. We are also thankful all the healthcare professionals working in the postpartum service, and our medical secretary Elif Delen Deveci.

Conflict of interest

All authors declare no conflict of interest.

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