Effect of coronavirus-19 infection on maternal and perinatal outcome: A case control study

Abstract

Introduction: Coronavirus 2019 virus infections have an impact on the obstetric population. Methods: We performed a single centre, prospective case-control study in a tertiary care centre during the first wave of the pandemic, over a period of six months. All Labouring women who tested positive for SARS-CoV2 on the date of admission were included in the study (cases). As a control, SARS-CoV2 negative women who delivered before and after the coronavirus-positive delivery were included. Results: The control group were significantly younger than the cases (p = 0.001). The odds of spontaneous labour were observed to be significantly higher among the cases as compared to the control group (p = 0.002). The likelihood of NICU admission was significantly higher among the cases compared to the control group on applying Fischer exact test (p < 0.001) Conclusion: SARS-CoV2 positive mothers are more likely to deliver neonates with feeding difficulties and requiring NICU admission, compared to SARS-CoV2 negative mothers.

Keywords

Coronavirus COVID 19 infection pregnancy neonate respiratory distress SARS-CoV2

Background

COVID-19 infections have changed the face of medical care worldwide since the first case was reported to the World Health Organisation (WHO) Country Office by China on December 31, 2019. It was named by WHO as a new coronavirus disease in February, 2020: Coronavirus 2019 (COVID-19). In few months it spread to all regions so rapidly that it was declared a global pandemic by WHO on March 11, 2020.¹

Pregnant women, due to their immunosuppressive state as well as the physiological changes which occur (e.g. increased heart rate, stroke volume, tidal volume, oxygen consumption, decreased lung capacity and oedema of respiratory tract mucosa), are particularly prone to some respiratory pathogens and COVID-19 is no exception. During this global health crisis, pregnant women and their newborns were also significantly affected.^2–4 The diagnosis of COVID-19 is confirmed by reverse transcription-polymerase chain reaction (RT-PCR) assay.^5,6

The virus is transmitted mainly via respiratory droplets and/or contact and human-to-human transmission and family clustering have been reported.^7,8 Whereas its transmission mainly occurs through human-to-human contact, the novel coronavirus has shown its potential to transmit via multiple routes.⁹ It remains unclear whether or not this potentially fatal virus can be transmitted vertically and what the possible effects of disease on the pregnancy outcomes are.

There is currently little evidence-based guidance specific to pregnant women regarding the evaluation or management of COVID-19. The objectives of our study were to assess the maternal and fetal outcome in asymptomatic as well as symptomatic pregnant women with SARS-CoV2 infection and to compare the feto-maternal outcome of SARS-CoV2 positive women with SARS-CoV2 negative women.

Material and methods

We performed a case-control, prospective, single centre study in the Department of Obstetrics and Gynaecology, Hamdard Institute of Medical Science & Research and Hakeem Abdul Hameed Centenary Hospital, New Delhi, India. It was done from May 2020 to Oct 2020 over a period of six months, during the first wave of the pandemic. The hospital is located in the South Delhi area and caters to a lower to middle socioeconomic strata of the population living in the area nearby, with tertiary level maternal and neonatal care facilities available within. The average delivery rate of our institute is 1500 deliveries per year. This hospital has a tertiary care level nursery facility. All the term antenatal women (37 weeks or more) and preterm antenatal women (under 37 weeks) in labour, whether presenting to the outpatient department or gynaecology emergency were advised to test for SARS-CoV2 infection by RT-PCR or Cartridge Based Nucleic Acid Amplification Test (CBNAAT). Rapid antigen test was done whenever feasible to get immediate results. The pregnant women who tested positive by either rapid antigen test, RT-PCR or CBNAAT were included in the study as cases. Their pregnancy was managed following standard obstetric management with a check on COVID related respiratory and other symptomatology. Caesarean deliveries were done according to obstetric indication only. COVID antigen testing was advised to all close contacts of SARS-CoV2 positive pregnant women. The standard protocol of notification and contact tracing of a positive case was followed. At the time of delivery of cases, the deliveries by either vaginal delivery or lower segment caesarean section (LSCS) before and after the timing of the SARS-CoV2 positive case were taken as controls. Pregnant women who presented before term and were not in labour irrespective of their COVID status, or labouring women who were not willing to undergo COVID-19 testing, or not willing to participate in the study were excluded from the study.

The neonatal outcome was assessed in both cases and the control group after delivery. Investigations were ordered according to the clinical status of the neonate. All neonates were tested for COVID status as per protocol. All the details such as demographic profile, obstetric profile, investigations, delivery details, mode of delivery, any antepartum, intrapartum or postpartum complications and neonatal complications were collected. Both mother and neonate in both the groups were discharged after giving proper instructions regarding postnatal care of the baby, warning signs and postpartum contraception.

Patients were advised to return to the hospital for evaluation if they experienced any postpartum complaints including excessive bleeding, high-grade fever, dyspnoea, difficulty in breathing, severe pain, syncopal attack or obstipation. In the case of minor ailments, they were advised to consult by telephone. Follow-ups were done at 2 weeks and 6 weeks to assess the status of the mother and baby, by detailed clinical interview.

The primary outcome measure studied and the feto-maternal outcome was compared in both groups. Other parameters observed as outcome measures were the clinical spectrum SARS-CoV2 infection in pregnancy. Standard statistical analysis was done, with the comparison between groups using the Fisher exact test. A p-value of <0.05 was considered statistically significant.

Results

A total of 70 pregnant women who were SARS-CoV2 positive and fulfilled the inclusion criteria were grouped as cases while 116 antenatal SARS-CoV2 negative women were grouped as controls. In the cases group, the total number of neonates assessed was 72 as there were two twin deliveries. The demographic details are tabulated in Table 1. In the age group distribution, it was observed that among controls there were a higher proportion of subjects in the age group 20–25 and 26–30 years compared to cases (p = 0.001). Other demographic characteristics were uniformly distributed among cases and controls with no significant differences.

Table 1.

Demographic characterstics of study cases and controls.

	Cases (n = 70)number (%)	Controls (n = 116)number (%)	p-value
Age (years)
20–25	28 (40)	46 (39.6)	0.001
26–30	22 (31)	60 (52)
31–35	16 (23)	6 (5)
>35	4 (5.7)	4 (3.4)
Parity
Primiparous	30 (43)	58 (50)	0.344
Multiparous	40 (57)	58 (50)	0.344
Gestation (weeks)
<37	12 (17)	14 (12)	0.096
37–40	42 (60)	58 (50)
>40	16 (23)	44 (38)
BMI (kg/m²)
Underweight (< 18.5)	0 (0)	6 (5.2)	0.271
Normal (18.5- 22.9)	52 (74)	80 (69)
Overweight (23–24.99)	14 (20)	22 (19)
Obese (≥ 25)	4 (5.7)	8 (6.9)

BMI: body mass index. p < 0.05 is taken as significant.

The complaints with which women presented to our hospital were labour pain (54, 77.1%; 74, 63.8%), vaginal fluid loss (8, 11.4%; 22, 18.9%), impending eclampsia features (6, 8.6%; 6, 5.2%), decreased fetal movements (2; 2.8%,0; 0%), vaginal bleeding (0; 0%,2; 1.7%) and post-term pregnancy (0, 0%;12, 10.3%) among cases and controls respectively. The SARS-CoV2 positive pregnant women reported no COVID-related symptoms. The nature of labour whether induced or spontaneous labour are tabulated in Table 2. It was observed that spontaneous labour was observed to be significantly more common among the cases compared to the control group.

Table 2.

Nature of labour.

Labour	Case (n = 70)number (%)	Control (n = 116)number (%)	p-value
Spontaneous	62 (89)	80 (69)	0.002
Induced	8 (11)	36 (31)	0.002

p < 0.05 is taken as significant.

The various obstetric complications such as fetal growth restriction (FGR) (8.6% cases, 12.1% controls), pre-eclampsia (8.6% cases, 5.2% controls), gestational diabetes mellitus (2.8% cases, 6.9% controls), preterm labour (8.6% cases, 5.2% controls), premature rupture of membranes (11.4% cases, 18.9% controls), intrauterine death (2.8% cases, 0% controls), oligohydramnios (0% cases, 1.7% controls) were not significantly different between cases and controls. Two intrauterine deaths occurred among the cases, one at preterm gestation (32 weeks and 3 days) and the other at term (38 + 2 weeks and 2 days) gestation. Neither death was associated with maternal high-risk factors such as preeclampsia, diabetes, intrahepatic cholestasis of pregnancy, FGR, oligohydramnios or congenital malformation. Histopathology of the placenta in both the cases did not reveal any abnormality.

The mode of delivery was vaginal in 46/70 (65.7%) patients among cases and in 90/116 (77.6%) patients among controls. Caesarean delivery was required in 22 women. Instrumental delivery was performed in two cases and four controls. The indications for caesarean delivery in the two groups were fetal distress (cases 12, 54.5%; controls 18, 81.8%), malpresentation (2, 9.1%; 0, 0%), meconium-stained liquor with fetal distress (2, 9.1%; 2, 9.1%), previous caesarean delivery (6, 27.3%; 0, 0%) and failed induction (0, 0%; 2, 9.1%), which were uniformly distributed among cases and controls. The birth weight of neonates is compared in Table 3; there was no significant difference.

Table 3.

Birth weight.

Birth weight (KG)	Case^a (n = 72)number (%)			Control (n = 116)number (%)			p-value
< 2.5	12 (167)	Preterm	6	20 (17)	Preterm	6	0.919
< 2.5	12 (167)	Term	6	20 (17)	Term	14
≥ 2.5	60 (83)			96 (83)

There were two twin deliveries among the cases.

It was observed that the likelihood of Neonatal Intensive Care Unit (NICU) admission was observed to be significantly higher among the cases as compared to the control group. These data are tabulated in Table 4.

Table 4.

Neonate condition immediately postpartum.

Immediate neonatal period	Case^a (n = 72)number (%)	Control (n = 116)number (%)	p-value
Motherside	48 (67)	114 (98)	<0.001
NICU	22 (31)	2 (2)
Still birth	2 (3)	0 (0)

There were two twin deliveries among cases. p < 0.05 is taken as significant.

For the 22 (30.5%) neonates among cases who were admitted to the nursery, the duration of stay was less than 24 h in 4 (18.1%) neonates, 24–72 h in 10 (45.4%) neonates and/or more than 72 h in 8 (36.4%) neonates. Only two neonates from the control group went to the nursery for about 2 days and were discharged in stable condition. Among the cases, of the 22 neonates who were admitted to the NICU, 20 were discharged in stable condition and two neonates died on the 5th day. Both the neonates who died were born at term with weights of 2.2 kg (38 weeks and 5 days' gestation; fetal growth restriction (FGR)) and 2.9 kg (38 weeks and 1 days' gestation). The baby with FGR was delivered by caesarean section in view of fetal distress with APGAR scores of 4, 6, 6 at 1,5 and 10 minutes respectively. The other baby was delivered vaginally with normal APGAR scores but had severe dyspnoea and feeding issues. COVID RT-PCR could not be done in these two babies due to cost issues. Both babies died on the 5th day as a result of birth asphyxia with hypoxic-ischaemic encephalopathy. The details of neonates who went to nursery are tabulated in Table 5.

Table 5.

Neonatal outcome and risk factors.

Parameter				Case^a (n = 22)number (%)	Control (n = 2)number (%)
Gestation (weeks)			<28	0	0
			28–32	0	0
			32–37	4	0
			>37	18	2
Maternal risk factor		HT		0	0
		DM		0	0
		ICP		0	0
		PROM		2	0
Fetal factors	FGR			6	1
Fetal factors	Oligohydraminos			0	0

There were two twin deliveries among cases.

POG: period of gestation; HT: hypertension; DM: diabetes mellitus; ICP: intrahepatic cholestasis of pregnancy; PROM: prelabour rupture of menbranes; FGR: fetal growth restriction.

Table 6 shows the data on intolerance to oral feeds among the neonates. It was observed that among the cases, the majority (72.7%) had feed intolerance whereas among controls none had feed intolerance. It was observed that among the cases, of the 22 babies who went to the NICU 18 (81.8%) babies had respiratory distress. All babies with respiratory distress required oxygen whereas in the four babies without respiratory distress, oxygen support was required in two neonates. Among controls, two babies were shifted to the NICU without respiratory distress with no need of supplemental oxygen. One baby was transferred to NICU due to low birth weight (1.57 kg at 37 weeks). The other baby was transferred due to feeding issues as the mother did not have adequate milk production and the baby had intermittent transient asymptomatic hypoglycaemic episodes.

Table 6.

Feed intolerance.

Feed intolerance	Case^a (n = 22)number (%)	Control (n = 2)number (%)
Present	16 (73)	0 (0)
Absent	6 (27)	2 (100)

There were two twin deliveries among cases.

All the neonates of SARS-CoV2 positive mothers who underwent rapid antigen testing in the immediate postnatal period were found to be negative. Laboratory parameters such as complete blood count, C-reactive protein, coagulation profile, liver function tests were normal for all neonates admitted in the nursery. There were no complications such as haematoma formation, sepsis, dyspnoea and need of blood transfusion in neonates of either cases or controls.

On follow up at 2 weeks and 6 weeks, both mother’s and baby’s status were found to be unremarkable in both the groups who were discharged in stable condition. None developed any symptoms related to SARS-CoV2 infection or postpartum complications.

Discussion

The health of pregnant women needs to be considered during this rapidly changing COVID-19 pandemic. Although during this pandemic time several studies and guidelines have been published on pregnant women, data remains inadequate. In the present study, we found that all our SARS-CoV2 positive pregnant women were asymptomatic in terms of COVID related symptoms. Spontaneous labour was significantly higher among SARS-CoV2 positive cases as compared to controls, as was NICU admission. Obstetric complications, mode of delivery, period of gestation at the time of, neonatal birth weight and neonatal mortality were not different between SARS-CoV2 positive and SARS-CoV2 negative pregnant women.

Yan et al. studied 116 patients to report the maternal and neonatal outcome of SARS-CoV2 infection in pregnancy.⁴ Severe pneumonia was present in 8 cases (6.9%) although no maternal death was reported. Of these 8 patients, one patient had a missed spontaneous abortion in the first trimester. The spontaneous preterm birth rate (under 37 weeks' gestation) was 6.1%. Most of the neonates were negative for the SARS-CoV2. They concluded that spontaneous fetal losses and spontaneous preterm birth were not increased by SARS-CoV2 infection. They did not find evidence of vertical transmission of SARS-CoV2 when the infection manifested during the third trimester of pregnancy.⁴ In our study we did not find evidence of vertical transmission and the rate of preterm birth is similar in our study.

Breslin et al. in their study reported the first 7 confirmed cases of SARS-CoV2 infection in pregnant women presenting to a single large New York City tertiary referral centre. Out of 7 women, 5 had symptoms and 4 were admitted to the hospital. Among these four admitted women, 2 required only supportive care with intravenous hydration. The other 2 women required intensive care unit admission, but both of these women were asymptomatic on presentation, which was for indicated labour induction.¹⁰ This is in contrast to our study as we have all asymptomatic patients with respect to COVID-19 related symptoms.

The UK Obstetric Surveillance System published their findings on 427 women with SARS-CoV2 infection admitted to the hospital.¹¹ In their data, the median gestational age at hospital admission was 34 weeks and the median gestational age at birth was 38 weeks. They found that most of the women (81%) were hospitalised in the third trimester of pregnancy or peripartum period.¹¹ Other studies have reported no evidence to suggest that COVID-19 causes developmental problems or miscarriages,^12–16 but the probability of vertical transmission was not ruled out. The preterm birth rate has been reported as 27%, 47% of which were iatrogenic for maternal compromise and 15% were iatrogenic for fetal compromise. 10% of term babies required admission to the neonatal unit..^11,12 Khalil et al. in a systematic review found that the pregnancy outcomes were generally good but iatrogenic preterm birth appeared to be increased.¹⁷ This is in contrast to our study where we have found that all cases of preterm births presented in spontaneous labour.

Lamouroux et al. reviewed 71 neonates born to women with SARS-CoV2 infection in the third trimester and reported that neonatal infection was diagnosed in 4 cases (5.6%) by PCR test on cord blood samples and neonatal swab within 48 h of birth.¹⁸ Few studies report on the features of neonates born to SARS-CoV2 positive mothers. Zhu et al. in their study on the clinical profile of 10 newborns born to SARS-CoV2 positive mothers, found that the first symptom in the neonates was shortness of breath or respiratory difficulty (n = 6).¹⁹Other presenting symptoms were fever (n = 2), thrombocytopenia accompanied by abnormal liver function (n = 2), rapid heart rate (n = 1), vomiting (n = 1) and pneumothorax (n = 1). All these neonates were negative for COVID 19 virus on pharyngeal swab specimens collected between 1 to 9 days of birth.¹⁹ In our study, we have found that the predominant neonatal clinical signs were respiratory difficulty or dyspnoea (82%) and feeding intolerance (73%) whereas laboratory parameters like complete blood count, liver function tests, C-reactive protein, coagulation profile were normal.

Yee et al. performed a meta-analysis of eleven studies involving with 9032 pregnant women with SARS-CoV2 infection and 338 infants aiming were to evaluate the impact of SARS-CoV2 infection on pregnant women. They found that most patients had mild symptoms but their laboratory parameters were disproportionately abnormal. Preterm delivery occurred in 30% and the mean birth weight was 2855.9 grams. They found that fetal death and was observed in about 2%, whereas neonatal death was found to be 0.4%.²⁰ Five newborns were found to be SARS-CoV positive. In our study, preterm delivery was observed in 8.6% of SARS-CoV2 positive mothers and no neonate was found to be positive on testing. There were two neonatal deaths among the SARS-CoV2 positive cases.

Research on previous coronavirus outbreaks had not clearly identified whether vertical transmission of virus occurs, but a few cases of transmission had been reported.^21,22 It was demonstrated during the H1N1 influenza pandemic in 2009 that pregnant individuals were at higher risk of severe pneumonia, acute respiratory distress syndrome, mechanical ventilation and death in comparison to reproductive-aged non-pregnant women.²³ Similarly for SARS in 2003 and Middle East respiratory distress syndrome (MERS) in 2012, pregnant patients were more likely to develop organ dysfunction and higher mortality was seen.^24,25

Limitations

We conducted testing for SARS-CoV2 infection in the third trimester of pregnancy in subjects presenting in labour, so data on the effect of this novel virus on the first and second trimester of pregnancy cannot be evaluated. Similarly, no conclusive comment can be given on vertical transmission because of the lack of SARS-CoV2 infection testing in early pregnancy. As this data collection was started in the beginning of the COVID 19 epidemic in India during the first wave (and due to financial constraints), antibody testing could not be done in mothers or infants. Our sample size is small and results cannot be extrapolated to the general population.

Conclusion

The SARS-CoV2 positive pregnant women and their newborns should be monitored as these newborns may have complications such as feeding issues without clear evidence of SARS-CoV2 infection. We are still living with the changing symptomatology of this rapidly evolving disease and new variant strains. Pregnant women and newborns have altered immunity, therefore this vulnerable population need to be monitored carefully during this pandemic.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The institutional ethics committee Approval No: HIMSR/IEC/014/2021.

Informed consent

Written informed consent was obtained from the patients for their anonymized information to be published in this article.

Guarantor

Not applicable.

Contributorship

NG and NB researched literature and conceived the study. NG, NBh and AN was involved in protocol development, gaining ethical approval, patient recruitment and data analysis. SP had done the statistical analysis. NG wrote the first draft of the manuscript. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

ORCID iD

Nidhi Gupta

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