Impact of COVID-19 pandemic on maternal and neonatal outcomes: A narrative review and evidence from the PregCovid registry

INTRODUCTION

The world has witnessed many pandemics through the middle ages. The bubonic plague (14^th century) known as Black Death wiped out a quarter or more of the affected populations.^[1] Smallpox resulted in the untimely collapse of the native American civilizations, killing about 90% of the inhabitants.^[2] The Spanish flu in the early 20^th century infected half a billion people and killed about 50 million people globally with about 10–15 million fatalities in India alone.^[3] Pregnant women, with their lower immune status, have always been vulnerable to sudden outbreaks of epidemics.^[4] The 2009 H₁N₁ Influenza pandemic which infected about 700 million to 1.4 billion global population,^[5] was associated with an increase in maternal mortality by 25–75%, greater disease severity and adverse fetal outcomes in affected pregnant women.^[6] Maternal Zika Virus infection has been associated with microcephaly and Guillain-Barre Syndrome (GBS).^[7] Miscarriage, preterm deliveries, and intrauterine growth restrictions were reported in pregnant women with Severe Acute Respiratory Syndrome (SARS).^[8]

Wuhan in the Hubei Province of China reported the first Coronavirus Disease 2019 (COVID-19) case in December 2019. The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a zoonotic virus with bats as the possible reservoir and mammals like pangolins, mink, and cats as possible intermediary.^[9] Human to human transmission of the virus was confirmed in December 2019.^[10] Emigration of Wuhan inhabitants and the New Year travel peak led to the rapid spread of the disease within as well as outside China. About three-fourths of the initial COVID-19 cases in China reported contact with a Wuhan resident and one-third reported a visit to the city.^[11] On January 30, 2020, COVID-19 was declared a public health emergency of international concern and on March 11, 2020, it was declared a pandemic.^[12] India reported its first COVID-19 case on January 30, 2020, from Thrissur, Kerala. Soon, two more people tested positive. All three were Indian medical students returning from Wuhan.^[13] Since then, more than 533 million cases of COVID-19 and associated 6 million fatalities have been reported from the world whereas 43 million cases and 0.5 million deaths have been reported in India till June 2022.^[14]

Pregnant women with comorbidities, malnutrition, and anemia are vulnerable to severe infection due to SARSCoV-2.^[15] A rural cohort of pregnant women recruited from 2009 to 2016 in India reported anemia in >90% of participants, malnourishment in about one-third of the participant and both the conditions in 35% participants.^[16] Malnourishment can result in pregnancy induced hypertension, postpartum hemorrhage and can even prove fatal.^[17] However, in the earlier days of COVID-19 spread, the impact of the SARS-CoV-2 on pregnancy in India was unknown. A Chinese case series evaluating maternal outcomes and complications in pregnant women diagnosed with SARS-CoV-2 infection reported a 20% incidence of preterm births.^[18] A systematic review covering the data of pregnant women with confirmed COVID-19 reported adverse maternal and neonatal outcomes.^[19] Comparative studies on perinatal outcomes in women with COVID-19 showed that comorbidities such as diabetes mellitus, hypertension, and asthma were frequently reported from High-Income Countries (HICs); whereas hypothyroidism, anemia, and co-infections were mainly reported in Low- and Middle-Income Countries (LMICs).^[20] In addition, risk of adverse pregnancy outcomes was found to be higher in LMICs.^[20] The newer and emerging data from HICs did not adequately represent the impact of COVID-19 on pregnant women in India.^[20] The progressive pandemic situation in India and lack of knowledge on novel coronavirus and its effect on pregnant women advocated the need for recording, documenting and analyzing population specific data. Maharashtra state was one of the worst affected states in India due to COVID-19. However, there was no data on epidemiological, demographic, maternal and neonatal outcomes. In addition, mother to child transmission of SARS-CoV-2 virus was not documented in the Indian population. To address these knowledge gaps, PregCovid registry (https://pregcovid.com/) was initiated. In this review, we summarize effects of SARS-CoV-2 infection on maternal, neonatal outcomes, and mother to child transmission based on the evidence generated through the PregCovid registry.

GENESIS OF PREGCOVID REGISTRY

The PregCovid registry was launched in April 2020 by the Indian Council of Medical Research-National Institute for Research in Reproductive and Child Health (ICMRNIRRCH), Mumbai in collaboration with the Medical Education and Drugs Department (MEDD), Government of Maharashtra, and Topiwala National Medical College and Bai Yamunabai Laxman (BYL) Nair Charitable Hospital (NH). The aim of the PregCovid registry was to gain insights into socio-epidemiological and clinical characteristics of pregnant and post-partum women with laboratory confirmed COVID-19 and its impact on maternal and neonatal outcomes. The PregCovid registry was implemented through NH and 18 Government Medical Colleges under MEDD, in Maharashtra State [Figure 1]. The details of the data collection tools and quality controls are published elsewhere.^[21] Worldwide registries on COVID-19 and pregnancy have contributed significantly to generating evidence on the impact of COVID-19 on maternal and neonatal outcomes [Table 1].

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Figure 1:

PregCovid registry study sites in Maharashtra, India.

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TIMES OF COVID-19 PANDEMIC IN INDIA

The COVID-19 cases started rising from March 2020 mainly in Maharashtra with Mumbai becoming the pandemic epicenter. Nearly 1/3^rd of the total cases of COVID-19 in India were reported from Maharashtra alone. The details of the first, second, and third waves of COVID-19 in

Maharashtra are presented in [Figure 2]. During the initial part of the first wave (January–June 2020), circulating B.1 lineage caused a surge in cases.^[22] Delta variant (B.1.617.2) dominated the second wave (May and June 2021).^[23] The Omicron variant was responsible for COVID-19 cases during the third wave (January–March 2022) in India.^[24] The sub-variants of the Omicron (BA.4 and BA.5) are in circulation globally. Interestingly, BA.4 and BA.5 variants of omicron were not associated with an increased risk of COVID-19 disease severity or increased hospitalizations.^[25]

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Figure 2:

Timelines of COVID-19 in India.

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UNIVERSAL SCREENING POLICY

Clinical presentation of COVID-19 disease ranges from asymptomatic, mild, and moderate to severe disease. Universal screening policy for SARS-CoV-2 infection in pregnant women was implemented in India as per the ICMR guidelines.^[26] To understand the impact of the universal testing policy, we collected data from 15 collaborating hospitals during the early phase of the first wave. A total of 1140 pregnant women presenting either in labor or most likely to have a delivery in the coming 5 days were screened for COVID-19 by RT-PCR. The prevalence of COVID-19 in pregnancy during this period was 12.3% (n = 141) varying from zero to 40% across hospitals in Maharashtra. The study demonstrated presence of nearly 90% of the asymptomatic pregnant women when screened for COVID-19 indicating one symptomatic for every 9 asymptomatic women in the community.^[27] Sutton et al. reported similar findings with a 13.5% prevalence of infection and 87.9% asymptomatic pregnant women with SARS-CoV-2 at admission in New York, U.S.A.^[28] Multiple studies during the pandemic first wave reported the rates of asymptomatic pregnant women ranging from 43% to 89%.^[29,30] PregCovid strongly recommended compliance with the universal testing policy for COVID-19 for pregnant women in India. Subsequent findings from the PregCovid study on the clinical profiles of pregnant and postpartum women with COVID-19 (n = 4203) reported that the majority of the participants (87.3%, n = 3669) were asymptomatic.^[31]

It was suggested that the universal screening policy was useful for the protection of newborns and other patients, the protection of healthcare workers, and also useful to curb spread of the infection in the community.^[27] A systematic review evaluating the universal testing policy in pregnancy reported a 5.3% prevalence of SARS-CoV-2 infection and among these, 75% were asymptomatic for COVID-19 at the time of testing.^[32] The findings of PregCovid and other registries suggest that universal testing policy among pregnant women presenting either in labor or likely to deliver within a week was useful to identify pregnant women with infection, to prevent maternal complications and to reduce transmission to the fetus and HCWs, especially in areas with a high prevalence of COVID-19.

PSYCHOLOGICAL IMPACT OF COVID-19 ON PREGNANT AND POST-PARTUM WOMEN

Maternal mental health is a public health issue in India and globally with 10–35% of pregnant and postpartum women suffering from depression.^[33] Pregnant and post-partum women are more likely to develop anxiety, stress, and depression during the COVID-19 pandemic due to various reasons. The increased vulnerability for mental illness in pregnancy is associated with biological changes occurring due to hormonal changes, psychological changes due to apprehensions concerning the course, outcome of pregnancy, transmission to the baby and social factors due to need of family support and care during pregnancy and the post-partum period.^[34] Implementation of measures to contain the transmission of COVID-19 including lockdown, restriction of movement and social isolation/ quarantine strategies led to additional health problems including mental health disorders.^[35] However, the COVID-19 crisis situation in India made it difficult to seek care and treatment from health facilities and providers.^[33] In mid-2020, during the rising cases of COVID-19, we reported postpartum psychosis^[36] and delirium^[37] in pregnant women managed at NH. Three women with asymptomatic COVID-19 were diagnosed with postpartum psychosis within 7 days of delivery based on the presence of symptoms such as delusion of persecution, the delusion of reference, self-harm behavior, auditory hallucinations, ideas of reference and ideas of persecution. Two women required separation from their newborns while one required supervision. All women recovered within 7 days of treatment with antipsychotic medications.^[36] SARS-CoV-2 infected pregnant woman reported symptoms including aggression, altered sensorium, sleep disturbances, headache, and violent behavior. Diagnosis of delirium was confirmed by neurological and psychiatric evaluation.^[37] A systematic review on postpartum psychosis in the pre-pandemic period in HICs (United States, Sweden, Denmark) and LMICs (Nigeria and India) reported postpartum psychosis incidence range between 0.89 and 2.6/1000 births and a prevalence of 5 in 1000 births (United States).^[38] A recent systematic review reported a cumulative incidence of postpartum psychosis ranging from 1.1 to 16.7/1000 births in LMICs (Nigeria, Tanzania, India).^[39] A study from the United States exploring the correlation between COVID-19 and postpartum psychosis reported that the pandemic should be considered as a risk factor for postpartum psychosis.^[40] The risk of having adverse infant health outcomes, namely, malnutrition and febrile illness was found to be 1.61 (95% CI: 1.34–1.95) times higher among mothers who had perinatal depression in African women.^[41] Another study from India^[42] on women with postpartum psychosis highlighted issues faced by women while accessing psychiatry services and getting inpatient admission at a Mother-Baby Unit. Difficulty to follow COVID-19 appropriate behavior, guilt for having contracted COVID-19 and fear of transmission of infection to the infant and family members were expressed as major concerns by the participating women.^[42] An online, cross-sectional survey of 6894 pregnant and postpartum women hosted on the Pregistry platform reported elevated posttraumatic stress (43%), anxiety/depression (31%), and loneliness (53%). It is widely studied that mental disorders in pregnancy influence adverse pregnancy and neonatal outcomes.^[43,44] Hence, identifying and addressing mental health issues must be a high priority for healthcare providers. Capacity building for the early detection of psychiatric illnesses and their appropriate management is strongly recommended for obstetricians and the healthcare workforce.^[37]

SARS-COV-2 AND CO-INFECTIONS IN PREGNANCY

The burden of infectious diseases in India is enormous. SARS-CoV-2 in pregnancy was an added burden on the existing health hazards. The proportion of pregnant women with COVID-19 presenting with co-infections is 6 times more common in LMICs than HICs (0.5% vs. 0.1%).^[20] In the WHO Africa region, it is estimated that 34% of women were exposed to malaria infection in pregnancy^[45] whereas the Indian burden of malaria in pregnancy awaits assessment.^[46] Malaria, dengue, and COVID-19 have similar presentations as they share common symptoms such as fever, tiredness, and headache.^[47,48] leading to a higher probability of misdiagnosis. In our initial case report, out of the three women co-infected with malaria and SARS-COV-2, one had an intrauterine fetal death while premature rupture of membranes (PROMs) was reported in another. Women co-infected with dengue and SARS-CoV-2 also had PROM and signs of intrauterine fetal growth restriction.^[49]

Moreover, India has the highest burden of tuberculosis (TB) in the world.^[50] Pregnant women are at increased risk for TB in high burden countries when compared with non-pregnant women^[51] and untreated TB in pregnancy can have a mortality of up to 40%.^[52] The Indian National TB Elimination Program has been unfavorably affected by the COVID-19 pandemic.^[53] Both TB and COVID-19 infections affect the lungs. It was reported from the PregCovid study (n = 879) that women with active pulmonary TB (0.7%, n = 6) and SARS-CoV-2 infection had low oxygen saturation at admission. Active TB also led to a higher proportion of symptomatic COVID-19 cases (n = 4) than women with a history of TB (n = 12). Two women with active TB developed ARDS and required intensive care while maternal death occurred in a woman with extensively drug resistant TB.^[54] Based on the data of the PregCovid registry, TB was significantly associated with the severity of symptoms in COVID-19 (OR 18.4 [4.3–80.0]).^[31] Coinfections in the PregCovid registry cohort (n = 4203) reported were TB (1%), HIV (0.3%), hepatitis B (0.3%), malaria (0.2%), and dengue (0.1%).^[31] A multicounty registry-based cohort study involving 172 centers from 34 countries reported 0.9% (n = 767) of TB-COVID-19 co-infected pregnant women.^[55] To minimize the deleterious impact of overlapping endemics with the COVID-19 pandemic in vulnerable population - differential diagnosis, strengthening of healthcare facilities and intervention strategies must be implemented. In countries with a heavy TB case load, pregnant women must undergo testing for TB and COVID-19 if respiratory symptoms appear.

CO-MORBIDITIES AND COVID-19 IN PREGNANT WOMEN

The presence of cardiovascular disease, chronic respiratory disease, diabetes mellitus, asthma, and hypertension with COVID-19 has been associated with increased in-hospital complications and mortality. Several earlier studies in 2020 from China reported hypertension as the most common comorbidity while mortality was higher in patients with diabetes or coronary heart disease.^[56] People infected with COVID-19 and having at least one comorbidity showed poor clinical outcomes compared to those without any comorbidity.^[57] Jering et al. reported that rates of venous thromboembolism and myocardial infarction were higher in COVID-19 infected pregnant women relative to the non-infected.^[58]

Pregnant women with Rheumatic Heart Disease (RHD) are at risk of adverse outcomes due to physiological changes involving increased stroke volume putting more pressure on the heart valves.^[59] Three women with RHD and two with Peripartum Cardiomyopathy in pregnant women with COVID-19 (n = 879) were reported in our study. Pregnancy outcomes were compared with uninfected pregnant women in the pre-pandemic period (n = 43).^[60] Low birth weight, preterm PPROMs, preterm delivery, and neonatal death were observed in COVID-19 infected pregnant women with heart disease.^[60]

GBS is rare in pregnancy (1.2–1.9 cases/per 100,000 people annually) and a delay in diagnosis due to non-specific symptoms mimicking physiological pregnancy changes. Any pregnant woman presenting with malaise, finger tingling, muscle weakness, and respiratory difficulty must be screened for GBS.^[61] The disease is usually preceded by nonspecific respiratory or gastrointestinal symptoms.^[62] In the PregCovid study, a symptomatic pregnant woman on neurological examination was diagnosed with GBS which was possibly triggered by the SARS-CoV-2 infection. Her gestation age was 12 weeks and she was previously diagnosed with Systemic Lupus Erythematosus and Antiphospholipid Syndrome. Her obstetric ultrasonography appeared normal, however, within 10 days of developing weakness, she aborted spontaneously. She received IVIG therapy, antibiotics, heparin, steroid and hydroxychloroquine and recovered fully.^[63] A case report from turkey by Tekin et al. in a woman with 37 week gestation and SARS-CoV-2 infection acute motor-sensory axonal neuropathy variant of GBS were reported. Cesarean section delivery was performed due to fetal distress and due to the presence of transient tachypnea, the newborn was admitted for intensive care.^[64] In another case report, a woman with 37 week gestation, diagnosed with COVID-19 6 weeks before admission, reported bifacial weakness and paresthesia associated with vestibulocochlear neuritis.^[65] CSF analysis in our study showed elevated cell count with normal protein and glucose levels^[63] whereas the increased level of protein and no white blood cells were found in two studies.^[64,66]

MATERNAL OUTCOMES

COVID-19 in pregnant women has been associated with an increased risk of pre-eclampsia, stillbirths, preterm births, PPROM, caesarean birth, and maternal mortality.^[67,68] In women infected during 1^st and 2^nd trimesters of pregnancy increased risk of preterm delivery and stillbirth were reported.^[69] The incidence rates for caesarean delivery were found to be higher in COVID-19 positive pregnant women^[67,70,71] Some studies have described obstetric indications for caesarean birth as intrauterine fetal distress, history of stillbirth, elevated liver functions, and previous cesarean birth.^[72,73] The salient findings of the registries on COVID-19 and pregnancy from India^[31,74] and abroad^[75-83] are described in Table 2.

MOTHER TO CHILD TRANSMISSION OF SARS-COV-2

ACE-2 receptor, a hallmark of vulnerability to SARS-CoV-2 is expressed on the ovaries, uterine lining, vagina and placenta indicating that vertical transmission of SARSCoV-2 from mother to child is possible. The initial report from China^[106] on six pregnant women infected with COVID-19 stated that no virus was found in their amniotic fluid and cord blood; also the neonatal throat swab and breast milk samples were negative for SARS-CoV-2. We reported hydrops fetalis in a woman with 8 weeks of gestation who had asymptomatic COVID-19. SARS-CoV-2 was detected in the amniotic fluid and fetal membranes while localized spike proteins (S1 and S2) were found in placental villi.^[107] Dumont et al. reported that pathological examination of the placenta in women with SARS-CoV-2 and oligohydramnios revealed histiocytic intervillositis, ischemic necrosis of villi and intervillous deposition of fibrin, depicting an acute onset of placental insufficiency, and fetal distress. However, neonatal nasopharyngeal samples were negative for SARSCoV-2 in this study.^[108] Our study reported generally avascular villi with peri-villus deposition of fibrin and lysis of the syncytiotrophoblast layer at some places. The decidua was also inflamed suggested by the presence of fibrin deposition and leukocyte infiltration.^[107] Argueta et al. analyzed placenta of 55 SARS-CoV-2 infected women in late pregnancy of which 42% tested positive for viral RNA. Highly infected placental tissues showed trophoblast necrosis, peri-villus fibrin deposition, and infiltration of maternal immune cells with signs of inflammatory damage which likely contributed to adverse birth outcomes such as stillbirth and preterm birth that required extended intensive care.^[109] Ferraiolo et al. have reported placental swabs positive for SARS-CoV-2 RNA^[110] while Hsu et al. in their study demonstrated the presence of SARS-CoV-2 antigens throughout the placenta under the umbilical cord.^[111] Ours was the first study providing evidence associating hydrops fetalis and intrauterine fetal demise with placental SARS-CoV-2 infection and its congenital transmission.^[107]

MATERNAL MORTALITY

The case fatality rate (CFR) in pregnant and postpartum women with SARS-CoV-2 infection during different waves of the pandemic is presented in [Table 3]. During the early phase of the pandemic, there was inconsistent information on maternal mortality associated with COVID-19 as some of the studies reported very low CFR whereas others reported a high CFR.^[20] A systematic review involving data from more than 10,500 pregnant and postpartum women with SARS-CoV-2 during the early phase of the pandemic from 35 countries worldwide reported a 2% maternal death rate related to COVID-19.^[20]

In India, the PregCovid registry study reported 0.8% CFR during the COVID-19 first wave (March 2020–January 2021).^[31] There were regional differences in CFR in Maharashtra state in India, with Marathwada (1.1%) and Pune (1.1%) reporting higher CFR than Vidarbha (0.8%), Mumbai Metropolitan (0.7%), and Khandesh (0.6%) regions. Majority of the maternal deaths due to COVID-19 (71%) occurred during the antepartum period while 29% of maternal deaths occurred in the postpartum period. A higher risk of maternal death was observed in pregnant women with comorbidities including anemia, TB, and diabetes mellitus.^[31] The CFR reported during the first wave in Maharashtra, India was comparable with UK populations (0.7–1%)^[81,104] and the US population (1.3%)^[112] but was higher than the multinational PAN-COVID (0.5%) and AAP-SONPM registries (0.4%).^[76]

Some of the countries such as Brazil,^[113] Iran,^[114,115] South Africa,^[116] Malawi^[117] and Mexico^[118-121] reported higher maternal mortality during early phase of the COVID-19 pandemic. In Brazil, maternal mortality was reported as 12.3% between February and September 2021.^[113] Early reports from a single center study in Iran between March 2020 and June 2020 showed 15 maternal deaths (46.8%) among 32 pregnant women with laboratory diagnosed COVID-19.^[114] However, a cross-sectional multicenter study conducted during the same period reported seven maternal deaths (0.04%) out of 182 pregnant women infected with COVID-19.^[115] An increase in maternal mortality ratio (MMR) by 56.8% was observed in Mexico during the 1^st year of the pandemic (February 2020–February 2021), in which MMR due to COVID-19 was 13.6.^[118] A single center study in Mexico reported higher CFR (2.3%) from the start of the pandemic till May 2020^[119,120] while the Mexican National Registry of Coronavirus reported 1.4% maternal deaths between April 2020 and July 2021.^[121]

Ethnic and racial variations in maternal mortality were reported as black women and Hispanic women faced higher risk of death due to COVID-19 in Brazil.^[113] Similar observations were also reported from UK wherein Black, Asian, Minority Ethnic (BAME) pregnant women were disproportionately affected by COVID-19.^[81] A study in USA, relative to the pre-pandemic period, reported an increase of 8.9 maternal deaths per 100000 live births in Hispanic women during the pandemic period, 16.8 maternal deaths in black women and 2.9 maternal deaths in white women.^[122] The numbers indicating racial variations in COVID-19 related mortality are however, an underestimation of the actual magnitude of the existing disparities between the mortality in the black women and white women the USA.^[123]

The delta variant (B.1.617.2) dominant second wave was more lethal to pregnant and postpartum women than alpha and omicron dominant waves of COVID-19 in India. The PregCovid registry data of NH showed an eight-fold increase in maternal mortality in the second wave (CFR 5.7%) as compared to the first wave (CFR 0.7%). COVID-19 pneumonia and respiratory failure were associated with more than 90% of maternal deaths (93%, 28/30).^[98] A similar impact of the delta wave was found in other parts of India and outside India. Khoiwal et al., reported a higher maternal death rate (16.2%) during the COVID-19 delta wave compared to the alpha wave (1.7%) in the north Indian population.^[124] Similar to the PregCovid study, a study from Jamshedpur in Eastern India also reported a steep increase in maternal deaths due to COVID-19 in the second wave (3.6% vs. 0.0%) than in the first wave.^[125]

The seven-fold rise in the proportion of maternal deaths was reported in the delta dominant phase of the pandemic (2.9% vs. 0.4%,) in Turkey.^[126] Another study in Turkey reported a higher maternal mortality rate in the delta period compared to the pre-delta period (7% vs. 1.3%).^[127] An upward trend in maternal mortality was also reported from Brazil that showed a two-fold increase in maternal deaths by COVID-19 during the second wave of the pandemic (7.7% in the first wave vs. 15.4% in the second wave).^[128] Another retrospective cohort study recruited pregnant women from two tertiary care hospitals, one in Turkey and one in the UK, and reported 3.6 times higher maternal death rate during the delta dominant period relative to the pre-delta period of the pandemic (5.3% vs. 1.5%).^[129] A study from 194 obstetric units in the UK reported that there was no considerable difference in maternal death rates in the alpha and the delta periods (0.4% vs. 0.4%). Maternal deaths reported from the wild-type variant dominant period were 0.7%, similar to PregCovid study estimates during the COVID-19 first wave.^[104]

Although the omicron dominant third wave of the COVID-19 pandemic exhibited a higher transmission rate compared to the previous two waves in India, the impact on pregnant women was minimal. The PregCovid registry data from NH during the 1^st month of the third wave of the pandemic (December 2021–January 2022) showed about a 3.5-fold rise in symptomatic COVID-19 cases in pregnant and post-partum women during the omicron dominant period (45.5%) as compared to the alpha variant period (14.2%). The proportion of moderate to severe COVID-19 disease in pregnant and post-partum women was significantly lower during the third wave (0.6%) compared to the first wave (2.4%) and second wave (14.4%).^[101] These findings of the PregCovid registry from NH suggested a reduction in severe COVID-19 cases and lower maternal mortality in the omicron dominated period of the pandemic in the Mumbai Metropolitan Region, India compared to the alpha and delta periods.

A retrospective cohort study between December 2021 and February 2022 at three tertiary care hospitals, two in Turkey and one in the UK, was consistent with the PregCovid study findings of no maternal deaths during the study period, both in the vaccinated and non-vaccinated pregnant women.^[130] Another study from Turkey and UK reported that the maternal mortality rate in the third wave was similar to the pre-delta period (1.3% vs. 1.3%).^[129]

Wide variations in COVID-19 related maternal mortality are observed across the globe. Variations in mortality could be attributed to many factors, namely: (1) Differences in the pandemic preparedness between HICs and LMICs, (2) differences in the case reporting systems between countries along with a lack of a standardized set of rules for medical certification of death, (3) differences in the circulating strains during study periods. Delta dominant period of the COVID-19 pandemic was associated with higher maternal mortality rates than the alpha, gamma, and omicron periods [Table 3], (4) differences in race and ethnicity, socioeconomic conditions, and demographic disparities in the study population, (5) availability of affordable and competent healthcare systems and (6) accessibility to COVID-19 vaccines. Fast track development and roll-out of COVID-19 vaccines have saved more than 19 million lives globally.^[131] Transparent vaccine approval procedures, campaigns for vaccine awareness and to stop misinformation, equitable distribution, and promotion for vaccination in conflicted areas can further save thousands of lives. A sustainable and collective global response to improve vaccination coverage will aid to mitigate the mortality associated with COVID-19.

NEONATAL OUTCOMES OF MOTHERS WITH COVID-19

There is growing evidence of the impact of SARS-CoV-2 on newborns. The incidence of SARS-CoV-2 is reported in nearly 3–7% of neonates born to COVID-19 infected mothers.^[132,133] CRONOS study (Germany) revealed 4.5% SARS-CoV-2 infection in neonates born to mothers infected ≤2 weeks before delivery.^[134] However, neonatal outcomes were not affected by the time of maternal SARS-CoV-2 infection. Majority of studies did not report major adverse neonatal outcomes.^[135-137] US-based PRIORITY also did not observe significant differences in neonatal outcomes among the infected and non-infected groups.^[75] However, severe course and adverse outcomes are reported in neonates.^[138] INTERCOVID study found 13% positivity in newborns of COVID-19 infected women and reported that the severe perinatal morbidity and mortality index and the severe neonatal morbidity index were significantly higher compared with newborns of non-infected women.^[77] The USA population and UK registries reported an increased risk of preterm delivery and NICU admission in neonates of COVID-19 infected mothers.^[73,139] A prospective observational study from the Spanish GESNEO-COVID cohort reported increased risk of preterm birth and adverse prognosis of SARS-CoV-2 infected newborns.^[78] In the UAE, women with moderate to severe COVID-19 were found to have an increased risk of preterm deliveries, lower birth weight, neonatal infection, and neonatal intensive care admissions.^[140] The National Neonatology Forum, India’s cohort study including 1713 suspected and confirmed SARS-CoV-2 infected newborns revealed a 1.5% horizontal transmission and a 8% perinatal transmission. It showed increased morbidity in infected infants related to prematurity and perinatal events.^[141]

Some studies have been reported clinical profile and outcomes of neonates born to SARS-CoV-2 infected mothers during the delta period of the COVID-19 pandemic. A higher incidence of SARS-CoV-2 in newborns during the second wave has been reported in Spanish population^[142] whereas a higher incidence of neonatal complications and NICU admissions among SARS-CoV-2 infected neonates was also reported during the omicron wave in the UK.^[129]

A retrospective analysis of 2524 neonates (from 5 centers in Maharashtra, India) from PregCovid registry born to mothers with SARS-CoV-2 infection during the first wave (n = 1782) and second wave (n = 742) of the COVID-19 pandemic showed that the prevalence of neonatal SARS-CoV-2 infection was almost similar (4.2% vs. 4.6%). However, the second wave showed a higher incidence of preterm birth (15.0%, 111/742), birth asphyxia (3.8 times higher) and prematurity (2.1 times higher). The second wave also had a significantly higher proportion of neonates required NICU care (19.0%, 141/742) than the first wave (14.8%, 264/1782). Higher neonatal complications were reported in Mumbai metropolitan region than other parts of Maharashtra. The neonates mainly presented with hyperbilirubinemia (4.04%), respiratory distress (3.2%), and feeding difficulties (1.8%).^[143] Higher proportion and severity of adverse neonatal outcomes in the second wave highlights the need to devise appropriate strategies for management of neonates.

The evidence generated from the PregCovid registry was submitted to Director General, ICMR on June 14, 2021. Subsequently, evidences of impact of Second wave of COVID-19 on pregnant women in India were also submitted to ICMR, New Delhi for review of the evidence by Chairman, National Technical Advisory Group in Immunization (NTAGI) on June 18, 2021. Based on the recommendations from NTAGI, the Union Ministry of Health and family Welfare (MoHFW) on July 2, 2021, pregnant women became eligible for COVID-19 vaccination in India. Thus, the evidence generated from the PregCovid registry was not only useful for improved clinical management but also useful for facilitating the policy decision on COVID-19 vaccination of pregnant women in India.

COVID-19 VACCINATION IN PREGNANT WOMEN

Despite clear pre-pandemic guidance, all the randomized clinical trials of COVID-19 vaccines excluded pregnant and lactating women.^[144] Therefore, there was a delay in policy decision on vaccination on COVID-19 for pregnant and lactating women in India and globally. A population-based study in Canada, compared three groups - COVID-19 vaccination during pregnancy, vaccination after pregnancy and no COVID-19 vaccination, and reported that COVID-19 vaccination during pregnancy showed no significant increase in the risk of adverse outcomes.^[145] Recent systematic review and meta-analysis reported the significantly lower risk of stillbirth in the COVID-19 mRNA vaccinated cohort compared to unvaccinated women. No evidence of an increased risk of adverse outcomes were reported in COVID-19 mRNA vaccinated pregnant women compared to unvaccinated cohort thereby suggesting safety of COVID-19 mRNA vaccines.^[146] Despite this, there exists vaccine hesitancy for COVID-19 vaccination amongst pregnant women.^[147] The probable reasons for COVID-19 vaccination could be: (a) Data paucity on safety and effectiveness of COVID-19 vaccine in pregnant women globally, (b) inadequate counseling leading to lack of trust on healthcare workers, and (c) misleading information circulating through social media. Addressing vaccine hesitancy is very challenging and requires a multisectoral involvement.

LESSONS LEARNT FROM THE PREGCOVID REGISTRY AND WAY FORWARD

• PregCovid Registry serves as a replicable and generalizable model that can be implemented through a network of tertiary care hospitals. A robust surveillance system, quality control mechanisms, and committed frontline healthcare workers with scientific vigor can prove crucial in mitigating the emerging and reemerging infections.

• The PregCovid registry covered population with a range of SARS-CoV-2 infection severity from asymptomatic, mildly symptomatic, moderately symptomatic to severely symptomatic disease, making it generalizable to entire obstetric populations.

• The PregCovid registry captured the data from the beginning of the pandemic covering first, second and third wave data from all over the Maharashtra State and therefore the dataset has very vital information for comparison with global populations.

• The PregCovid registry experience is not just applicable to rapid response to COVID-19 pandemic but useful for other infections in pregnancy.

• The registry demonstrated the strength in collaboration right from the medical graduates to the head of the department across 19 government medical colleges in Maharashtra and these networks should be strengthened further for addressing the larger goals of maternal and child health.

• Based on the experience of setting up and managing the PregCovid registry, we recommend setting up a network in medical colleges in different geographical zones all over India for addressing the future pandemics.

• Universal screening of pregnant women for COVID-19 can aid in identifying all the cases and limit the spread of infection in the community.

• Maternal mental health is a vital public health issue in India and COVID-19 increases the vulnerability to postpartum depression and psychosis. Early detection and appropriate management of psychiatric illnesses is a priority.

• Co-infections and comorbidities in pregnant women with COVID-19 could be detrimental to the recovery efforts.

• While the delta dominant second wave severely affected the maternal mortality, still births, preterm births, preeclampsia and increased hospitalizations, the omicron dominant third wave caused a surge in number of cases but minimally affected hospitalization rate, pregnancy complications and maternal mortality.

• COVID-19 is associated with lower birth weight, neonatal infections and an increase in neonatal ICU admission rates.

• Addressing vaccine hesitancy is a challenging task and a multi-sectorial participatory approach could prove useful in improving the coverage.

CONCLUSION

PregCovid registry, implemented since April 2020, has documented and reported crucial aspects of pregnancy and SARS-CoV-2 infection in a near real-time manner. Further, it has provided evidence-based inputs to form and revise policies to improve healthcare during the COVID-19 pandemic. The registry serves as a model that can be implemented at tertiary care hospitals across India to understand various maternal-neonate outcomes and support the decision-making process in daily clinical practice. The registry plans to determine long term impact of COVID-19 in these women and their infants in the future. The registry also envisions a collaboration with similar regional, national and international registries to form an international consortium for data sharing, reporting, and combine analysis to advocate feasible global policy level interventions to mitigate COVID-19 and similar emerging and re-emerging diseases in the future.