key: cord-0785080-dp9ht3hn
authors: Gajbhiye, Rahul K.; Sawant, Mamta S.; Kuppusamy, Periyasamy; Surve, Suchitra; Pasi, Achhelal; Prusty, Ranjan K.; Mahale, Smita D.; Modi, Deepak N.
title: Differential impact of COVID‐19 in pregnant women from high‐income countries and low‐ to middle‐income countries: A systematic review and meta‐analysis
date: 2021-07-14
journal: Int J Gynaecol Obstet
DOI: 10.1002/ijgo.13793
sha: 5286953d1bd1ef491c76b903fb181dd8fee18b0b
doc_id: 785080
cord_uid: dp9ht3hn

BACKGROUND: SARS‐CoV‐2 has infected a large number of pregnant women. OBJECTIVE: To compare clinical, perinatal outcomes of women with COVID‐19 from high‐income countries (HICs) and low‐ to middle‐income countries (LMICs). SEARCH STRATEGY: Online databases were searched. SELECTION CRITERIA: Original studies on pregnant women with COVID‐19 were included. DATA COLLECTION AND ANALYSIS: Information on clinical presentation, co‐morbidities, pregnancy outcomes, neonatal outcomes, and SARS‐CoV‐2 infection in neonates was extracted. MAIN RESULTS: The pooled estimate of SARS‐CoV‐2 positive neonates is 3.7%. Symptomatic presentations are less common in LMICs compared to HICs (odds ratio [OR] 0.38). Diabetes (OR 0.5), hypertension (OR 0.5), and asthma (OR 0.14) are commonly reported from HICs; hypothyroidism (OR 2.2), anemia (OR 3.2), and co‐infections (OR 6.0) are commonly reported in LMICs. The overall risk of adverse pregnancy outcomes is higher in LMICs compared to HICs (OR 2.4). Abortion (OR 6.2), stillbirths (OR 2.0), and maternal death (OR 7.8) are more common in LMICs. Preterm births and premature rupture of membranes are comparable in both groups. Neonatal deaths (OR 3.7), pneumonia (OR 7.5), and neonatal SARS‐CoV‐2 infection (OR 1.8) are commonly reported in LMICs. CONCLUSIONS: In LMICs, pregnant women and neonates are more vulnerable to adverse outcomes due to COVID‐19. PROSPERO registration no: CRD42020198743.

disease COVID-19, has rapidly spread worldwide and infected a large number of individuals including pregnant women. Adverse pregnancy outcomes are documented in a limited number of women infected with other coronaviruses such as the SARS-Co-V and Middle East Respiratory Syndrome. 3 Thus, there is a need to study the effects of SARS-CoV-2 infections in pregnancy. The study protocol was exempted from review by the institutional ethics committee of ICMR-National Institute for Research in Reproductive Health (NIRRH) (D/ ICEC/Sci-49/52/2020).

To address the issue of COVID-19 and pregnancy outcomes, case reports, case series, observational studies, and cohort and casecontrol studies are published that describe the maternal and fetal presentation of SARS-CoV-2 infection in pregnant women. However, these reported studies have yielded conflicting findings leading to contradictory conclusions. Some reports indicate that there are no major adverse outcomes of SARS-CoV-2 infection in pregnancy, 4, 5 others have reported serious pregnancy complications such as preterm births, neurological disorders, miscarriages, and maternal deaths in women infected with SARS-COV2 during pregnancy. [6] [7] [8] [9] [10] [11] [12] [13] Multiple systematic reviews have been conducted that have majorly described the risk of vertical transmission and maternal presentation associated with COVID-19. These studies have indicated that there are higher odds of having severe disease, low birth weight infants, and preterm delivery in pregnant women with COVID-19; the neonates born to these mothers also have a higher risk of hospitalization. 6, [14] [15] [16] Thus pregnant women with COVID-19 will need special medical attention.

The scale of the COVID-19 outbreak has resulted in the disruption of maternal health services and is predicted to adversely impact pregnancy outcomes, specifically in low-and middle-income countries (LMICs). 17 However, the understanding of the impact of COVID-19 disease on obstetric outcomes of women in LMICs is limited as much of the evidence is based on pooled estimates of the global data or registry data from high-income countries (HICs). 14-16 A single study has compared the maternal presentation of COVID-19 by country of origin. 18 However, the comparisons are mainly done from studies reported from Spain, France, and China. It is believed that there is no comparative information on maternal presentations and pregnancy outcomes in women with COVID-19 from LMICs and HICs.

Herein, the maternal presentations and outcomes of pregnant women with COVID-19 globally were systematically assessed and the data obtained from LMICs and HICs were compared. The incidence of vertical transmission of SARS CoV-2 was also assessed.

For this review, the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines were followed. The study protocol was registered at PROSPERO (CRD42020198743).

The PubMed, Embase, Web of Science, Scopus, Google Scholar literature database, ScienceDirect, preprint servers and specialized COVID resources were searched for articles on pregnant women.

The keywords and MeSH terminology used were a combination of "coronavirus," "2019 n-COV," "SARS-CoV-2," "SARS virus" or "COVID-19," "corona virus disease 2019," "pregnancy," "maternal," "mothers," "neonates," and "infants." Snowballing strategy and Ripe-tomato.org, a resource site for data on pregnant women and COVID-19 (https://ripe-tomato.org/covid -19/), was also searched manually to identify any missed articles. Articles in non-English languages that could be translated into English using Google Translate were also included.

The PRIMSA flowchart for the present systematic review is presented in Figure 1 . Articles published between March 1 to December 31, 2020, were reviewed. Two authors shortlisted original studies on pregnant women with SARS-CoV-2 infection. Only those studies that reported the data on the laboratory-confirmed diagnosis of SARS-CoV-2 were included. Duplicate articles, reviews, narrative articles, abstracts, and gray literature such as media reports, blogs, and information from unverified sources were excluded. Articles that did not have the primary outcome as maternal presentations or pregnancy outcomes were also excluded. The extracted data were verified independently and the inconsistencies in the data entries were sorted. It was not possible to rank the quality of the studies included due to the inherent nature of the data. Data were sorted based on country of origin and the information was pooled for HICs and LMICs (as per the World Bank Data of 2020).

Information was collected on maternal presentations, that is, the proportion of women presenting with fever, cough, myalgia, dyspnea, chest pain, or headache. The information on pregnancy outcomes included type of delivery (cesarean or vaginal), preterm and term delivery, premature rupture of membranes (PROM), abortion, stillbirths, and maternal deaths. The neonatal outcomes included the numbers of neonates positive for SARS-CoV-2, the numbers with respiratory distress, and neonatal deaths.

Individual patient data or pooled data from papers were recorded in a table format. Pooled data were used with a random-effects meta-analysis to estimate the incidence of outcomes as proportions with 95% confidence intervals (CIs). Heterogeneity was reported as I 2 statistics and analysis was performed using Stata 15 package (StataCorp., College Station, TX, USA).

Through database searches and snowballing, 2593 articles were identified. After screening and assessment of eligibility ( Fig. 1) , 225 studies reporting the data of 10 582 women were found eligible for inclusion (Table S1 ). These studies are from 35 countries ( Fig. 2) with the majority of the data from the United States (24%), India (11%), Brazil (9%), Colombia (9%), China (7%), Spain (7%), Iran (7%), France (6%), and the United Kingdom (5%). co-morbidities. Placental disorders such as placenta previa, placenta accreta, and placental abruption were reported in less than 1% of women with COVID-19. There were some reports of co-infections that included hepatitis B, influenza, dengue, malaria, tuberculosis (TB), Legionella pneumophila, and mycoplasma.

Among the pregnant women with COVID-19 who had delivered, the cumulative incidence of vaginal delivery was 48.5% (2352/4841, 95% CI 47-1-50.0) and 51.5% (2489/4841, 95% CI 50.0-52.8) for cesarean delivery. Among the adverse pregnancy outcomes (Fig. 3c) , preterm birth was the most common (22%, 95% CI 20.81-23.15). 

The infant data of mothers with COVID-19 are shown in Figure 3c .

Of the data on 4797 newborns, there were 23 and headache (3.8% vs 1.6%) were significantly higher (P < 0.01) in women from HICs compared to those from LMICs (Fig. 4a, Table S2 ).

Although diarrhea was reported as common in both groups (HIC vs LMIC 3.9% vs 3.2%), the marginal reduction was not statistically significant (P > 0.05).

Among the co-morbidities (Fig. 4b, Table S2 ), diabetes mellitus, including gestational diabetes mellitus (HIC vs LMIC 12.3% vs 6.8%), and hypertension, including pre-eclampsia (HIC vs LMIC 11.0% vs 6.1%), were more commonly reported in pregnant women in from HICs compared to those from LMICs. Asthma was almost six times more commonly reported in women from HICs compared to LMICs (HIC vs LMIC 6.3% vs 1.0%). The differences were statistically significant (P < 0.01). In LMICs, hypothyroidism (HIC vs LMIC 0.8% vs 1.8%), anemia (HIC vs LMIC 0.2% vs 0.6%), and co-infections (HIC vs LMIC 0.1% vs 0.5%) were more commonly reported compared to HICs, and these differences were statistically significant (P < 0.01).

Adverse pregnancy outcomes (Fig. 4c, Table S2 ) were more commonly seen in LMICs compared to HICs (overall OR 2.49, I 2 = 94.0%, P = 0.000). Women in LMICs were more likely to experience pregnancy losses. The odds of abortion were 6.2 times higher (HIC vs LMIC 0.3% vs 1.6%) and stillbirth was twice as likely (HIC vs LMIC 0.5% vs 0.9)% in LMICs compared to HICs. These differences are statistically significant (P < 0.01) The risk of death was almost eight times higher in LMICs compared to HICs (HIC vs LMIC 0.4% vs 3.1%). This difference is statistically significant (P < 0.01). However, preterm births and PROM are comparable in both groups.

Adverse neonatal outcomes (Fig. 4c, Table S2 ) were also more common in women in LMICs compared to those in HICs. The rates of neonatal deaths were four times more common (HIC vs LMIC 0.2% vs 0.8%) and pneumonia was 7.5 times more common (HIC vs LMIC 0.3% vs 2.0%) in LMICs compared to HICs. These differences are statistically significant (P < 0.01). However, RDS was not significantly different between the two groups.

In LMICs, the neonates born to mothers with COVID-19 were twice as likely to be positive for SARS-CoV-2 compared to those in HICs (HIC vs LMIC 2.8% vs 5.1%). This difference was statistically significant (P < 0.01). The initial identification of COVID-19 was based on a diagnosis of severe presentation of respiratory distress. It was eventually evident that most cases of laboratory-confirmed SARS-COV-2 infection were asymptomatic. 19 In an Indian cohort of 1169 pregnant women, 20 the prevalence of symptomatic cases was 11.5% while that of asymptomatic cases was 88.5%. In the present systematic review, the clinical manifestations of COVID-19 in the symptomatic cases were highly heterogeneous where fever (23%) and cough (24%) were the most commonly reported symptoms.

These numbers are comparable to those reported in other systematic reviews. 4, 15 Some studies have shown that some ethnicities are more likely to have a severe presentation of COVID-19 during pregnancy 15, 21 To address whether socioeconomic status has had an impact on the clinical presentation of COVID-19 during pregnancy, data based on country of origin were analyzed and it was observed that symptomatic presentations were more commonly reported from studies in HICs compared to LMICs. Although there was a lot of heterogeneity across the studies, this was unexpected as it was anticipated that most of the data were out of tertiary referral centers and only symptomatic women may present to the hospital in LMICs. It will be important to address the LMIC population and determine why these women have presented with less severe symptoms.

The commonality of asymptomatic and less severe presentations of COVD-19 in pregnant women in LIMCs is a matter of concern.

With the scarcity of resources for testing, many women without their COVID-19 status would be hospitalized and these could be a source of SARS-CoV-2 infection in the community and among healthcare workers. The results of the present study further emphasize the need for the strict implementation of universal screening of SARS-CoV-2 in an obstetric population and the LMICs must implement these more rigorously to prevent outbreaks in hospitals.

Epidemiological evidence suggests that hypertension and diabetes are risk factors for poor outcomes of COVID-19. In addition, in pregnant women hypertensive disorders, diabetes, and asthma were the major co-morbidities associated with COVID-19.

Intriguingly, the prevalence of co-morbidities was very different in LMICs versus HICs. Pregnant women with COVID-19 in HICs were more likely to be diabetic or hypertensive or asthmatic compared to those in LMICs. Hypothyroidism or anemia or co-infections are commonly reported in women in LMICs compared to those in HICs. Globally, the estimated prevalence of hypothyroidism in pregnancy is in the range of 2%-3%. In the present study, it F I G U R E 4 Comparison of (a) maternal presentations, (b) co-morbidities, and (c) pregnancy and newborn outcomes in women with COVID-19 from HICs and LMICs. The events, total values, percentages, and P values are given in Table S2 . Abbreviations: DM, diabetes mellitus; GDM, gestational diabetes mellitus; GH/HT, Gestational hypertension/Hypertension; HIC, high-income country; LMIC, low-and middle-income country; PCR, polymerase chain reaction; PROM, premature rupture of membrances; RDS, respiratory distress syndrome. However, the incidence of hypothyroidism in pregnant women with COVID-19 in LMICs is 1.8% versus 0.8% for those in HICs.

However, the reasons for such differences are unclear. Similar to hypothyroidism, women with COVID-19 in LMICs were more likely to suffer from anemia (OR 3.2). This could be due to a higher incidence of anemia among pregnant women in LMICs 23 ; however, anemia itself is identified to be an independent risk factor for COVID-19 in the general population. 24 Further, in women with COVID-19, adverse pregnancy outcomes were preterm deliveries (21.9%), PROM (4%), and fetal distress The incidence of maternal deaths in COVID-19 is a matter of controversy. Some studies reported negligible death rates of pregnant women with COVID-19, while others reported a high proportion.

Herein, it was estimated that a maternal death rate of 2% (188/10 492 women) related to COVID-19. This is comparable to those observed in systematic reviews. 15 

The present systematic review is based on almost all the data pub- in the reported incidence of multiple parameters across studies and this is largely due to variations in sample size, reporting criteria, and study designs.

In pregnant women with COVID-19 at term, there is evidence of adverse pregnancy and neonatal outcomes. Well-defined studies will be required to generate clear evidence on vertical transmission of SARS-CoV-2. The data in the present study suggest that pregnant women and their neonates in LMICs are more vulnerable to adverse outcomes due to COVID-19, although there is considerable heterogeneity across the reported studies. High-quality systematic reporting from registries will be required to sort these issues. Coupled with compromised health services, COVID-19 itself will jeopardize the roadmap toward achieving the Sustainable Development Goals in maternal and child health in the LMICs. With the availability of the vaccine, high priority must be given to pregnant women to at least partially rescue the damage done by COVID-19 to maternal health in LMICs.

The laboratories of RG, DM, and SM are funded by grants from the 

The authors have no conflicts of interest.

RG conceived the study. RG and DM designed the study. MS, PK, RG, and DM screened the abstracts for inclusion in the study. MS, PK, SC, RKP, and AP analyzed the data. SM coordinated the discussions and helped in data interpretation. RG and DM drafted the manuscript, which was then critically revised by all authors. All authors approved the final manuscript.

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