The impact of COVID-19 in pregnancy: Part I. Clinical presentations and untoward outcomes of pregnant women with COVID-19

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019, COVID-19) is a pandemic disease with rapidly and widely disseminating to the world. Based on experiences about the H1N1, Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) coronavirus pandemics, pregnant women who are infected are disproportionately more likely to develop severe illness and need more hospitalizations, intensive care, and finally die of diseases compared with those nonpregnant counterparts or those pregnant women without infection. Although more than one half of pregnant women with COVID-19 are asymptomatic, and as well as their symptoms are frequently mild, this observation presents a further challenge regarding service provision, prevention, and management, in which this may result in overlooking the risk of COVID-19 during pregnancy. As predictable, despite much advance in critical care in recent decades, during the 2020 COVID-19 pandemic, pregnant women with COVID-19 are really at higher risk to progress to severe illness; require hospitalization; need intensive care, such as the use of mechanical ventilation as well as extracorporeal membrane oxygenation (ECMO), and of most important, die than their nonpregnant counterparts and pregnant women without COVID-19. The magnitude of the risk to pregnant women further extend to their newborn from COVID-19 with resultant significantly increasing perinatal and neonatal morbidity and mortality rates. The heightened risk of untoward outcomes in pregnant women emphasizes an urgent need of national or international recommendations and guidelines to optimize prevention and management strategies for COVID-19 in pregnancy. Active and passive prevention of COVID-19 is approved as effective strategies for women who attempt to be pregnant or during pregnancy. Understanding that pregnant women who are a vulnerable population is essential to improve the care in the novel and urgent COVID-19 pandemic. The current review is a part I to summarize the up-to-date information about the impact of laboratory-confirmed SARS-CoV-2 infection on pregnant women and focus on clinical presentations and untoward pregnancy outcomes of these pregnant women infected with SARS-CoV-2.

1. INTRODUCTION

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (coronavirus disease 2019, COVID-19) is a pandemic disease with rapidly and widely disseminating to the world.^1–5 New laboratory-confirmed victims associated morbidity and mortality rates have rapidly increased, resulting in globally challenging health care systems.^6–8 Obstetric and childbirth healthcare services are not escaped.⁹ On July 12, 2021, globally, as of 5:08 pm CEST, 12 July 2021, there have been 186,638,285 confirmed cases of COVID-19, including 4,035,037deaths, reported to the World Health Organization (WHO).¹⁰ Although the definite number of pregnant women getting SARS-CoV-2 infection is unknown, it is believed that millions of pregnant women may have SARS-CoV-2 infection, based on the estimated prevalence of SARS-CoV-2 infected pregnant as 1–10%.^11–13 As a new disease, evidence-based knowledge about COVID-19 in pregnant is limited.⁶ Therefore, the decisions about prevention, diagnosis, and management can be made according to previous experience with influenza or other novel coronavirus infections, clinical judgments, and basic knowledge. Pregnant women’s vulnerability to infectious disease pandemics has been recognized for centuries that predispose them to untoward outcomes compared with the general adult population.^14,15 In 1918, 50% of pregnant women infected by Spanish influenza died of disease.^14,15 The similar finding was further confirmed during the 2009 H1N1 pandemic, in which pregnant women were disproportionately more likely to have severe illness, require hospitalization, require intensive care unit (ICU) administration, and require mechanical ventilation, as well as require extracorporeal membrane oxygenation (ECMO).^14,15 Additionally, these pregnant women getting H1N1 infection finally die than their nonpregnant counterparts and pregnant women without H1N1 infection, even though many advances in critical care have been continuously developed since then.¹⁴ The more similar experience was found during the past decades, since the more geographically contained novel coronavirus, such as Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) were widely disseminated in certain areas or countries.^14,15 Although the aforementioned findings have been well known, the attacks of the new infectious diseases still change a fundamental lifestyle and challenge health care systems worldwide,^6–9 contributing to the uncertainty of prevention and management of pregnant women with COVID-19. However, this issue is of urgent need and paramount importance, based on a lot of pregnant women who cannot avoid SARS-CoV-2 attacks. According to the Centers for Disease Control and Prevention (CDC) in the United States of America, there are 100,472 pregnant women with COVID-19, contributing to a total of 17,221 hospitalized cases, and 113 deaths in these pregnant women with COVID-19 to date.¹⁶ The current review attempts to summarize the accumulated updated information about the impact of COVID-19 on pregnant women.

2. ANATOMIC, PHYSIOLOGIC, AND IMMUNOLOGIC CHANGES DURING PREGNANCY

It is important for pregnant women undergo substantial anatomic, physiological, and immunologic changes that are not only essential for coping with the increased metabolic demands of the pregnancy but also to meet the developmental needs of the fetus.^6,15–20 Understanding these changes is critical for all physicians taking care of pregnant women as clinical assessment of pregnant women can be confusing and challenging.²⁰ Increased maternal oxygen demand, elevated diaphragm, increased abdominal pressure, lowered chest wall compliance, decreased lung capacity, edema of the respiratory mucosa, and inability to clear secretions within the respiratory tract decrease the maternal tolerance of hypoxia and encourage rapid progression to respiratory failure in the gravida.^15,20 Additionally, two main challenges of maternal immune system should be faced. One is a protection of the fetus against an immunological attack and the other is a maintenance of adequate defense against various microbial threats. However, a trend seems to become a relative immunocompromised status of pregnant women, contributing to the unique susceptibilities to infectious diseases pandemics. These infectious diseases predispose pregnant women to worsening pregnancy outcomes ranging from severe maternal illness to spontaneous abortion, and even maternal death and perinatal death, which were experiences previously by the Spanish influenza, H1N1, SARS, and MERS pandemics.^6,14–21 A recent review attempted to identify the possible immunological changes, involving the worse outcomes in this vulnerable population, including a shift in CD4+ T cell population (T helper cells) toward the T helper cell type 2 (Th2) phenotype over Th1 (Th2 system dominance accompanied with TH2 cytokines as anti-inflammatory and comprising interleukin [IL]-4, IL-10, IL-13, and transforming growth factor-beta to attenuate cell-mediated immunity); a decrease in circulating natural killer (NK) cells; a decrease in circulating plasmacytoid dendritic cells (pDCs); an increase in circulating progesterone levels; and alterations in the innate immune system, including the pattern recognition receptors Toll-like receptors (TLRs), contributing to overall infectious morbidity by increasing maternal susceptibility to intracellular pathogens, such as viruses.¹⁷ Although some of them still need to be investigated, many of them are believed as the reasons why pregnant women are more severely affected by COVID-19 pandemic since 2020.

Additionally, besides systemic immunological changes as well as anatomic, and physiological changes during pregnancy, hemostatic changes of pregnancy have further contributed to a negative impact on the vulnerability to SARS-CoV-2 infection in pregnant women. Pregnant women have a hypercoagulable state with increased thrombin, circulating coagulation and fibrinolytic factors (plasmin), and increased intravascular inflammation and subsequent endothelial cell damage, contributing to a 4-fold higher venous thromboembolism (VTE) risk compared with age-matched controls.^17,22–25 All are implicated in the pathogenesis of SARS-CoV-2 infection as well as COVID-19 associated coagulopathy (CAC),^16,24 which is an evolving entity that encompasses changes of laboratory coagulation, thrombosis, and bleeding and leads to endothelial and platelet activation akin to what is observed in disseminated intravascular coagulation (DIC), and DIC-related mortality in pregnant women.²⁵ However, information regarding CAC and CAC associated maternal morbidity and mortality remained limited. Although consensus recommends that thromboprophylaxis is needed in pregnant women with laboratory-confirmed SARS-CoV-2 infection,²⁶ there is significant variability in physicians prescribing of anticoagulation in COVID-19 pregnancy in a real-world clinical practice.²⁵ One survey using the RedCap online platform from Canada reported that among 75 respondents and 1546 pregnant women laboratory-confirmed SARS-CoV-2 infection (4% were severe), low-molecular-weight heparin (LMWH), the anticoagulant of choice in CAC was provided by 77% of respondents, with 60% using standard-prophylactic dosing.²⁵ In our experience and domestic data in Taiwan (unpublished), we did not learn any information that these pregnant women with COVID-19 have been treated with any anticoagulant agents. All raise a basic barrier to prevent and manage pregnant women during the COVID-19 pandemics, since extremely little knowledge is known for the pregnant women. This situation underscores the urgent need not only to include pregnant women in clinical trials but also to invest in public health surveillance systems for pregnancy, involving much larger numbers of women.²⁷ Although this goal needs time to achieve, some clinical presentations will help us to identify the pregnant women with COVID-19 at higher risk of occurrence CAC, and they include thrombocytopenia, elevated chronic reactive protein (CRP), D-dimer, and lymphopenia.²⁵

Besides the aforementioned additive or synergistic risk factor contributing to maternal mobility or mortality in pregnant women with COVID-19, pregnant women often face several unique pregnancy-related complications, such as pregnancy induced hypertension (PIH), preeclampsia, eclampsia, and gestational diabetes mellitus (GDM).^28–34 Moreover, overweight (obesity) and advanced age (for example, ≥35 years of age) are also frequently noted in modern obstetrics, resulting in worse outcomes of pregnancy.^35–39 All of them have been known as well correlation with adverse pregnancy outcomes, regardless of concomitance with SARS-CoV-2 infection or not.^{6,9,11,12,14,26–66}

3. CLINICAL PRESENTATIONS

Most transmissions of SARS-CoV-2 occur through close contacts, which is defined as 15 minutes face-to-face contract within 2 m, mediated mainly by contact of the mucosa either by nose, mouth, or eyes of infected individuals with respiratory droplets or rarely through contacts with contaminated fomites touched by unwashed hands of infected individuals.⁴⁴ After SARS-CoV-2 infection, the time from exposure to development of symptoms (the incubation period) is approximately 5–6 days, but sometimes can be longer to reach 14 days.⁴⁴ Beside the incubation period (incubation phase or asymptomatic phase), two subsequent phases, although not all three phases will be passed through the entire clinical course, have been described as followings, including involvement of the upper respiratory tract phase and finally involvement of the lower respiratory tract (including progression to acute respiratory distress syndrome [ARDS] as hypoxia, ground glass infiltrates, and progression to ARDS) phase.⁴⁴ During the incubation phase, host innate or adaptive immune response in this phase is limited, with a resultant total absence of clinical presentations, and many of them are stayed in this phase. It is reported that women during the reproductive age, regardless of during the pregnancy or nonpregnancy status, have a trend to stay in this phase, since more than one half (three quarters) of these SARS-CoV-2 infected women are asymptomatic.^11,16

According to the reports from CDC in United States, based on evaluation of 23,434 pregnant women with confirmed COVID-19 infection, only 44.4% (n = 10,404) of pregnant women have various clinical presentations (clinical symptoms and signs), and the above-mentioned frequency was less than 45.1% (174,198/386,028) of symptomatic nonpregnant women do.¹¹ This observation about the less frequency or much tendency to asymptomatic clinical symptoms or signs in pregnant women infected with SARS-CoV-2 has been found everywhere, even though the data was collected from the hospitalizations.^63,65 One report from United Kingdom showed 37% of 1148 hospitalized women who had confirmed SARS-CoV-2 in pregnancy were asymptomatic.⁶³ In Mexico, a cohort study reported that 86% of the patients were asymptomatic (95% confidence interval [CI], 76%–92%).⁶⁵ Additionally, many largest meta-analysis studies also confirmed that pregnant and recently pregnant women with COVID-19 were less likely to have symptoms, compared with age-matched nonpregnant women (odds ratio [OR] 0.28, 95% CI, 0.13%–0.62%, I² = 42.9%).⁵⁴ The percentage of asymptomatic pregnant women were significantly much higher than that of asymptomatic nonpregnant women (risk ratio [RR] 3.94, 95% CI, 1.69%–9.20%) when both were infected with SARS-CoV-2.⁴⁵ All hint that these pregnant women infected by SARS-CoV-2 have a near 4-fold increased risk to be asymptomatic compared with age-matched nonpregnant women. Allotey et al found the overall rate of COVID-19 diagnosis in pregnant and recently pregnant women attending or admitted to hospital for any reason was 10% (95% CI, 7%–12%; 73 studies; 67,271 women) and the rate was varied greatly by different strategies.⁵⁴ Pregnant women were sampled by universal screening showing that 7% (95% CI, 5%–8%; 60 studies; 57,144 women) had laboratory-confirmed SARS-CoV-2 infection, but by contrast, 28% (95% CI, 15%–43%; 11 studies; 2436 women) of pregnant women were diagnosed as having COVID-19 sampled on the basis of symptoms.⁵⁴ The above findings further emphasized that a clinically meaningfully high percentage of absent of any symptoms or signs in pregnant women who have been infected by SARS-CoV-2. The study reported at theast three quarters (73%, 95% CI, 62%–82%; 38 studies; 906 women) with COVID-19 in the universal screening population were asymptomatic.⁵⁴

The most common symptoms or signs of symptomatic pregnant women with COVID-19 are presented in order, as 50.3% with cough, 42.7% with headache, 36.7% with muscle aches, and 32% with fever.¹¹ Except two as short of breath (25.9% versus 24.8%) and nausea or vomiting (19.7% versus 16.6%), nearly all items evaluating symptoms or signs were presented in less frequency, including cough (50.3% versus 51.3%), fever (32% versus 39.3%), muscle aches (36.7% versus 45.2%), chills (24.2% versus 29.3%), headache (42.7% versus 54.9%), diarrhea (14.2% versus 21.9%), abdominal pain (8.4% versus 9.3%), running nose (12.8% versus 13.1%), new loss of taste or smell (13.5% versus 17.1%), wheezing (1.7% versus 2.1%), and chest pain (3.5% versus 4.1%).¹¹ The less frequency of symptoms or signs in pregnant women with COVID-19, based on USA CDC data were further supported by another meta-analysis.⁵⁴ In detail, compared with age-matched nonpregnant women with COVID-19, pregnant and recently pregnant women with COVID-19 were less likely to have fever (OR 0.49, 95% CI, 0.38%–0.63%; I² = 40.8%), dyspnea (OR 0.76, 95% CI, 0.67%–0.85%; I² = 4.4%), and myalgia (OR 0.53, 95% CI, 0.36%–0.78%; I² = 59.4%).⁵⁴ A more recent meta-analysis, which consists of nine studies comprising 591,058 women (28,797 pregnant and 562,261 nonpregnant women) also further supports the aforementioned observation.⁴⁵ Pregnant women with COVID-19 who experienced clinical symptoms or signs had a statistically and clinically significantly fewer frequencies than nonpregnant women with COVID-19 did with RR 0.74 (95% CI, 0.64%–0.85%) for fever; RR 0.92 (95% CI, 0.89%–0.95%) for myalgia; RR 0.40 (95% CI, 0.39%–0.43%) for diarrhea; RR 0.86 (95% CI, 0.77%–0.95%) for chest tightness; and RR 0.45 (95% CI, 0.21%–0.97%) for expectoration.⁴⁵ All are statistically and clinically meaningful less frequency of symptom presentations amongst pregnant women as compared to age-matched nonpregnant women with COVID-19. Table 1 is a summary of symptoms or signs between pregnant and nonpregnant women with COVID-19.

Table 1.

Symptoms or signs between pregnant and nonpregnant women with laboratory-confirmed SARS-CoV-2 infection

Characteristics	Pregnant (%)a	Pregnantb (95% CI)	Nonpregnant (%)a	RRc or ORd
Asymptomatic	55.6	42.5% (31.6–53.8%)	54.9	3.9 (1.7–9.2)c
Symptomatic	44.4		45.1	0.3 (0.1–0.6)d
Cough	22.3	29.6% (24.0–35.2%)	23.2	0.9 (0.7–1.0)c
Headache	19.0	7.8% (5.9–9.8%)	24.8	0.8 (0.7–0.8)c
Muscle ache	16.3	11.9% (8.1–16.3%)	20.4	0.5 (0.4–0.8)d
Fever	14.2	25.4% (20.2–30.6%)	17.8	0.5 (0.4–0.6)d
Sore throat	12.6	10.4% (6.8–14.5%)	15.6	0.6 (0.1–3.2)c
Short of breath	11.5	13.9% (9.8–18.4%)	11.2	0.8 (0.7–0.9)d
Chills	10.8		13.2
Nausea/vomiting	8.6	8.2% (5.0–11.9%)	7.5	0.8 (0.3–2.4)c
Diarrhea	6.3	4.6% (3.0–6.5%)	9.9	0.4 (0.4–0.4)c
Anosmia/ageusia	6.0	14.4% (7.1–23.2%)	7.7	0.9 (0.9–0.9)c
Runny nose	5.7	4.8% (3.1–7.0%)	5.9	1.4 (0.3–7.1)c
Abdominal pain	3.7	2.5% (0.5–5.6%)	4.2	1.6 (0.4–6.1)c
Chest pain	1.6	2.8% (1.0–5.1%)	1.8	0.9 (0.8–1.0)c
Wheezing	0.7		1.0	0.8 (0.7–0.9)c
Fatigue		15.4 (8.3–23.5%)		0.6 (0.4–1.1)c
Congestion		2.5% (0.0–14.5%)		0.5 (0.0–10.3)c

The data are presented as percentage (%), mean, 95% CI, and RR.

^aThe data are modified from the reference 11, including 23,434 pregnant women with COVID-19 and 386,028 nonpregnant women with COVID-19.

^bThe data are modified from the reference 46, including 31,016 pregnant women with confirmed COVID-19.

^cThe data are modified from the reference 45 to compare the relative risk between pregnant women with COVID-19 and age-matched nonpregnant women with COVID-19.

^dThe data are modified from the reference 54, including 34,046 pregnant women with COVID-19 and 567,075 nonpregnant women with COVID-19.

CI = confidence interval; RR = relative risk.

However, the above-mentioned frequency of symptoms or signs in pregnant women with COVID-19 should be carefully interpretated, since the reported data are based on symptomatic pregnant women with COVID-19. In fact, if all pregnant women with COVID-19, regardless of presence or absence of symptoms, all items about symptoms or signs are less than one quarter. Only 22.3% with cough, 19.0% with headache, 16.3% with muscle aches, and 14.2% with fever have been found.¹¹ In agreement with previous Allotey’s study as high as three quarters of the 906 women with COVID-19 in the universal screening population being absent of symptoms,⁵⁴ recent evidence also showed less than one-quarter of pregnant women with COVID-19 presented various symptoms or signs, including the most common symptoms were headache (24.5% based on four studies), cough (23.1% based on six studies), myalgia (17.7% based on four studies), and fever (17.5% based on seven studies).⁴⁵ It is rationale to suppose that a large number of pregnant women getting SARS-CoV-2 infection will not search for medical care and subsequently overlook the potential dangers of this disease if no routine universal screening is applied to this vulnerable population. Besides, less frequency of symptoms or signs in pregnant women with COVID-19, their milder symptoms or signs in clinical presentations may further increase the risk of underestimation of worse outcome of pregnancy. The proverb as “pour oil on the flame” is a better reflection when pregnant women are stayed in this COVID-19 pandemic.

To emphasize the followings again, symptoms or signs of pregnant women getting SARS-CoV-2 infection, are more likely to have “mild” clinical presentations,¹¹ making both physicians and pregnant women have a potential to underestimate the subsequent risk of untoward outcomes in these pregnant women with COVID-19. The statistically significant fewer and milder symptoms or signs in pregnant women with COVID-19 cannot be a reflective of clinical meanings.^67–74 Evidence has shown that these pregnant women with COVID-19 are more likely to develop severe diseases and subsequently die of diseases than nonpregnant women with COVID-19.^6,11,54,60 The CDC in United States indicated that pregnant women had a statistically significant and clinically meaningful risk of the need of intensive care unit (ICU) administration with a 3-fold increase (RR 3.0), and subsequent need of mechanical ventilation (RR 2.9), and the request of extracorporeal membrane oxygenation (ECMO, RR 2.4).¹¹ Now, we have many advances in medical care which have been applied to these pregnant women with COVID-19; however, we still fail to decrease the mortality related to COVID-19 in pregnant women, since compared with age-matched nonpregnant women with COVID-19, the mortality rate or pregnant women with COVID-19 is increased at least 70%.¹¹ A meta-analysis has further confirmed that these pregnant women with COVI-19 have a 3-fold increase of mortality (RR 2.9, 95% CI, 1.1%–7.5%) compared with age-matched nonpregnant women with COVID-19.⁵⁴ Table 2 is a summary of recent publications comparing the morbidity and mortality between pregnant and nonpregnant women with COVID-19.

Table 2.

Summary of recent publications comparing the morbidity and mortality between pregnant and nonpregnant women with COVID-19

Items	Preg/nona (%)	RRa (CI)	Preg/nonb (%)	ORd or RRb (CI)	PPc (%)
ICU	1.05/0.39	3.0 (2.6–3.4)	1.8/1.7	2.1 (1.5–3.0)d
Ventilation	0.29/0.11	2.9 (2.2–3.8)	0.8/0.6	2.6 (2.3–2.9)d	7.7 (3.7–12.9)
ECMO	0.07/0.03	2.4 (1.5–4.0)	0.06/0.03	2.0 (1.2–3.3)d	0.3 (0–1.2)
Death	0.15/0.12	1.7 (1.2–2.4)		1.1 (0.9–1.3)b

The data are presented as percentage (%), RR, OR, and 95% CI.

^aThe data are modified from the reference 11, including 23434 pregnant women with COVID-19 and 386028 nonpregnant women with COVID-19.

^bThe data are modified from the reference 45 to compare the relative risk between pregnant women with COVID-19 and age-matched nonpregnant women with COVID-19.

^cThe data are modified from the reference 46, including 31016 pregnant women with COVID-19. Risk estimation was based on the reported studies, which were varied in total number of enrollment.

^bThe data are modified from the reference 54, including 34046 pregnant women with COVID-19 and 567075 nonpregnant women with COVID-19.

CI = confidence interval; ECMO = extracorporealmembrane oxygenation; ICU = intensive care unit admission; Non = nonpregnant; OR = odds ratio; PP = pooled proportion.; Preg = pregnant; RR = relative risk; Ventilation = invasive ventilation or mechanical ventilation.

In July 2021 issue of the Clinical Infectious Diseases, the risk may be more apparent.⁶¹ Based on 703 hospitals in the Premier Healthcare Database during March-September 2020 enrolling 489,471 delivery hospitalizations, including 6550 (1.3%) pregnant women with confirmed COVID-19, the authors found that pregnant women with COVID-19 had an increased risk for ARDS (RR 34.4, 95% CI, 29.0%–40.8%), sepsis (RR 13.6, 95% CI, 10.2%–18.1%), mechanical ventilation (RR 12.7, 95% CI, 9.2%–17.5%), shock (RR 5.1, 95% CI, 3.4%–7.8%), ICU admission (RR 3.6, 95% CI, 2.8%–4.5%), acute renal failure (RR 3.5, 95% CI, 2.8%–4.3%), thromboembolic disease (RR 2.7, 95% CI, 1.7%–4.4%), and adverse cardiac event/outcome (RR 2.2, 95% CI, 1.6%–2.9%), contributing to a 17-fold increase of maternal death (RR 17.0, 95% CI, 8.2%–35.5%).⁶⁰ Meta-analysis also demonstrated that while compared with age-matched pregnant women without COVID-19, pregnant women with COVID-19 still have a statistically significant and clinically meaningful risk of the need of intensive care unit (ICU) administration with a near 19-fold increase (RR 18.6, 95% CI, 7.5%–45.8%), and preterm birth before 37 gestational weeks (RR 1.5, 95% CI, 1.1%–1.9%) and cesarean section (RR 1.1, 95% CI, 0.9%–1.4%).⁵⁴ Table 3 shows a summary of recent publications comparing the maternal morbidity and mortality between pregnant women with and without COVID-19. All further hint us that pregnant women need more effective strategies to protect them to minimize or avoid SARS-CoV-2 infection, since COVID-19 infection during pregnancy are more like to develop a catastrophic life-threatening disease. Moreover, during the COVID-19 outbreak, pregnant women should face COVID-19 related life-threatening status with more concerns.

Table 3.

Summary of recent publications comparing the maternal morbidity and mortality between pregnant women with and without COVID-19

Items	Pre/Absa (%)	RR (CI)a	Pre/Absa (%)	OR (CI)b	Pre/Absa (%)	OR (CI)c	Ranged (%)
ICU	4.5/1.5	3.6 (2.8–4.5)	4.2/0.2	18.6 (7.5–45.8)	8.4/1.6	5.0 (3.1–8.1)	1.4–83.6
Ventilation	1.6/0.1	12.7 (9.2–17.5)	0.8/0.6				1.4–83.6
Severe	4.7/1.6	3.5% (2.8–4.3)	0.06/0.03
Com	4.4/0.7	6.3 (5.5–7.3)
PB			12.4/7.8	1.5 (1.1–1.9)	22.5/13.6	1.6 (1.3–1.9)	14.3–63.8
C/S			36.1/35.6	1.1 (0.9–1.4)	49.0/38.4	1.3 (1.2–1.4)	23–95.8
Death	0.1/0.01	17.0 (8.2–35.4)	0.7/0.2	2.9 (1.1–7.5)	1.6/0.1	22.3 (2.9–172.1)	0–15.8

The data are presented as percentage (%), RR, OR, and 95% CI.

^aThe data are modified from the reference 60, including 6550 pregnant women with COVID-19 and 482921 pregnant women without COVID-19.

^bThe data are modified from the reference 54, including 34046 pregnant women with COVID-19 and 11842 pregnant women without COVID-19. Risk estimation was based on the reported studies, which were varied in total number of enrollment.

^cThe data are modified from the reference 40, including 706 pregnant women with COVID-19 and 1424 pregnant women without COVID-19.

^dThe data are modified from the reference 66, including 44 articles to enroll pregnant women with COVID-19.

C/S = cesarean section; CI = confidence interval; Com= complications; ICU = intensive care unit admission; OR = odds ratio; PB = preterm birth < 37 weeks of gestation; Pre/Abs = presence of COVID-19 versus absence of COVID-19; RR = relative risk; Severe = severe illness; Ventilation = invasive or mechanic ventilation.

Besides an increasing maternal morbidity and mortality in pregnant women infected by SARS-CoV-2, their fetus or offspring are also involved in the dangers. Perinatal and neonatal morbidity and mortality rates are reported to be increased dramatically and significantly in pregnant women with COVID-19 compared with those in pregnant women without.^{11,16,17,26,40,44,54,66} The spontaneous preterm birth rate to pregnant women with COVID-19 was a 3-fold increase compared with that of pregnant women without COVID-19.⁵⁴ Neonates born to pregnant women with COVID-19 were 5 times as likely to be admitted to the neonatal intensive care unit (NICU) compared with those to women without (OR 4.9).⁵⁴ Table 4 is a summary of recent publications comparing the perinatal or neonatal morbidity or mortality between pregnant women with and without COVID-19.

Table 4.

Summary of recent publications comparing the perinatal or neonatal morbidity and mortality between pregnant women with and without COVID-19.

Items	Rangea	Pre/Absb,c	OR (CI)b,c
Stillbirth	0%–8.0%	0.9/0.5b	2.8 (1.3–6.5)b
Death	0%–9.2%	0.4/0.2b	2.8 (0.9–8.4)b
ICU	1.6%–76.9%	25.6/11.3b	4.9 (1.9–12.8)b
SPMMI		17.0/7.9c	2.1 (1.7–2.8)c
SGA	1.3%–20.0%

The data are presented as percentage (%), RR, OR, and 95% CI.

^aThe data are modified from the reference 66, including 44 articles to enroll pregnant women with COVID-19.

^bThe data are modified from the reference 54, including 34046 pregnant women with COVID-19 and 11842 pregnant women without COVID-19. Risk estimation was based on the reported studies, which were varied in total number of enrollment.

^cThe data are modified from the reference 40, including 706 pregnant women with COVID-19 and 1424 pregnant women without COVID-19.

CI = confidence interval; ICU = intensive care unit admission; OR = odds ratio; Pre/Abs = presence of COVID-19 versus absence of COVID-19; RR = relative risk; SGA = small for gestational age; SPMMI = severe perinatal morbidity and mortality index, including any of the morbidities listed in the SNMI (severe neonatal morbidity index, including at least one of the following morbidities: bronchopulmonary dysplasia, hypoxic ischemic encephalopathy, sepsis, anemia requiring transfusion, patent ductus arteriosus, intraventricular hemorrhage, necrotizing enterocolitis, or retinopathy of prematurity).

As shown by previous section, pregnant women have a higher risk of comorbidity, and most of them are strongly correlated with pregnancies themselves. Unfortunately, pregnant women with comorbidity may have a further higher risk to develop untoward pregnancy outcome when they get SARS-CoV-2 infection concomitantly.

4. INCREASED UNTOWARD PREGNANCY OUTCOMES IN WOMEN WITH CO-MORBIDITY WHO GET SARS-COV-2 INFECTION DURING PREGNANCY

It is well known that pregnant women with COVID-19 have fewer and milder clinical presentations than age-matched nonpregnant women with COVID-19 do; however, these pregnant women with COVID-19 are more likely to develop severe diseases, resulting a high mortality rate. Additionally, pregnant women with COVID-19 also have worse pregnancy outcome, which not only increase maternal morbidity and mortality but also are associated with increasing perinatal and neonatal morbidity and mortality compared with pregnant women without COVID. Therefore, identification of risk factors associated with progression of COVID-19 is urgently important, since early prevention and prompt management of this vulnerable population may delay or ameliorate either severity or progression of disease, which has been found in the management of various clinical conditions, regardless of life-threatening diseases or not.^75–80

Based on report from CDC in United States,¹¹ there are many risk factors associated with more worse pregnancy outcome in pregnant women with COVID-19 compared with age-matched nonpregnant women with COVID-19, including nonwhite ethnicity (Hispanic or Latina with RR 2.4, 95% CI, 1.3%–4.3%; Asia, nonHispanic with RR 1.4, 95% CI, 0.7%–2.7%), and presence of underlying health condition (diabetes with RR 1.5, 95% CI, 0.6%–3.5% and cardiovascular disease with RR 2.2, 95% CI, 1.0%–4.8%). While compared with pregnant women with COVID-19 who do not have the following risk factors, these pregnant women with COVID-19 who have any one of the following risk factors have faced more severe and/or life-threatening clinical situations, and some of them really increase mortality rate. For example, compared with white-ethnicity pregnant women with COVID-19, nonwhite-ethnicity pregnant women with COVID-19 have a higher risk of ICU admission (OR 1.7), invasive ventilation (OR 2.2), and maternal death (OR 1.6).⁵⁴ Other identified risks associated with worse prognosis are shown in Table 5. A cohort study from the UK, including 427 women, found risk factors identified for hospitalization with COVID-19 disease are similar to those in the general population, including having comorbidities, such as asthma, hypertension, or diabetes (OR 1.5, 95% CI, 1.1%–2.1%); or maternal age ≥35 years (OR 2.3, 95% CI, 1.8%–2.7%) and obesity (body mass index ≥30) (OR 2.5; 95% CI, 2.0%–3.2%); and nonwhite ethnic population, such as Asian (OR 4.0, 95% CI, 3.1%–5.1%), Black (OR 8.1, 95% CI, 6.2%–10.5%), and Chinese/others (OR 2.7, 95% CI, 1.7%–4.0%).⁴⁸

Table 5.

Summary of risk factors associated with worse outcome of pregnant women with COVID-19.

Items	nonwhite ethnicity	Any comorbidity	Chronic HT Pre-eclampsia*	Diabetes GDM*	≥35	BMI
Severe	0.9 (0.6–1.6)a4.5 (3.4–6.0)c	1.8 (1.5–12.2)	2.0 (1.1–3.5) 4.2 (1.3–14.0)a,*	2.1 (1.6–2.8)a1.5 (1.1–2.1)c1.2 (0.7–2.1)a,*	1.8 (1.3–2.6)a2.3 (1.8–2.7)c	2.4 (1.8–3.1)a2.5 (2.0–3.2)c
ICU	1.7 (1.2–2.3)	1.7 (1.3–2.2)	4.7 (2.4–9.4) 179 (7.7–4186)*	4.7 (1.9–11.2) 3.3 (1.6–6.9)*	2.1 (1.7–2.6)	2.7 (1.1–6.6)
Ventil	2.2 (1.3–4.0)	5.3 (1.8–15.7)	63.8 (9.7–420.5)	18.6 (0.3–1324)	1.7 (0.6–5.0)	6.6 (2.0–22)
Death	1.6 (1.1–2.5)	2.5 (0.8–8.2)	1.6 (1.1–2.5)	14.9 (4.2–52.8)	0.9 (0.2–3.7)	2.3 (1.2–4.3)
PPb %	64.8 (44.1–83.1)				31.3 (23.5–39.6)	19.3 (10.5–30)

The data are presented as OR and 95% CI.

^aThe data are modified from the reference 54, including 34046 pregnant women with COVID-19. Risk estimation was based on the reported studies, which were varied in total number of enrollment.

^bThe data are modified from the reference 46, including 31016 pregnant women with COVID-19. Risk estimation was based on the reported studies, which were varied in total number of enrollment.

^cThe data are modified from the reference 48, including 427 pregnant women with COVID-19 admitted to hospital among an estimated 86293 women with COVID-19.

≥35: maternal age ≥ 35 years; BMI = body mass index ≥ 30; CI = 95% confidence interval.; Death = maternal death; GDM = gestational diabetes; HT = hypertension; ICU = intensive care unit admission; OR = odds ratio; PP = pooled proportion; Severe = severe diseases; Ventil=invasive or mechanical ventilation.

Huntley et al performed a systematic review and meta-analysis to compare the risk of perinatal and neonatal death among pregnant women with and without COVID-19.⁸¹ A total of 728 deliveries to pregnant women with COVID-19 and 3826 deliveries to contemporaneous pregnant women without COVID-19 were analyzed. They also identified maternal age ≥35 years and obesity with an increased risk to get SARS-CoV-2 infection during the pregnancy. All hint us that any woman attempts to conceive or has already conceived should be well informed to their risks during this COVID-19 outbreak, since they may have a higher risk to get SARC-CoV-2 infection, and subsequently they have a higher risk to develop to severe disease and result in a COVID-19 related death during the pregnancy.

In conclusion, although not directly comparable, the symptoms or signs of pregnant women with COVID-19 based on the frequency and severity are less and milder than those of nonpregnant women. However, these pregnant women with COVID-19 are more likely to progress to severe diseases and subsequently result in COVID-19 related death compared with nonpregnant women. Compared with pregnant women without COVID-19, the pregnant women with COVID-19 also have a higher risk to develop severe diseases and have a higher risk of maternal death. Besides the significantly increased risk of maternal morbidity and mortality, the perinatal and neonatal outcomes born to pregnant women with COVID-19 are also significantly worse, such as a three-fold increase to be admitted to the NICU than those to pregnant women without COVID-19. All emphasize an urgent need of national or international recommendations and guidelines to optimize prevention and management strategies for COVID-19 in pregnancy. Additionally, the healthcare team should help pregnant women to minimize the risk of SARS-CoV-2 infection and provide an adequate counseling and optimal medical service for those pregnant women, regardless of they have SARS-CoV-2 infection or not.

ACKNOWLEDGMENTS

This article was supported by grants from the Ministry of Science and Technology, Executive Yuan, Taiwan (MOST 109-2314-B-075B-014-MY2 and MOST 110-2314-B-075-016-MY3), and Taipei Veterans General Hospital (V110C-082, and VGH109E-005-5). The authors appreciate the support from Female Cancer Foundation, Taipei, Taiwan.