The 2019 Novel Coronavirus Disease in Pregnancy

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299

P. C. Guest (ed.), Clinical, Biological and Molecular Aspects of COVID-19, Advances in Experimental Medicine and Biology 1321, https://doi.org/10.1007/978-3-030-59261-5_27

The 2019 Novel Coronavirus Disease in Pregnancy:

A Systematic Review

Somayeh Makvandi, Mitra Mahdavian, Goli Kazemi-Nia, Amir Vahedian-Azimi, Paul C. Guest, Leila Karimi,

and Amirhossein Sahebkar

Abstract

In December 2019, a respiratory disease caused by a coronavirus called SARS-CoV-2 (COVID-19) began in Wuhan, China, and quickly became a pandemic. In such situa- tions, pregnant women are suspected of being among the vulnerable groups. The aim of this study was to report clinical symptoms, laboratory findings, and obstetrical complications, maternal, fetal, and neonatal complications of COVID-19 infection in pregnant women. We

searched the Cochrane library, MEDLINE/

PubMed, and Web of Sciences from their inception to April 5, 2020. Any study involving pregnant women with COVID-19 which evaluated the effect of the disease on pregnancy outcomes and fetal and neonatal complications was included in the study. The outcomes were the symptoms and laboratory findings, obstetrical complications, mode of delivery, and maternal, fetal, and neonatal complications. The search resulted in 69 titles and abstracts, which were narrowed down to

S. Makvandi

Department of Midwifery, School of Nursing and Midwifery, Islamic Azad university Ahvaz branch, Ahvaz, Iran

M. Mahdavian

Department of Midwifery, School of Nursing and Midwifery, Islamic Azad university Bojnourd branch, Bojnourd, Iran

G. Kazemi-Nia

Sina Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

A. Vahedian-Azimi

Trauma Research Center, Nursing Faculty, Baqiyatallah University of Medical Sciences, Tehran, Iran

P. C. Guest

Laboratory of Neuroproteomics, Department of Biochemistry and Tissue Biology, Institute of Biology, University of Campinas (UNICAMP), Campinas, Brazil

L. Karimi (*)

Behavioral Sciences Research Center, Life style institute, Nursing Faculty, Baqiyatallah University of Medical Sciences, Tehran, Iran

e-mail: [email protected] A. Sahebkar (*)

Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland

Halal Research Center of IRI, FDA, Tehran, Iran e-mail: [email protected];

[email protected]

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12 studies involving 68 women. The three most common symptoms of patients were fever, cough, and fatigue. The most common laboratory findings were an increase in C-reactive protein (CRP) and lymphopenia.

The most common obstetrical complication was preterm labor (33.3%). No maternal deaths were reported. The Cesarean section rate was 83.3% and the vertical transition rate was 2.23%. The findings showed that the clinical symptoms and laboratory measures of pregnant women affected by COVID-19 did not differ from the general population. In general, the prognosis of mothers who suffered from COVID-19 and their newborns was satisfactory. However, there is a need for further rigorous studies to confirm these findings as the pandemic progresses.

Keywords

COVID-19 · Novel coronavirus infection · Pregnancy outcome

27.1 Introduction

Coronaviruses are one of the largest viral fami- lies that can cause common cold to more severe diseases such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) [1]. Coronaviruses have been prevalent in some birds and mammals, but there have been several examples of their occurrence in humans in recent years. The new coronavirus disease, which began in December 2019 with a widespread human outbreak in Wuhan, China, is known as COVID-19 [2]. The disease has quickly crossed borders between countries and conti- nents, forcing the World Health Organization to declare a state of emergency. This has now become a pandemic and has attracted the atten- tion of many countries [3].

In cases of disease epidemics, pregnant women should be classified as a vulnerable group due to lower body immunity. Changes in the cardiovascular system during pregnancy,

including an increase in heart rate, increased oxygen consumption, and decreased lung capac- ity, increase the risk of developing severe respiratory diseases in pregnant women [4, 5].

In the context of the 2019 coronavirus pandemic, there are several unanswered questions about the effects of the disease on a pregnant woman and her fetus and neonate:

1. Are the clinical symptoms and laboratory findings of pregnant women suffering from COVID-19 infection similar to those in general patients?

2. Do pregnant women with COVID-19 infection have a higher risk for pregnancy complications?

3. What is the rate of vertical transmission of the disease to the fetus or neonate?

To answer these questions, a systematic review of the available related evidence was conducted.

27.2 Methods

27.2.1 Data Sources and Search Strategy

Two investigators (SM and LK) conducted searches of the Cochrane library, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE/PubMed, and Web of Sciences up to April 5, 2020. Additionally, Google Scholar was searched with the aim of exploring the citations of final studies included in the systematic review.

The search strategy used was:

“COVID-19” OR “COVID19” OR “2019 novel coronavirus infection” OR “2019-nCoV infection” OR “COVID-19 pandemic” OR “coronavirus disease-19” OR “2019-nCoV disease”

OR “2019 novel coronavirus disease” OR

“coronavirus disease 2019.”

AND

“Pregnancy” OR “Pregnancy Outcomes” OR

“Pregnancy Outcome” OR “Outcome, Pregnancy” OR “Outcomes, Pregnancy.”

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The reference lists of articles were checked for further relevant publications.

27.2.2 Inclusion Criteria

Any type of study involving pregnant women with COVID-19 and evaluating the effect of the disease on pregnancy outcomes and fetal and neonatal complications was included in the study.

Only studies published in English were reviewed.

27.2.3 Outcomes

Our outcomes were the symptoms and laboratory characteristics of COVID-19, obstetrical complications, mode of delivery, maternal complications, detection of coronavirus in products of conception, and the infants and fetal and neonatal complications.

27.2.4 Study Selection and Data Extraction

Two authors independently reviewed the search output. We screened titles and abstracts of search results to exclude irrelevant studies. We then retrieved full text articles of seemingly relevant studies and examined these to see whether or not they met the inclusion criteria. The reviewers (SM and LK) resolved any disagreement through discussion and consensus agreement. We designed a data extraction form. Data were extracted by the two reviewers using the agreed form. Any disagreement was resolved by consensus.

27.3 Results

27.3.1 Results of the Search

Figure 27.1 shows the PRISMA flowchart for study inclusion and exclusion. A total of 69 studies corresponding to our search strategy were identified. Of these, 14 irrelevant records were

excluded based on the title and abstract review.

The full-text articles for the remaining 55 articles were retrieved. After review of the full-text articles, 43 articles were excluded and 12 studies met our inclusion criteria for systematic review. The characteristics of these studies are presented in Table 27.1.

27.3.2 Participants and Settings

A total of 68 participants were included across all 12 studies, ranging from one to 15 persons per study. Mothers ranged in age from 22 to 41 years old. One patient was in the first trimester, four women were in the second trimester of pregnancy, and another 63 were in the third trimester.

Five women had a history of past medical conditions. Eleven studies were conducted in China [6–16], and one was performed in Honduras [17].

27.3.3 Outcomes

27.3.3.1 Symptoms of COVID-19 at Admission

The three most common symptoms of patients at the time of hospitalization were fever (76.5%), cough (39.7%), and fatigue (13.2%), respec- tively. Other symptoms included dyspnea (11.8%), myalgia (10.3%), sore throat (8.8%), diarrhea (5.9%), nasal congestion (5.9%), and skin rash (1.5%; one patient) (Table 27.1).

27.3.3.2 Laboratory Characteristics Examination of lung computerized tomography (CT) scans or chest X-rays showed some evidence in favor of coronavirus disease in 45 of the 51 patients tested (88.2%). The most common laboratory finding was an increase in C-reactive protein (CRP), which was detected in 31 of the 44 cases tested (74.3%). The next most common biomarker tested was for the presence of lymphopenia, which occurred in 30 out of 43 cases (70.5%). Other laboratory findings included decreased platelet counts (23.1%) and increased levels of liver enzymes (11.62%) (Table 27.1).

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27.3.3.3 Mode of Delivery

Fifty women had a Cesarean section (83.33%).

Ten had a vaginal delivery (16.66%) and eight were still pregnant by the end of the study.

27.3.3.4 Obstetrical Complications Of the 60 cases that gave birth, 20 were preterm (33.3%). Other complications included 11 cases of fetal distress (18.3%), six cases of premature rupture of membranes (PROM) (10%), three cases of gestational diabetes (4.5%), two cases of preeclampsia (3%), and two cases of gestational hypertension (3%).

27.3.3.5 Maternal Complications

There were no reports of maternal deaths in the studied cases. The need for mechanical ventilation was found in only one case (1.5%).

27.3.3.6 Fetal and Neonatal Complications

From 45 tests for detection of coronavirus in products of conception and the infants, there were 44 negative tests (97.7%) and one test was positive (2.2%). One case of stillbirth [10], one case of neonatal death [11], and seven cases of lung infection were reported [11, 12, 14]. No severe asphyxia was reported.

27.4 Discussion

In the present review, the most common symptoms of the disease in pregnant women were fever, cough, and fatigue. These findings sug- gest that the symptoms at the onset of the disease in pregnant women do not differ from those in the normal population. A report of 72,314 records in China showed that in patients with coronavirus, typical symptoms were fever, cough, and fatigue [18]. In another study, Huang et al. showed that common symptoms at onset of illness were fever (98%), cough (76%), and myalgia or fatigue (44%) and less common symptoms were sputum production, headache, hemoptysis, and diarrhea [2]. These findings are consistent with our study.

In a study of 149 patients with COVID-19 infection, Yang et al. found that among the laboratory biomarker measures, elevated CRP and lymphopenia were the most common findings [2]. These results are also consistent with present study. Therefore, in terms of laboratory measures, it seems that there is no difference between pregnant women and non-pregnant patients.

The findings showed that the rate of Cesarean section for termination of pregnancy was much higher than for vaginal delivery. An expert Records identified through

database searching:

n=69

Full paper articles assessed:

n=55

Studies included in the systematic review:

n=12

Irrelevant records excluded based on the title and abstract review: n=14

Articles excluded based on the full text: n=43 Fig. 27.1 Flowchart for

systematic review

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Table 27.1Characteristics of included studies First authorCuifang FanDehan LiuHuijun ChenNan YuSiyu ChenXiaotong WangYangli Liu

Lysien Ivania ZambranoHuaping ZhuYang LiLan DongSuliman Khan CharacteristicsNumber of cases215975113110113 Age of mothers (years)29–3423– 4026–4029–3425–312822–364125–35302927–33 Gestational age (weeks)36–3712– 3836–3937–4138–413025–383131–39353434–38 Symptoms of COVID-19Fever21376−+10+9−+2 Cough−9411−2+5+−3 Fatigue−4−−−−4+−−−− Dyspnea−111−−3−−−+1 Myalgia−33−−−−+−−−− Sore throat112−−−1−1−−− Diarrhea−111−−−−1−−− Nasal congestion2−−−1−−−−−+− Skin rash1−−−−−−−−−−− Laboratory characteristicsEvidence on lung CT or CXR in favor of coronavirus disease

21587+NMNM10++NM Lymphopenia112554+NMNMNM−+2 Low plateletNMNMNM2−NMNMNMNM+NMNM Elevated CRPNM1067−+NMNMNMNM+2 Elevated liver enzymesNMNM32−−NMNMNMNM−− (continued)

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Table 27.1(continued) First authorCuifang FanDehan LiuHuijun ChenNan YuSiyu ChenXiaotong WangYangli Liu

Lysien Ivania ZambranoHuaping ZhuYang LiLan DongSuliman Khan Obstetrical complicationsGestational hypertension−−1−−−−+−−NM− Gestational diabetes−1−−2−−−−−NM− Preeclampsia−−1−1−−−−−NM− Fetal distress−−2−−−3−6−NM− PROM−−2−−−1−3−NM− Premature delivery−−4−−+6−6++1 Mode of deliveryVaginal delivery−1−−3−−−3−−3 Cesarean210972+10−7++− Pregnant at end of study−4−−−−3+−−−− Maternal complicationsDeath−−−−−−−−−−−− Mechanical ventilation−−−−−−1−−−−− Fetal and neonatal complications

Detection of coronavirus in products of conception and the infants NegativeNMOnly six were checked and were negative Of the threecases checked, one was positive

NegativeNegativeNegativeNANegativeNegativeNegativeNegative Stillbirth−−−−−−1NA−−−− Low birth weight−−2−−+−NA7−−− Lung infection2NM−1−−−NA4−−− Severe asphyxia−−−−−−−NA−−−− Neonatal death−−−−−−−NA1−−− In hospital−−−−−−−−4−−− NM not mentioned, NA not applicable, CRP C-reactive protein

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consensus for managing pregnant women and neonates born to mothers with suspected or confirmed novel coronavirus infection stated that at present, there is no conclusive evidence of the best delivery method to reduce the risk of vertical transmission [19]. In other words, whether or not Cesarean section can reduce the risk of vertical transmission in COVID-19 has not yet been confirmed. According to the evidence, the decision on the time and type of delivery in pregnant women suffering from COVID-19 infections is a multidisciplinary effort influenced by several factors such as the patient’s clinical condition and obstetrical factors [20].

Examination of obstetric complications in women with COVID-19 infection showed that preterm delivery was more common than other complications. The findings of a study by Mascio et al. showed that in 41% of pregnant women with the disease, preterm delivery occurred as the most common obstetrical complication [20]. This could be due to premature termination of pregnancy due to the potential risks of COVID-19 infection to the mother and fetus.

There were no reports of maternal deaths in the studied cases. In line with this finding, a review of 41 pregnant women with COVID-19 infection did not report any maternal deaths [5].

This suggests that the mortality rate of pregnant mothers due to COVID-19 is lower than that which occurred with SARS and MERS. A review by Dashraath et al. concluded that the mortality rate in pregnant women due to SARS and MERS was 18 to 25 percent [5].

In the present study, the vertical transition rate of COVID-19 was 2.2%. However, it was not possible to judge whether or not this finding is conclusive. This is because the majority of the women studied were in the last trimester of pregnancy, and it is not clear what the rate of transmission to the fetus would have been if the disease had occurred earlier in the pregnancy.

Finally, it is important to remember that there is little data on the effect of 2019 novel coronavirus

on pregnancy and its maternal, fetal, and neonatal complications. The articles reviewed above were all from small studies and quality was not assessed.

Therefore, the interpretation of the findings of this study should be considered with caution.

Another limitation of the present study was that only English-language studies were included.

Due to the fact that the outbreak of this disease has been Wuhan City, China, articles in Chinese may also have been published in this regard.

Another potential limitation of this study relates to the fact that analysis of biomarkers was limited to measurement of circulating CRP, lymphocyte levels, and markers of liver damage. This may be a critical factor to consider in future studies as reports indicate different manifestations of COVID-19 infection due to different patient sus- ceptibilities and disease severities [21]. The Handbook of COVID-19 Prevention and Treatment has recommended the use of serum antibody testing for monitoring immune response of the host to infection [22]. It has also recommended testing for circulating CRP levels as most cases of COVID-19 infection with signifi- cantly elevated CRP have been linked to more severe disease, consistent with the Centers for Disease Control and Prevention (CDC) guidelines in the USA [23]. In line with this, an eleva- tion in CRP levels was the most consistent finding in the studies analyzed in this review.

Lymphopenia is considered a cardinal laboratory biomarker with prognostic potential in systemic infections such as in COVID-19 cases [24]. In addition, lactate dehydrogenase (LDH) may serve as a biomarker of liver damage, and CRP and IL-6 may be used to identify cases with severe inflammation and poor prognosis. Another finding in COVID-19 patients has been reports of hypercoagulation [25]. Thus biomarkers asso- ciated with activation of the clotting cascade should be assessed. This could be performed rap- idly using test strips which measure clotting time in combination with a metered readout and monitoring using a Smartphone app, as described by Vegt and Guest in 2018 [26].

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27.5 Conclusions

The findings of this review study showed that the clinical symptoms and laboratory findings of pregnant women affected by COVID-19 infection did not differ from the general population.

However, preterm labor and Cesarean section appeared more likely to occur in pregnant women suffering from COVID-19 infection than their counterparts. In general, the prognosis of newborns of infected mothers was satisfactory. Due to the lack of data, the authors strongly recom- mend that more quality studies be performed on pregnant women affected by COVID-19 infection in all three trimesters of pregnancy to achieve more accurate and definitive results. We also rec- ommend the incorporation of additional biomarker readouts in these studies to detect and monitor COVID-19-related disease complications.

Acknowledgments Thanks to guidance and advice from the “Clinical Research Development Unit of Baqiyatallah Hospital”.

Funding Source None

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