key: cord-0759920-s00bzo5l
authors: Pettirosso, Elicia; Giles, Michelle; Cole, Stephen; Rees, Megan
title: COVID‐19 and pregnancy: A review of clinical characteristics, obstetric outcomes and vertical transmission
date: 2020-08-10
journal: Aust N Z J Obstet Gynaecol
DOI: 10.1111/ajo.13204
sha: 9058ebc4169a3821d24952cc1a570352b5e35c63
doc_id: 759920
cord_uid: s00bzo5l

BACKGROUND: Since its emergence in December 2019, COVID‐19 has spread to over 210 countries, with an estimated mortality rate of 3–4%. Little is understood about its effects during pregnancy. AIMS: To describe the current understanding of COVID‐19 illness in pregnant women, to describe obstetric outcomes and to identify gaps in the existing knowledge. METHODS: Medline Ovid, EMBASE, World Health Organization COVID‐19 research database and Cochrane COVID‐19 in pregnancy spreadsheet were accessed on 18/4, 18/5 and 23/5 2020. Articles were screened via Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines. The following were excluded: reviews, opinion pieces, guidelines, articles pertaining solely to other viruses, single case reports. RESULTS: Sixty articles were included in this review. Some pregnant participants may have been included in multiple publications, as admission dates overlap for reports from the same hospital. However, a total of 1287 confirmed SARS‐CoV‐2 positive pregnant cases are reported. Where universal testing was undertaken, asymptomatic infection occurred in 43.5–92% of cases. In the cohort studies, severe and critical COVID‐19 illness rates approximated those of the non‐pregnant population. Eight maternal deaths, six neonatal deaths, seven stillbirths and five miscarriages were reported. Thirteen neonates were SARS‐CoV‐2 positive, confirmed by reverse transcription polymerase chain reaction of nasopharyngeal swabs. CONCLUSIONS: Where universal screening was conducted, SARS‐CoV‐2 infection in pregnancy was often asymptomatic. Severe and critical disease rates approximate those in the general population. Vertical transmission is possible; however, it is unclear whether SARS‐CoV‐2 positive neonates were infected in utero, intrapartum or postpartum. Future work should assess risks of congenital syndromes and adverse perinatal outcomes where infection occurs in early and mid‐pregnancy.

In December 2019, the novel coronavirus SARS-CoV-2 first appeared in Wuhan, China, with both the virulence and transmissibility to infect on pandemic proportions. By 1 June 2020, there were more than 6 million infections worldwide and over 371 100 deaths. 1 These figures are increasing daily and crude global mortality is estimated at 3-4% by the World Health Organization. 2 Coronavirus disease 2019 (COVID-19) characteristically presents with fever, cough and fatigue. A severe case is defined by progression to pneumonia with hypoxia, occurring in approximately 14% of infections. 3 In 5% of cases, this progresses to critical illness, with acute respiratory distress syndrome, septic shock or other systemic complications, and usually requires mechanical ventilation. 3 The Australian Government introduced strict physical distancing measures in mid-March; since then the rate of new infections has been steadily declining. As of 1 June 2020, there were 7204 recorded cases and 103 deaths in Australia 4 -a mortality rate of 1.4%. While almost all Australian deaths have occurred in people aged 60 or older, the highest total number of infections exists in the 20-29-year-old age group 4 which overlaps with women of reproductive age. Clinical presentation in pregnancy, maternal outcomes and neonatal outcomes of COVID- 19 infection are yet to be thoroughly understood. Furthermore, the potential for SARS-CoV-2 vertical transmission is currently uncertain.

Other viral illnesses in pregnancy have shown disproportionately high rates of adverse maternal and perinatal outcomes. In 2010 a US study revealed that 5% of all deaths to H1N1 influenza occurred in pregnant patients, while 23% of infected pregnant women required intensive care unit (ICU) admission. 5 Seasonal influenza also poses an increased risk of preterm birth 6 and hospital admission, 7 particularly if contracted during the third trimester of pregnancy. 8 Severe acquired respiratory syndrome (SARS) exhibited a mortality rate of around 25% in pregnant women, with up to 50% of infected pregnant women requiring ICU admission. 9 In pregnancies complicated by Middle-East respiratory syndrome (MERS), fetal death in utero occurred at a rate of 30% while 33% of ongoing pregnancies were delivered preterm. 10 There is no evidence of in utero transmission from either SARS or MERS. 9, 10 The aims of this review are to: (i) describe what is known about COVID-19 clinical disease in pregnant women; (ii) discuss obstetric outcomes; (iii) describe the risk of vertical transmission; (iv) use this data to highlight management issues in the pregnant population; and (5) identify gaps in the existing knowledge.

The EMBASE and Medline Ovid databases were searched on 18

April, 18 May and 23 May 2020 using the keywords and Boolean terms 'coronavirus OR COVID-19 OR COVID 19 OR SARS-CoV-2 OR n19-CoV' and subject headings 'pregnancy outcome' and 'pregnancy complications'. The full search strategy for both databases is listed in Data S1. A broad search of the World Health Organization 'Global literature on coronavirus disease' database was also conducted using the keywords 'pregnancy' and 'pregnant'. These platforms collectively returned 911 papers of intersymptomatic patients, fever was the most common sign, occurring in 10-100% of cases both at admission and postpartum. Only one study compared clinical symptoms between COVID-19 positive pregnant and non-pregnant groups: fever was less prevalent in pregnant than non-pregnant patients (44% vs 100%, P < 0.05), while there was no significant difference in cough, dyspnoea or fatigue incidence. 34 Six studies universally tested all pregnant women at presentation with nasopharyngeal swab: Sutton et al. 12 , Gagliardi et al. 42 , Khalil et al. 43 , Vintzileos et al. 44 , Doria et al. 45 and Miller et al. 46 These papers reported asymptomatic infection in 43.5-92% of SARS-CoV-2 positive patients.

Maternal, obstetric and neonatal outcomes of rtPCR confirmed SARS-CoV-2 positive pregnant patients are listed in Table 2 . Of the 13 cohort studies that reported on disease severity, severe COVID-19 illness (pneumonia requiring oxygen support or noninvasive ventilation) occurred in 0-18% of patients. Critical disease (defined as progression to acute respiratory distress syndrome, sepsis or acute organ dysfunction) was reported in 0-5% of cases.

The exception to this was Pierce-Williams et al. 47 where severe and critical COVID-19 were, respectively, described in 69% and 31% of cases. A total of 111 severe and 40 critical cases were reported across the 13 cohort studies.

Extrapulmonary complications occurred in some severe and critical patients, including cardiac impairment, renal failure and coagulopathy. 18, 40, [47] [48] [49] [50] [51] Cardiomyopathy with global hypokinesis and moderately reduced ejection fraction on echocardiogram was reported in two patients. 49 Unless stated otherwise, all symptoms occurred at presentation. While some studies described suspected positive patients based on chest computed tomography or clinical symptoms, only reverse transcription polymerase chain reaction (rtPCR) positive patients have been included in this table unless otherwise specified. If a parameter was not discussed, this is indicated with a hyphen (- 

Maternal & Child Health Hospital >1 Wuhan hospital Zhongnan Hospital ‡D, live deliveries (where # is unequal to # pregnant patients); T, terminations; M, miscarriage. Unless otherwise specified: All neonates are born to SARS-CoV-2 positive mothers confirmed by rtPCR; % maternal outcomes based on # positive pregnant women, # neonatal outcomes based on # live deliveries. If a parameter was not discussed, this is indicated with a hyphen (-). If the outcome was not identified, the cell is blank. § WHO guidelines for categorisation of COVID-19 disease severity. Severe disease: fever or suspected respiratory infection, plus one of the following: respiratory rate> 30 breaths/min; severe respiratory distress; or SpO2 ≤ 93% on room air. Critical disease: patients with acute respiratory distress syndrome (ARDS), sepsis or acute organ dysfunction, usually requires mechanical ventilation Liao et al. 39 10% SARS-CoV-2 positive vs 9.4% control, P > 0.05).

Conversely, Li et al. 33 noted an increased incidence of preterm birth in the SARS-CoV-2 positive group (23.5% vs 5% control, P < 0.05). Caesarean section was performed for over 40% of deliveries in all but five studies. 24, 39, 50, 57, 60 Nineteen neonates were SARS-CoV-2 positive, based on rtPCR of nasopharyngeal swabs. Three of these were febrile, 15 were asymptomatic and one was born at 31 +2 weeks; he developed disseminated intravascular coagulopathy (DIC) but was recovering at the time of publication. There were no reported deaths of SARS-CoV-2 positive neonates. Six neonates had Apgar scores of less than seven at either one or five minutes postpartum. Five of those were preterm while one was term and SARS-CoV-2 positive. Six deaths of SARS-CoV-2 negative neonates were reported, due to:

multiple organ failure and DIC (n = 1), 61 preterm birth (n = 2), 48 severe neonatal asphyxia (n = 1), 52 pneumonia (visualised on chest X-ray) (n = 1) 18 and for unknown reasons (n = 1). 18 There were seven reported stillbirths: two for unclear reasons, 51,60 three following spontaneous labour in mechanically ventilated patients, 48 one due to acute maternal hypoxaemia necessitating delivery 48 and one due to preterm rupture of membranes. 48 There were five spontaneous miscarriages. Two occurred at 8 +0 weeks 54 and 17 +0 weeks, 62 while gestation was not reported for the other three. 48 The possibility of vertical transmission was assessed with rtPCR of neonatal nasopharyngeal secretions, placenta, cord blood, amniotic fluid and breastmilk (Table 3) where no evidence of vertical transmission exists. 74, 75 The timing of sampling and contact with the infected mother may be pivotal to ascertaining when this transmission occurred. Only Khan et al. 23 and Patane et al. 55 swered, and further systematic reviews will be required as more data is accumulated in this rapidly evolving pandemic.

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