How might COVID-19 affect pregnant women and their babies?

On March 16th, 2020, the UK government issued advice on self-isolation for members of the population who were deemed to be ‘vulnerable’ to COVID-19 infection. This included women who were pregnant, regardless of gestational age 22. The evidence in favour of isolation in pregnancy has since been questioned, particularly with regards to pregnant healthcare workers. The latest guidance from the Royal College of Obstetricians and Gynaecologists on COVID-19 sought to address this by recommending a removal from patient-facing roles in those healthcare workers who were beyond 28 weeks gestation. Those who remain within the first or second trimester could continue to work with reasonable precautions to avoid infectious contact 23.

What is the theoretical risk of COVID-19 infection in pregnancy?

The theoretical risk of COVID infection in pregnancy should ideally be considered in two categories:
  1. What is the risk to the mother, including the risk of progression to severe disease?
  2. What are the risks to the fetus, including transmission, in-utero infection and post-natal disease?

Why is a pregnant woman ‘at risk’?

There is no doubt that pregnancy results in modulation to the maternal immune system. It was initially proposed that pregnancy itself as an immunosuppressive state, in order to prevent rejection of a semi-allogenic fetus 24. However, it seems far more likely that the maternal immune system adapts during pregnancy in order to strike a balance between fetal tolerance and maternal susceptibility to infection, effects which may be mediated by oestrogen and progesterone 25. Indeed, epidemiological data does not suggest an increased susceptibility to infections in pregnancy, however the course and prognosis of a disease may be altered.
Modulation to the immune system during pregnancy may result in an environment favouring TH2 (humoral/antibody) rather than TH1 (cytotoxic) immune responses 26. Pregnant women remain able to mount appropriate antibody responses to vaccines and appear to demonstrate a reduction in pro-inflammatory cytokines but an increase in pro-phagocytotic factors. Innate immunity, driven by macrophages and neutrophils, appears maintained or enhanced 27. While the concept of immune suppression may be over-simplified, this shift to favour humoral immunity may result in an altered response to viral respiratory pathogens, while an overall functioning of innate immunity would otherwise prevent increased pathogen susceptibility. These changes are thought to be more prominent in the third trimester of pregnancy.
It is important to also consider the cardiovascular and respiratory changes that the body undergoes to adapt to the needs of the developing fetus. There is a modest increase in heart rate and stroke volume during pregnancy, with an overall increase in cardiac output and corresponding left ventricular hypertrophy. To increase oxygen provision and carbon dioxide excretion there is also a reduction in the functional residual capacity and inspiratory reserve volume of the lungs to allow for an increase in tidal volume. The gravid uterus pushes upwards, elevating the diaphragm and altering chest compliance, resulting in difficulties in ventilation. In other words, the pregnant mother operates at the limits of her physiological capacity, which means further deficits to lung function caused by a respiratory infection could result rapidly decompensated disease.
Taken together, we should consider women of advancing gestation to be equally likely to contract SARS-COV-2 as the general population but more at risk of having severe or decompensated disease if present. This is corroborated by evidence from the 2009 influenza pandemic, where pregnant women had an increased risk of hospitalisation, severe disease and pre-term delivery due to fetal distress or deteriorating maternal disease 28.

What is the risk of severe maternal disease with COVID-19?

At the moment, it appears too early to say. There is evidence that pregnant women with SARS suffered from more severe disease than non-pregnant women, with adverse maternal outcomes 29. The absolute number of pregnant women infected with SARS was small, however it is hypothesised that COVID-19 would have a similar effect in pregnancy 30.
A retrospective analysis of 9 pregnant women in the third trimester of pregnancy confirmed to have COVID-19 on throat swab did not show an increase in severe disease 31. Larger analysis of pooled patient data has observed no increased risk of developing severe or critical COVID-19 in pregnancy and, as yet, no maternal deaths32, 33. Pregnant women appear to have a similar symptom presentation to the general population and a comparable disease course. Sadly, there is one case of a severe maternal infection at 34 weeks, reported as part of a case series of 13 patients34. In this case, premature delivery of a stillborn infant was required, and the patient subsequently developed multi-organ failure due to sepsis, requiring extra-corporeal membrane oxygenation.
To date, it appears encouraging that COVID-19 infection does not follow a similar pattern to SARS and H1N1 influenza in pregnancy, although the absolute numbers of infected women remain low.

What is the risk of SARS-COV-2 infection developing in the fetus?

The risk to the developing fetus remains difficult to quantity. Previous data from SARS did not show any specific cases of fetal infection but did demonstrate an increased risk of adverse pregnancy outcomes when maternal disease was present 35, 36.
To date, there is no evidence of vertical transmission of COVID-19 to the fetus, with negative swabs from the neonatal throat, amniotic fluid and placenta 31, 33, 34, 37, 38. Breast milk samples from early lactation do not show any viral RNA 31, 37. Placental histology of three confirmed cases of third trimester COVID-19 did not show any evidence of villitis, chorioamnionitis or SARS-COV-2 on qRT-PCR, but diffuse fibrin deposition was present around the villi39, which could indicate altered placental blood flow.
This begs the question – is it possible for SARS-COV-2 to infect the fetus? Most cases of vertical transmission of infection diseases in pregnancy are via haematogenous spread across the placenta. This seems an unlikely route for SARS-COV-2. Single cell analysis of early pregnancy specimens using RNA-sequencing has revealed that while the syncitiotrophoblast of the placenta does express ACE2, the fetal blood does not 40. This, presumably, does not preclude the direct passage of viral particles present in high levels during maternal viraemia, or through breaches in the placental barrier. Ascending infection from the maternal genital tract cannot be ruled out, as SARS-COV-2 is yet to be isolated from genital fluids41. However, it could it be possible for SARS-COV-2 to enter the amniotic fluid in cases of premature rupture of membranes (PROM). In these circumstances there would be a theoretical risk of viral entry to the fetal lung or gastrointestinal epithelium.
In the absence of first trimester studies of maternal COVID-19 infection, or any cases of proven fetal infection, we cannot conclude whether maternal COVID-19 would result in fetal anomalies. However, it is reassuring that SARS-19 did not result in fetal teratogenicity, despite an overall increase in poor obstetric outcomes. At this point, should we reassure our patients that the risk of anomalies is unlikely, but not proven? Certainly, this is an area worthy of urgent study. Erring on the side of caution and acknowledging the lack of reassuring evidence regarding the effect of COVID-19 on the early human embryo, the European Society of Human Reproduction and Embryology (ESHRE) in a statement from the 19th of March 2020 advised all patients defer getting pregnant until the epidemic ends42. This statement was echoed by other national and international societies and resulted in almost complete cessation of fertility treatments of any sort 43.
The risk of transmission of infection to the neonate at the time of birth remains unquantified. In the reported case studies above, all babies were born by caesarean section. There are five cases of infection early in the neonatal period to SARS-COV-2 positive mothers, however in each case it was deemed possible for neonatal COVID-19 infection to have been acquired by transmission in the neonatal period, with placental, uterine and amniotic fluid swabs either negative or not performed44, 45. The risks of vaginal delivery are unknown, but presumably small.

What would be the indirect effects of maternal COVID-19 on the fetus?

There is a theoretic risk of indirect fetal injury during maternal COVID-19 infection as a result of 1) severe maternal sepsis, 2) maternal cytokine storm resulting in placental injury or 3) direct placental infection resulting in placental disease. The effect on the fetus would likely be secondary to the gestation at which the insult was received and the severity of the initial maternal infection.
Disease in the first trimester could result in miscarriage due to placental or maternal infection, with a potential need for uterine evacuation in severe cases. In later gestations, placental injury from infection or cytokine damage might result in fetal hypoxia, manifesting as intra-uterine growth restriction or fetal distress, or placental abruption. SARS pregnancies appeared to demonstrate an increase in miscarriage when disease was acquired in the first trimester and intra-uterine growth restriction at latter gestations, however the patient numbers are too small to conclude a significant effect35, 36.
As yet, there is little data to suggest whether this may be true – all but 2 of the 55 reported cases of infection in Chinese patients occurred in the third trimester with a short interval between maternal infection and delivery. To date, there are 3 reported cases of PROM and 5 of fetal distress necessitating delivery 31, 34, 46, which may indicate an increased risk of fetal distress during labour. Multiple cases of delivery between 32-36 weeks gestation have been reported, but it is not clear whether these were iatrogenic or due to spontaneous onset of premature labour. There is one documented case of stillbirth in a woman suffering with COVID-19 whose neonate tested negative at delivery 34, but no reports of miscarriage. Intra-uterine growth restriction cannot be inferred from the present data due to a lack of maternal demographics allowing for personalised growth calculations.

How are we managing pregnant women in the UK with known or suspected COVID-19 infection?

The Royal College of Obstetricians and Gynaecologists have released new guidance for the management of COVID-19 in pregnancy, which is constantly evolving as our information on the pandemic is growing23. This document outlines how individual units should treat confirmed or suspected cases of COVID-19, including how to minimise the risk of spread to others within the department.
Some key points to highlight are:

How should we explain the risks of COVID-19 infection in pregnancy to our patients, when we don’t fully understand them ourselves?

The emergence of this new disease poses a significant challenge for the healthcare systems across the globe. Pregnant women, being a particularly vulnerable group, have been faced with additional uncertainties related to the effect of the virus on the pregnancy as well as their health and wellbeing. It is therefore important for any obstetrician and gynaecologist to be very frank with women attempting to start a pregnancy, as well as those that are already pregnant, that the evidence for significant harm or lack thereof is very limited. We must inform women that due to the pressures on the emergency services, there may be a delay in seeing them if they present with early pregnancy complications, such as pain or bleeding and that confirmation of a miscarriage or ectopic pregnancy may be delayed. Similarly, treatment options may be reduced due to availability of theatre or anaesthetic staff, or lack of personal protective equipment in cases of confirmed COVID-19 positive patients.
Recent concerns regarding the risk of spread COVID-19 during laparoscopic surgery has put in question the routine application of this well-established procedure as the mainstay of treatment of ectopic pregnancies 47. Laparoscopies will still be carried out with additional precautions; however, some units may choose to forgo this approach completely and offer open surgery as the only surgical option. First trimester combined screening for aneuploidies may also be delayed or stopped completely for the time being. This may result in an increased rate of aneuploid pregnancies detected later with additional physical and psychological comorbidities as a result of late diagnosis and mid trimester terminations. Current evidence seems to indicate an increased risk of caesarean deliveries in women affected by COVID-19 and these are also not without immediate and long-term comorbidities. As the situation is dynamic, it is our responsibility as healthcare professionals to keep up with the developments and relay any relevant information to our patients in order to alleviate the high parental anxieties and more importantly, do no harm.

Further areas of research

The COVID-19 pandemic remains an international public health concern of previously unparalleled proportions. Clearly, this is a constantly evolving situation. Any recommendations that are made can only be based on current evidence and are likely to change as our knowledge is updated.
It is a relief that there is no current suggestion of vertical transmission to the unborn fetus, though larger case studies will be required to determine this for definite and ensure there is no direct teratogenic effect of fetal infection. Case-control studies following infected women through the first trimester onwards will provide important information to elucidate this and will allow for correlation of maternal and fetal outcomes with infection. In response to this, the UK Obstetric Surveillance System (UKOSS) have created a system for mandatory reporting of all confirmed cases of COVID-19 in pregnancy to assess the incidence within the population and monitor outcomes.
Monitoring of COVID-19 in pregnancy will remain a challenge. At present, Public Health England will only permit testing of those patients whose symptoms are severe enough to require admission to hospital. A large cohort of asymptomatic or mildly affected SARS-COV-2 positive women will not be included within the UKOSS study as a result of this. Any data obtained as a result of this, or other, studies may be skewed towards the more severe end the spectrum of maternal and fetal disease. It will be many years before the longer-term effects of COVID-19 on pregnancy are understood.

Contributions to authorship

AR conceived the article and researched the original manuscript. DG, MB and LP provided specialist input, intellectual guidance and assistance with writing. All authors contributed to edits and approved the final draft.

Sponsorship

AR’s research fellowship is funded by the Addenbrookes Charitable Trust and National Institute of Health Research.

Conflicts of Interest

No authors have conflicts of interest to declare

References

1. Fehr AR, Perlman S. Coronaviruses: An Overview of Their Replication and Pathogenesis. Methods Mol Biol. 2015;1282:1-23.
2. Organisation WH. WHO Director-General’s opening remarks at the media briefing on COVID-19 - 11 March 2020. 2020.
3. Organisation WH. Coronavirus disease (COVID-19) Pandemic. 2020 [cited; Available from: https://www.who.int/emergencies/diseases/novel-coronavirus-2019
4. WHO, Organisation WH. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July 2003: World Health Organization; 2015 2015-07-24 13:14:33.
5. Chan JF, Kok KH, Zhu Z, Chu H, To KK, Yuan S, et al. Genomic characterization of the 2019 novel human-pathogenic coronavirus isolated from a patient with atypical pneumonia after visiting Wuhan. Emerg Microbes Infect. 2020;9(1):221-36.
6. Peiris JS, Yuen KY, Osterhaus AD, Stohr K. The severe acute respiratory syndrome. N Engl J Med. 2003 Dec 18;349(25):2431-41.
7. Liu Y, Gayle AA, Wilder-Smith A, Rocklov J. The reproductive number of COVID-19 is higher compared to SARS coronavirus. J Travel Med. 2020 Mar 13;27(2).
8. Phan LT, Nguyen TV, Luong QC, Nguyen HT, Le HQ, Nguyen TT, et al. Importation and Human-to-Human Transmission of a Novel Coronavirus in Vietnam. N Engl J Med. 2020 Feb 27;382(9):872-4.
9. @newscientist. You could be spreading the coronavirus without realising you’ve got it. New Scientist. 2020.
10. Li R, Pei S, Chen B, Song Y, Zhang T, Yang W, et al. Substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (SARS-CoV2). Science. 2020 2020-03-16.
11. Wilder-Smith A, Chiew CJ, Lee VJ. Can we contain the COVID-19 outbreak with the same measures as for SARS? Lancet Infect Dis. 2020 Mar 5.
12. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med. 2020 Feb 20;382(8):727-33.
13. Camargo SM, Singer D, Makrides V, Huggel K, Pos KM, Wagner CA, et al. Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. Gastroenterology. 2009 Mar;136(3):872-82.
14. Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Frontiers of Medicine. 2020.
15. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med. 2020 Feb 18.
16. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020 Feb 15;395(10223):497-506.
17. Mehta P, Centre for Inflammation and Tissue Repair UR, Division of Medicine, University College London, London, UK, McAuley DF, Wellcome-Wolfson Institute for Experimental Medicine QsUB, Belfast, UK, Regional Intensive Care Unit RVH, Belfast, UK, Brown M, et al. COVID-19: consider cytokine storm syndromes and immunosuppression. The Lancet. 2020;0(0).
18. Prevnention CfDCa. Management of Patients with Confirmed 2019-nCoV | CDC. @CDCgov; 2020.
19. Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72314 Cases From the Chinese Center for Disease Control and Prevention. Jama. 2020 Feb 24.
20. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Medicine. 2020 2020-03-03:1-3.
21. Rothan HA, Byrareddy SN. The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. J Autoimmun. 2020 Feb 26:102433.
22. Guidance on social distancing for everyone in the UK. In: England PH, editor. gov.uk; 2020.
23. Gynaecologists RCoO. Coronavirus (COVID-19) Infection in Pregnancy; 2020.
24. Medawar PB. Some immunological and endrocrinological problems raised by the evolution of viviparity in vertebrates. Symp Soc Exp Biol. 1953;44:320-38.
25. Kourtis AP, Read JS, Jamieson DJ. Pregnancy and Infection. N Engl J Med. 2014 Jun 5;370(23):2211-8.
26. Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993 Jul;14(7):353-6.
27. Pazos M, Sperling RS, Moran TM, Kraus TA. The influence of pregnancy on systemic immunity. Immunol Res. 2012 Dec;54(1-3):254-61.
28. Mosby LG, Rasmussen SA, Jamieson DJ. 2009 pandemic influenza A (H1N1) in pregnancy: a systematic review of the literature. Am J Obstet Gynecol. 2011 Jul;205(1):10-8.
29. Maxwell C, McGeer A, Tai KFY, Sermer M. No. 225-Management Guidelines for Obstetric Patients and Neonates Born to Mothers With Suspected or Probable Severe Acute Respiratory Syndrome (SARS). J Obstet Gynaecol Can. 2017 Aug;39(8):e130-e7.
30. Schwartz DA, Graham AL. Potential Maternal and Infant Outcomes from (Wuhan) Coronavirus 2019-nCoV Infecting Pregnant Women: Lessons from SARS, MERS, and Other Human Coronavirus Infections. Viruses. 2020 Feb 10;12(2).
31. Chen H, Guo J, Wange C, Luo F, Yu X, Zhang W. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records - The Lancet. Lancet. 2020;395(10226):809-15.
32. Organisation WH. Report of the WHO-China Joint Mission on Coronavirus Disease 2019. 2020.
33. Schwartz DA. An Analysis of 38 Pregnant Women with COVID-19, Their Newborn Infants, and Maternal-Fetal Transmission of SARS-CoV-2: Maternal Coronavirus Infections and Pregnancy Outcomes. Arch Pathol Lab Med. 2020 Mar 17.
34. Liu Y, Chen H, Tang K, Guo Y. Clinical manifestations and outcome of SARS-CoV-2 infection during pregnancy. J Infect. 2020 Mar 4.
35. Shek CC, Ng PC, Fung GP, Cheng FW, Chan PK, Peiris MJ, et al. Infants born to mothers with severe acute respiratory syndrome. Pediatrics. 2003 Oct;112(4):e254.
36. Wong SF, Chow KM, Leung TN, Ng WF, Ng TK, Shek CC, et al. Pregnancy and perinatal outcomes of women with severe acute respiratory syndrome. Am J Obstet Gynecol. 2004 Jul;191(1):292-7.
37. Li Y, Zhao R, Zheng S, Chen X, Wang J, Sheng X, et al. Lack of Vertical Transmission of Severe Acute Respiratory Syndrome Coronavirus 2, China. Emerg Infect Dis. 2020 Jun 17;26(6).
38. Zhang L, Jiang Y, Wei M, Cheng BH, Zhou XC, Li J, et al. [Analysis of the pregnancy outcomes in pregnant women with COVID-19 in Hubei Province]. Zhonghua Fu Chan Ke Za Zhi. 2020 Mar 7;55(0):E009.
39. Chen S, Huang B, Luo DJ, Li X, Yang F, Zhao Y, et al. [Pregnant women with new coronavirus infection: a clinical characteristics and placental pathological analysis of three cases]. Zhonghua Bing Li Xue Za Zhi. 2020 Mar 1;49(0):E005.
40. Vento-Tormo R, Efremova M, Botting RA, Turco MY, Vento-Tormo M, Meyer KB, et al. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature. 2018 Nov;563(7731):347-53.
41. Fan C LD, Fang C, et al. PRIME PubMed | Perinatal Transmission of COVID-19 Associated SARS-CoV-2: Should We Worry? PRIME PubMed; 2020.
42. Coronavirus Covid-19: ESHRE statement on pregnancy and conception. 2020 [cited 29.03.2020]; Available from: https://www.eshre.eu/Press-Room/ESHRE-News
43. Guidance for the care of fertility patients during the Coronavirus COVID-19 Pandemic. 2020 [cited 29.03.2020]; Available from: https://www.britishfertilitysociety.org.uk/2020/03/18/guidance-for-the-care-of-fertility-patients-during-the-coronavirus-covid-19-pandemic/
44. Lu Q, Shi Y. Coronavirus disease (COVID‐19) and neonate: What neonatologist need to know - Lu - - Journal of Medical Virology - Wiley Online Library. Jounral of Medical Virology; 2020.
45. Zeng L, Xia S, Yauan W. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA Pediatrics. 2020.
46. Dashraath P, Jeslyn, Karen LMX, Min L, Sarah L, Biswas A, et al. Coronavirus Disease 2019 (COVID-19) Pandemic and Pregnancy. American Journal of Obstetrics & Gynecology. 2020;0(0).
47. COVID-19: Joint Statement on Minimally Invasive Gynecologic Surgery. 2020 [cited 29.03.2020]; Available from: https://www.aagl.org/news/covid-19-joint-statement-on-minimally-invasive-gynecologic-surgery/