COVID-19 and pregnancy: An update

Four years into the COVID-19 pandemic, what we know about the novel coronavirus and pregnancy has evolved. From the early months of the pandemic in 2020, it was clear that pregnant patients were at higher risk of maternal complications and adverse pregnancy outcomes.¹ A meta-analysis including more than 100,000 pregnancies during the first year of the pandemic found a global increase in maternal death and stillbirth—but with the introduction of vaccinations came a decrease in overall morbidity and mortality from the disease.^2,3 Here is what we have learned about pregnancy and COVID-19.

Virology and variants

SARS-CoV-2 is the RNA virus responsible for causing COVID-19. The coronavirus family of viruses is named for the crown-like spikes on the surface of the viruses; it is one of the largest classes of RNA viruses in terms of size. When it was discovered, SARS-CoV-2 was the seventh coronavirus known to affect humans. Like SARS-CoV and MERS-CoV, it has the potential to cause severe disease. The other 4 strains (HKU1, NL63, OC43, and 229E) are associated with the common cold, and they are responsible for approximately one-fourth of colds overall.

The World Health Organization names new SARS-CoV-2 variants using the Greek alphabet. The initial variant that emerged in late 2020 was named the Alpha variant, followed by the Beta variant that was reported in South Africa later that year. The Delta variant emerged in the US in 2021 and was particularly devastating to pregnant patients. Compared with earlier strains, the Delta variant was more associated with increased disease severity and placental dysfunction in pregnancy.^4,5

The Omicron variant and its subvariants have been the predominant strain of SARS-CoV-2 since 2021. Although the Omicron variant does not seem to cause disease as severe as that associated with Delta, it is likely more transmissible because of several mutations on the spike protein, which is what the virus uses to attach to its host.⁶

COVID-19 disease severity

Symptoms of COVID-19 are similar in pregnant patients when compared to nonpregnant patients and include cough, fever, shortness of breath, and myalgia. Pregnancy itself does not increase the likelihood of contracting COVID-19. The National Institutes of Health (NIH) has classified COVID-19 into 5 categories: asymptomatic or presymptomatic, mild, moderate, severe, and critical. Although most pregnant patients will have asymptomatic or mild disease (various symptoms but without dyspnea or abnormal imaging), pregnant patients are at higher risk of admission to the intensive care unit, mechanical ventilation, extracorporeal membrane oxygenation, and death when compared with nonpregnant patients. Certain comorbidities increase these complications: advanced maternal age, both low maternal weight and obesity, anemia, hypertension, and cardiovascular disease.7 Unvaccinated patients are also at a higher risk of maternal morbidity and mortality, with one multinational study showing that severe complications were highest in patients who were both symptomatic and unvaccinated.³

The pandemic revealed racial and ethnic disparities in prevalence of the virus and severity of disease. As with the nonpregnant population, pregnant Black and Hispanic women are more likely to contract COVID-19 and to suffer severe complications.^8-11
COVID-19 vaccination rates are also lower in these groups. The cause of this is multifactorial and influenced by social determinants of health, including factors that affect access to care, racial and ethnic identity, and built environment as described by Emeruwa et al.¹¹

Fetal complications in COVID-19

Vertical transmission of SARS-CoV-2 is rare and occurs in less than 2% of cases.¹² More commonly, newborns may become infected by direct contact with a parent with COVID-19 postnatally. COVID-19 does not appear to cause birth defects, spontaneous abortion, or growth restriction.^13-15

Adverse fetal outcomes appear related primarily to preterm birth, which is increased among pregnant patients with severe COVID-19. Whether there is a physiologic link between preterm birth and COVID-19 infection is less clear, as medically indicated preterm birth was often used as a purported therapeutic intervention for severe disease during the earlier days of the pandemic.¹⁶ Despite this association, the overall preterm birth rate did not change in the US during this time.¹⁵

Whether stillbirth is more common among patients with COVID-19 is also unclear. The Delta variant of 2021 was linked to higher rates of stillbirth in a large report of over 1 million US births.⁵ However, there have been fewer stillbirths during the Omicron variant period than with the Delta variant.¹⁷

As we are only 4 years from the start of the pandemic, long-term data on children who were exposed in utero are limited. One small study did not find an increase in developmental delay in infants who were exposed to COVID-19.¹⁸

Preeclampsia

The risk of preeclampsia is likely increased with COVID-19 infection during pregnancy. Several studies have addressed this association. The largest, a pooled analysis of more than 700,000 patients, found a 7% rate of preeclampsia in pregnant patients affected by COVID-19 compared with 4.8% in unaffected patients.¹⁹ Although this risk was increased even among patients who did not have severe disease, disease severity increased the likelihood of developing preeclampsia. One proposed mechanism for this is shared pathophysiologic pathways for COVID-19 and preeclampsia, as both are multisystem disorders that involve endothelial dysfunction and inflammation. Whether low-dose aspirin prevents preeclampsia in these cases is unclear. The current US Preventive Services Task Force guideline recommends administration of low-dose aspirin to pregnant individuals with an absolute risk of preeclampsia of at least 8%, and COVID-19 infection is not included in these risk factors.

Treatments for COVID-19 in the pregnant patient

Hospitalization for COVID-19 has become less common with the introduction of vaccines and the less severe nature of the current variants. Nonetheless, the rate of hospitalization is likely to increase with seasonal surges. In general, pregnant patients who have evidence of severe or critical disease should be treated in an inpatient setting (Figure). In patients with moderate disease and additional risk factors for severe or critical illness, particularly if the patients are not vaccinated, a brief observation period may be considered on an individual basis.

The approach to inpatient management of pregnant patients with COVID-19 mirrors that of the nonpregnant population and is publicly available through the NIH website.

The NIH has divided management algorithms into 5 categories²⁰:

• Hospitalized for reasons other than COVID-19
• Hospitalized but does not require supplemental oxygen
• Hospitalized and requires conventional oxygen
• Hospitalized and requires high flow nasal cannula (HFNC) oxygen or noninvasive ventilation (NIV)
• Hospitalized and requires mechanical ventilation or extracorporeal membrane oxygenation (ECMO)

An initial assessment may include laboratory evaluation for abnormalities associated with severe disease (complete blood count, basic metabolic panel, hepatic function panel, lactate dehydrogenase, coagulation studies, and troponin). C-reactive protein and D-dimer have also been suggested, but these levels may be elevated in normal pregnancy. A chest radiograph and electrocardiogram should also be performed.

Management goals include maintenance of oxygenation (to an oxygen saturation goal of ≥ 95%), administration of medications as needed to prevent disease progression, prevention of venous thromboembolism, and management of any disease complications. Prone positioning is also safe and feasible in pregnancy with the aid of padding and pillows as needed.²¹

Remdesivir and dexamethasone

In patients who are hospitalized but do not require oxygen supplementation, treatment with remdesivir given 200 mg intravenously on day 1 followed by 100 mg daily for 5 days total (with extension to 10 days if no clinical improvement) is recommended. Remdesivir may shorten illness duration and reduce the need for mechanical ventilation.^22-24 Liver enzymes should be checked before and after treatment, with discontinuation of the drug if these reach 10 times the upper limit of normal.

If oxygen supplementation is needed, dexamethasone 6 mg orally daily for 10 days or until hospital discharge can be given in addition to remdesivir and has been shown to reduce mortality and mechanical ventilation.^20,25 Dexamethasone should be universally given to any pregnant patient with COVID-19 requiring HFNC, NIV, or ECMO. Although the NIH recommends the same dexamethasone course suggested for the nonpregnant individual, hydrocortisone or methylprednisolone can also be given in lieu of dexamethasone to minimize the potential fetal effects of repeated exposure to dexamethasone.²⁶ For the latter, dexamethasone or betamethasone may still be administered for fetal lung maturation if indicated.

Other pharmacotherapies

Intravenous tocilizumab may be added to remdesivir and dexamethasone in pregnant patients with rapidly increasing oxygen needs and evidence of systemic inflammation.²⁰ Tocilizumab is an IL-6 inhibitor that may decrease mortality in patients with COVID-19 and increased inflammatory markers.26 Lastly, oral baricitinib is a monoclonal antibody that may be used in select nonpregnant patients with severe disease, but because of limited pregnancy data, use in pregnant patients should be individualized.

Anticoagulation

The risk of venous thromboembolism (VTE) is increased with COVID-19, and so pharmacologic VTE prophylaxis is recommended to all pregnant women requiring hospitalization for this indication. Low molecular weight heparin, unfractionated heparin, and fondaparinux are options for VTE prophylaxis and should be individualized to other medical comorbidities, renal function, and delivery timing.

Outpatient management

As pregnancy is a risk factor for severe disease, outpatient treatment may be considered in select pregnant patients with higher risk for disease progression. Nirmatrelvir-ritonavir 300 mg/100 mg can be given orally twice daily for 5 days within 5 days of disease onset in patients with an additional risk factor for severe disease (eg, asthma, chronic lung disease, chronic kidney disease, obesity). Outpatient remdesivir can be given when nirmatrelvir-ritonavir is unavailable but may be inconvenient because of intravenous administration. Molnupiravir is not recommended for pregnant patients with limited pregnancy data, suggesting an association with miscarriage.20

Prevention of COVID-19

Vaccination remains the mainstay of prevention for COVID-19 in pregnant and nonpregnant individuals. Despite campaigns to improve vaccination among pregnant individuals, vaccination rates against COVID-19 in this group remain lower than in the nonpregnant population. Vaccination has been shown to reduce SARS-CoV-2 infections, severity of COVID-19, maternal mortality from COVID-19, and hospitalizations for infants aged up to 6 months born to vaccinated mothers.^3,27 The vaccine is safe to administer in pregnancy and has not been shown to increase miscarriage or obstetrical complications.²⁸ Fertility is also not impacted by the vaccine.^29,30 Although there is some evidence that newborn antibody titers may be higher if vaccination occurs later in pregnancy, it is advised that vaccination occur as early as possible for maternal protection. Vaccination is also safe in lactating patients, and there may be some transient benefit of antibody transfer via this route to the baby. Lastly, patients and providers are advised to stay up to date on recommendations regarding new booster doses as they are developed to target new variants.

References:

1. Di Mascio D, Khalil A, Saccone G, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: a systematic review and meta-analysis. Am J Obstet Gynecol MFM. 2020;2(2):100107. doi:10.1016/j.ajogmf.2020.100107

2. Chmielewska B, Barratt I, Townsend R, et al. Effects of the COVID-19 pandemic on maternal and perinatal outcomes: a systematic review and meta-analysis. Lancet Glob Health. 2021;9(6):e759-e772. doi:10.1016/S2214-109X(21)00079-6

3. Villar J, Soto Conti CP, Gunier RB, et al. Pregnancy outcomes and vaccine effectiveness during the period of omicron as the variant of concern, INTERCOVID-2022: a multinational, observational study. Lancet. 2023;401(10375):447-457. doi:10.1016/S0140-6736(22)02467-9

4. Shook LL, Brigida S, Regan J, et al. SARS-CoV-2 placentitis associated with B.1.617.2 (Delta) variant and fetal distress or demise. J Infect Dis. 2022;225(5):754-758. doi:10.1093/infdis/jiac008

5. DeSisto CL, Wallace B, Simeone RM, et al. Risk for stillbirth among women with and without COVID-19 at delivery hospitalization - United States, March 2020-September 2021. MMWR Morb Mortal Wkly Rep. 2021;70(47):1640-1645. doi:10.15585/mmwr.mm7047e1

6. Behrens GMN, Cossmann A, Hoffmann M. Omicron spike protein: a clue for viral entry and immune evasion. Signal Transduct Target Ther. 2022;7(1):339. doi:10.1038/s41392-022-01193-7

7. Smith ER, Oakley E, Grandner GW, et al. Clinical risk factors of adverse outcomes among women with COVID-19 in the pregnancy and postpartum period: a sequential, prospective meta-analysis. Am J Obstet Gynecol. 2023;228(2):161-177. doi:10.1016/j.ajog.2022.08.038

8. Pope R, Ganesh P, Miracle J, et al. Structural racism and risk of SARS-CoV-2 in pregnancy. eClinicalMedicine. 2021;37:100950. doi:10.1016/j.eclinm.2021.100950

9. Matsuo K, Green JM, Herrman SA, Mandelbaum RS, Ouzounian JG. Severe maternal morbidity and mortality of pregnant patients with COVID-19 infection during the early pandemic period in the US. JAMA Netw Open. 2023;6(4):e237149. doi:10.1001/jamanetworkopen.2023.7149

10. Onwuzurike C, Diouf K, Meadows AR, Nour NM. Racial and ethnic disparities in severity of COVID‐19 disease in pregnancy in the United States. Int J Gynaecol Obstet. 2020;151(2):293-295. doi:10.1002/ijgo.13333

11. Emeruwa UN, Spiegelman J, Ona S, et al. Influence of race and ethnicity on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection rates and clinical outcomes in pregnancy. Obstet Gynecol. 2020;136(5):1040-1043. doi:10.1097/AOG.0000000000004088

12. Jeganathan K, Paul AB. Vertical transmission of SARS-CoV-2: a systematic review. Obstet Med. 2022;15(2):91-98. doi:10.1177/1753495X211038157

13. Hernández-Díaz S, Smith LH, Wyszynski DF, Rasmussen SA. First trimester COVID-19 and the risk of major congenital malformations-International Registry of Coronavirus Exposure in Pregnancy. Birth Defects Res. 2022;114(15):906-914. doi:10.1002/bdr2.2070

14. Jacoby VL, Murtha A, Afshar Y, et al. Risk of pregnancy loss before 20 weeks’ gestation in study participants with COVID-19. Am J Obstet Gynecol. 2021;225(4):456-457. doi:10.1016/j.ajog.2021.06.080

15. Grobman WA, Sandoval GJ, Metz TD, et al; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. The temporal relationship between the coronavirus disease 2019 (COVID-19) pandemic and preterm birth. Obstet Gynecol. 2023;141(6):1171-1180. doi:10.1097/AOG.0000000000005171

16. Péju E, Belicard F, Silva S, et al; COVIDPREG Study Group. Management and outcomes of pregnant women admitted to intensive care unit for severe pneumonia related to SARS-CoV-2 infection: the multicenter and international COVIDPREG study. Intensive Care Med. 2022;48(9):1185-1196. doi:10.1007/s00134-022-06833-8

17. Stock SJ, Moore E, Calvert C, et al. Pregnancy outcomes after SARS-CoV-2 infection in periods dominated by delta and omicron variants in Scotland: a population-based cohort study. Lancet Respir Med. 2022;10(12):1129-1136. doi:10.1016/S2213-2600(22)00360-5

18. Pinheiro GSMA, de Souza RC, de Oliveira Azevedo VMG, et al. Effects of intrauterine exposure to SARS-CoV-2 on infants’ development: a rapid review and meta-analysis. Eur J Pediatr. 2023;182(5):2041-2055. doi:10.1007/s00431-023-04910-8

19. Conde-Agudelo A, Romero R. SARS-CoV-2 infection during pregnancy and risk of preeclampsia: a systematic review and meta-analysis. Am J Obstet Gynecol. 2022;226(1):68-89.e3. doi:10.1016/j.ajog.2021.07.009

20. Final coronavirus disease (COVID-19) treatment guidelines (February 29, 2024). National Institutes of Health. Accessed September 21, 2023. https://www.covid19treatmentguidelines.nih.gov/

21. Tolcher MC, McKinney JR, Eppes CS, et al. Prone positioning for pregnant women with hypoxemia due to coronavirus disease 2019 (COVID-19). Obstet Gynecol. 2020;136(2):259-261. doi:10.1097/AOG.0000000000004012

22. Amstutz A, Speich B, Mentré F, et al. Effects of remdesivir in patients hospitalised with COVID-19: a systematic review and individual patient data meta-analysis of randomised controlled trials. Lancet Respir Med. 2023;11(5):453-464. doi:10.1016/S2213-2600(22)00528-8

23. Ali K, Azher T, Baqi M, et al; Canadian Treatments for COVID-19 (CATCO); Association of Medical Microbiology and Infectious Disease Canada (AMMI) Clinical Research Network and the Canadian Critical Care Trials Group. Remdesivir for the treatment of patients in hospital with COVID-19 in Canada: a randomized controlled trial. CMAJ. 2022;194(7):E242-E251. doi:10.1503/cmaj.211698

24. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19 - preliminary report: reply. N Engl J Med. 2020;383(10):994. doi:10.1056/NEJMc2022236

25. RECOVERY Collaborative Group; Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med. 2021;384(8):693-704. doi:10.1056/NEJMoa2021436

26. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Sterne JAC, Murthy S, Diaz JV, et al. Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis. JAMA. 2020;324(13):1330-1341. doi:10.1001/jama.2020.17023

27. WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group; Shankar-Hari M, Vale CL, Godolphin PJ. Association between administration of IL-6 antagonists and mortality among patients hospitalized for COVID-19: a meta-analysis. JAMA. 2021;326(6):499-518. doi:10.1001/jama.2021.11330

28. Jorgensen SCJ, Hernandez A, Fell DB, et al; Canadian Immunization Research Network (CIRN) Provincial Collaborative Network (PCN) Investigators. Maternal mRNA Covid-19 vaccination during pregnancy and delta or omicron infection or hospital admission in infants: test negative design study. BMJ. 2023;380:e074035. doi:10.1136/bmj-2022-074035

29. Prasad S, Kalafat E, Blakeway H, et al. Systematic review and meta-analysis of the effectiveness and perinatal outcomes of COVID-19 vaccination in pregnancy. Nat Commun. 2022;13(1):2414. doi:10.1038/s41467-022-30052-w

30. Chen F, Zhu S, Dai Z, et al. Effects of COVID-19 and mRNA vaccines on human fertility. Hum Reprod. 2021;37(1):5-13. doi:10.1093/humrep/deab238