Pregnancy and COVID-19

Commentary by Mark Milad, PharmD

Introduction
According to the CDC, pregnant women seem to have the same risks from COVID-19 as adults who are not pregnant.1  However, pregnant women and newborns are considered key at-risk populations in strategies focusing on prevention and management of COVID-19 infection, because pregnant women are susceptible to respiratory pathogens and to development of severe pneumonia, which possibly makes them more susceptible to COVID-19 infection than the general population.2,3

COVID-19 and pregnancy are a growing area of research. There are several good resources including websites from the WHO4, CDC5, and published treatment guidelines.6 However, a great deal of research and analysis is still needed.

Several questions being asked about COVID-19 and pregnancy include: what is the time course of the disease in pregnancy, do the symptoms differ, does the disease look different in different parts of the world, does the risk to benefit change for the use of antenatal steroid for an early and late preterm delivery, what are the baby outcomes, how does treatment of preeclampsia or gestational diabetes change with COVID-19, and how should the pregnant women with COVID-19 be treated?7 Furthermore, there is no outcome data in neonates who were exposed during the first or second trimester of pregnancy.

This short discussion opens a dialogue about drug development, clinical trials, and topics that pertain to clinical pharmacology relevant for COVID-19 and pregnancy.

Clinical Trials
Clinical trials of COVID-19 and pregnancy are sorely lacking. At the time of writing this article (May 2020) it is 6 months after the first reported case of COVID-19 (Dec 2019), and only five clinical trials are registered under COVID-19 and pregnancy in ClinicalTrials.gov. The few registered studies are only a small fraction (1.2%) of the total number of trials for COVID-19 (410 trials). One of the five trials assesses the efficacy of treatment (high dose vitamin C). Many more trials and analyses are needed in this research area.

The United Nations document titled: Shared Responsibility, Global Solidarity: Responding to the Socio-Economic Impacts of COVID-198, includes a section titled, Women and girls must have a face in the response. This section includes important recommendations, two of which are paraphrased here as they relate to clinical pharmacology: collect sex-disaggregated data and continued delivery of sexual reproductive health services, such as access to contraceptives.

Vertical Transmission
Vertical transmission is the passage of a disease-causing agent (pathogen) from mother to baby during the period immediately before and after birth. To date no vertical transmission of COVID-19 has been observed while the baby is in the womb9. There is one small study and a case report with indirect evidence (circulating IgM antibodies found in the neonate) of vertical transmission10,11.   The CDC states that mother to child transmission of coronavirus during pregnancy is unlikely, but after birth the newborn is susceptible.12

After birth, during nursing, or other close contact, transmission may occur the same way as in adults, via respiratory droplets. The CDC and ACOG discuss methods of protecting transmission to the baby after birth, and these include separation and/or other protective measures such as masks, gloves, and hand washing.

Breast Feeding
SARS-COV-2, the virus that causes COVID-19, was not detected in the maternal milk.13 Therefore, the CDC recommends breast feeding as it provides protection against many illnesses and is the best source of nutrition.

Case reports are available that discuss the time course and supportive treatment of COVID-19 in the newborn.14

Antenatal Corticosteroids
Antenatal corticosteroids are medications given to pregnant women expecting preterm delivery. The dose regimen typically includes either: four doses of dexamethasone phosphate 6 mg IM given 12 hours apart, or two doses of the mixture of betamethasone phosphate and betamethasone acetate (Celestone®) 12 mg given 24 hours apart. Used in the appropriate setting, antenatal corticosteroids dramatically reduce morbidity and mortality in preterm infants due to hyaline membrane disease.

Corticosteroid use in COVID-19 remains controversial.15 ”Given the association between steroids and worsening morbidity of viral pneumonia and specifically COVID-19, steroids for fetal lung maturity should be used judiciously.“16 The interim guidance from the WHO ”recommends antenatal corticosteroid therapy for women at risk of preterm birth from 24 to 34 weeks of gestation when there is no clinical evidence of maternal infection, and adequate childbirth and newborn care is available. However, in cases where the woman presents with mild COVID-19, the clinical benefits of antenatal corticosteroid might outweigh the risks of potential harm to the mother. In this situation, the balance of benefits and harms for the woman and the preterm newborn should be discussed with the woman to ensure an informed decision, as this assessment may vary depending on the woman’s clinical condition, her wishes and that of her family, and available health care resources.“17 Baud et al stated, “We do not recommend administration of routine corticosteroids to all women with confirmed COVID-19 infection between 34 and 37 weeks of gestation.”18

The shorter duration of action of dexamethasone phosphate compared to the mixture of betamethasone phosphate and betamethasone acetate may be an advantage in this setting.19

Investigational Drugs
There are no drugs or other therapeutics approved by the US Food and Drug Administration to prevent or treat COVID-19. Current clinical management includes infection prevention and control measures and supportive care, including supplemental oxygen and mechanical ventilatory support when indicated. Interim guidelines for the medical management of COVID-19 will be provided soon by the Department of Health and Human Services COVID-19 Treatment Guidelines Panel.20

There are a few drugs which are being investigated for treatment or prevention of COVID-19. The efficacy and safety of these drugs are unknown.

Remdesivir
Remdesivir is an investigational intravenous drug with broad antiviral activity that inhibits viral replication through premature termination of RNA transcription. The investigational drug has in-vitro activity against SARS-CoV-2 and in-vitro and in-vivo activity against related betacoronaviruses. Remdesivir is still available for under a compassionate use protocol for use in pregnant women with severe COVID-19.21,22 Information on dosing remdesivir in pregnancy is not available.

“There are no data regarding the use of remdesivir during pregnancy to determine the drug-associated risk for major birth defects, miscarriages, or adverse maternal or fetal outcomes. . . .There are no data regarding the use of remdesivir during breast-feeding. It is unknown whether or not the drug is excreted into human breast milk.”23

Hydroxychloroquine and Chloroquine
Hydroxychloroquine and chloroquine are oral prescription drugs that have been used for the treatment of malaria and certain inflammatory conditions. These drugs are under investigation in clinical trials for pre-exposure or post-exposure prophylaxis of SARS-CoV-2 infection, and the treatment of patients with mild, moderate, and severe COVID-19. Hydroxychloroquine and chloroquine, when used for treatment and prevention of malaria, are generally considered safe in pregnancy.24

Different doses and regimens are being investigated for treatment and prevention of COVID-19 compared to malaria. As the dose, patient population, and progression of COVID-19 differ from those of malaria, the safety of hydroxycholorquine and chloroquine still needs to be assessed for prevention and treatment of COVID-19.

The clearance of chloroquine is about 34% greater in pregnancy compared to non-pregnant women, particularly in the second and third trimesters. Therefore, it is possible that a dose adjustment is needed in women during the second and third trimester.25 Chloroquine is extensively distributed in body tissues and fluids, including the placenta and breast milk.26

Registry
There is ongoing research on COVID-19 and pregnancy including the Pregnancy Coronavirus Outcomes at UCSF, which will track participants for a year to learn how the virus impacts maternal health, fetal development, preterm delivery, newborn health and outcomes for underserved women at higher risk of mortality during pregnancy. The study also will address transmission: whether a mother can pass the infection on to her child during pregnancy and birth or through breast milk.27

References

[1] https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-breastfeeding.html

[2] Qiao, Jie. “What are the risks of COVID-19 infection in pregnant women?.” The Lancet 395.10226 (2020): 760-762.

[3] https://www.unfpa.org/press/unfpa-statement-novel-coronavirus-covid-19-and-pregnancy

[4] https://www.who.int/news-room/q-a-detail/q-a-on-covid-19-pregnancy-childbirth-and-breastfeeding

[5} https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-breastfeeding.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fprepare%2Fpregnancy-breastfeeding.html

[6] Favre, Guillaume, et al. Guidelines for pregnant women with suspected SARS-CoV-2 infection. The Lancet Infectious Diseases (2020).

[7] https://www.geekwire.com/2020/kristina-adams-waldorf/

[8] https://www.un.org/sites/un2.un.org/files/sg_report_socio-economic_impact_of_covid19.pdf?utm_source=Unknown+List&utm_campaign=41b9ac5f35-EMAIL_CAMPAIGN_2020_01_09_06_17_COPY_02&utm_medium=email&utm_term=0_-41b9ac5f35-&mc_cid=41b9ac5f35&mc_eid=%5BUNIQID%5D

[9] Qiao, Jie. “What are the risks of COVID-19 infection in pregnant women?” The Lancet 395.10226 (2020): 760-762.

[10] Dong, Lan, et al. “Possible vertical transmission of SARS-CoV-2 from an infected mother to her newborn.” Jama (2020).

[11] Kimberlin DW, Stagno S. Can SARS-CoV-2 Infection Be Acquired In Utero? More Definitive Evidence Is Needed. JAMA. Published online March 26, 2020. doi:10.1001/jama.2020.4868

[12] https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/pregnancy-breastfeeding.html

[13] Zeng, Lingkong, et al. “Neonatal early-onset infection with SARS-CoV-2 in 33 neonates born to mothers with COVID-19 in Wuhan, China.” JAMA pediatrics (2020).

[14] Zeng L, Xia S, Yuan W, et al. Neonatal Early-Onset Infection With SARS-CoV-2 in 33 Neonates Born to Mothers With COVID-19 in Wuhan, China. JAMA Pediatr. Published online March 26, 2020. doi:10.1001/jamapediatrics.2020.0878

[15] Shang, Lianhan, et al. “On the use of corticosteroids for 2019-nCoV pneumonia.” The Lancet 395.10225 (2020): 683-684.

[16] Boelig, Rupsa C., et al. “Labor and Delivery Guidance for COVID-19.” American Journal of Obstetrics & Gynecology MFM (2020): 100110.

[17] World Health Organization. Clinical management of severe acute respiratory infection when noval coronavirus (2019-nCoV) infection is suspected. Interim guidance. March 13, 2020.

[18] Baud, David, et al. “COVID-19 in pregnant women–Authors’ reply.” The Lancet Infectious Diseases (2020).

[19] Jobe, Alan H., et al. “Pharmacokinetics and Pharmacodynamics of intramuscular and oral betamethasone and dexamethasone in reproductive age women in India.” Clinical and Translational Science (2019).

[20] https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html

[21] https://www.statnews.com/2020/03/22/gilead-suspends-access-to-experimental-covid-19-drug-remdesivir/

[22] https://clinicaltrials.gov/ct2/show/NCT04323761

[23] https://www.elsevier.com/__data/assets/pdf_file/0008/996767/Remdesivir-Drug-Monograph_270320.pdf

[24] https://www.ncbi.nlm.nih.gov/books/NBK294433/

[25] Karunajeewa, Harin A., et al. “Pharmacokinetics of chloroquine and monodesethylchloroquine in pregnancy.” Antimicrobial agents and chemotherapy 54.3 (2010): 1186-1192.

[26] Law, Irwin, et al. “Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers.” British journal of clinical pharmacology 65.5 (2008): 674-679.

[27] https://www.sfchronicle.com/bayarea/article/UCSF-study-investigates-coronavirus-impact-on-15193562.php

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