Nirmatrelvir–Ritonavir (Paxlovid) for Mild Coronavirus Disease 2019 (COVID-19) in Pregnancy and Lactation

Abstract

Nirmatrelvir–ritonavir (Paxlovid) is recommended to reduce the risk of hospitalization from coronavirus disease 2019 (COVID-19) in pregnancy. Data on use in pregnancy, including prescribing patterns and patient experience (adverse effects, incidence of rebound), are limited. We performed a cross-sectional study in which we surveyed a cohort of vaccinated pregnant or lactating individuals with breakthrough COVID-19. Of 35 pregnant respondents, 51.4% were prescribed and 34.3% took nirmatrelvir–ritonavir; of these, 91.7% experienced dysgeusia and 50.0% had rebound (50.0% positive test result, 33.3% return of symptoms). Three of five lactating respondents were prescribed and two took nirmatrelvir–ritonavir. There were no significant adverse outcomes. Unknown risk was the most common reason for declining nirmatrelvir–ritonavir. More research is needed to establish the safety of nirmatrelvir–ritonavir in pregnancy and lactation, to improve public health messaging, and to increase uptake of this treatment.

In Brief

Nirmatrelvir–ritonavir is well tolerated in pregnancy and lactation, although mild adverse effects and rebound may be common.

Nirmatrelvir–ritonavir (Paxlovid) reduces the risk of hospitalization and death resulting from coronavirus disease 2019 (COVID-19) in populations at high risk,¹ but data in pregnancy and lactation are lacking. Leading professional societies support its use in pregnancy.^2,3 Patient experience, such as adverse effects and incidence of rebound symptoms, has not been reported in these groups.

We surveyed a vaccinated cohort of pregnant or lactating individuals about their experience with nirmatrelvir–ritonavir for COVID-19. We aimed to assess the patient clinical experience after treatment, including the rate of rebound symptoms.

METHODS

This is a cross-sectional study of individuals who received their initial COVID-19 vaccination series during pregnancy or lactation, the COVIPAL (COVID-19 Vaccination in Pregnancy and Lactation) study. Enrollees receive periodic questionnaires to assess for breakthrough infections and other changes in their health. Individuals with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (confirmed by medical record review) between January and December 2022 received an additional survey about their experience with nirmatrelvir–ritonavir.

The study was approved by the IRB of the University of California, San Francisco (IRB No. 20-32077). All participants provided written informed consent before enrollment. Enrollees with COVID-19 received a REDCap-based survey with questions about their experience with nirmatrelvir–ritonavir (Appendix 1, available online at https://links.lww.com/AOG/D90). Medical records were reviewed to assess the following variables: gestational age at SARS-CoV-2 infection, gestational age at COVID-19 vaccination and booster dose(s), maternal age, gravidity, parity, self-reported race and ethnicity, comorbidities (hypertensive disorder, diabetes mellitus, pulmonary disease), obstetric outcomes, and hospitalizations. We analyzed descriptive data using medians (range) for continuous variables and frequencies by number (percent). Adverse effect severity was graded according to Division of AIDS criteria.⁴ We collected information about patient race and ethnicity because racial and ethnic disparities exist in outpatient COVID-19 treatment in the United States.⁵

RESULTS

Of 371 patients in the parent study, 64 had COVID-19 during the survey period. All cases were mild. Forty participants responded, including 35 pregnant and 5 lactating individuals (Fig. 1). Surveys were returned a median of 16 days after completion of nirmatrelvir–ritonavir.

Fig. 1.: Patient inclusion flowchart. COVIPAL, COVID-19 Vaccination in Pregnancy and Lactation; COVID-19, coronavirus disease 2019.

Respondent characteristics are described in Table 1. Of pregnant respondents, 18 (51.4%) received a nirmatrelvir–ritonavir prescription, of whom 66.7% opted to take the full 5-day course (n=12, 34.3% of pregnant respondents). Adverse effects were reported by 91.7%, most commonly dysgeusia (n=11, 91.7%), diarrhea (n=2, 16.7%), and mild abdominal pain (n=1, 8.3%) (Fig. 2A). Adverse effects lasted from 72 hours to 1 week. Six respondents (50.0%) reported a positive SARS-CoV-2 test result after completion of nirmatrelvir–ritonavir; four (33.3%) reported a return of COVID-19 symptoms, most commonly fatigue (100.0%) and nasal congestion (100.0%), cough (50.0%), and headache (50.0%) (Fig. 2B).

Table 1. - Characteristics of Pregnant or Lactating Patients Vaccinated Against Coronavirus Disease 2019 Who Were Prescribed Nirmatrelvir–Ritonavir

Characteristic	Patients
	Pregnant	Lactating
Prescribed medication	18	3
Age (y)	35 (31–44)	41 (38–44)
Race
Asian	5 (27.8)	1 (33.3)
Black or African American	0	0
White	10 (55.6)	1 (33.3)
None of the above	3 (16.7)	1 (33.3)
Ethnicity
Hispanic or Latine	3 (16.7)	0
Not Hispanic or Latine	9 (50.0)	2 (66.7)
Unknown	6 (33.3)	0
Gestational age at treatment (wk)	22 (9.3–39.4)	64 postpartum (4–114)
Trimester of pregnancy at time of infection or treatment
1st	3 (16.7)
2nd	9 (50.0)
3rd	6 (33.3)
Gravidity	1 (1–2)	4 (2–4)
Parity	0 (0–2)	2 (2–3)
Took prescribed medication	12 (66.0)	2
Experienced adverse effects*	11 (91.7)	1
Altered sense of taste	11 (91.7)	1
Diarrhea	2 (16.7)	0
Other	1 (8.3)	1
Return of COVID-19 symptoms after completed course†	4 (33.3)	0
Cough	2 (16.7)	0
Shortness of breath or difficulty breathing	1 (8.3)	0
Muscle or body aches	1 (8.3)	0
Headache	2 (16.7)	0
Sore throat	1 (8.3)	0
Congestion or runny nose	4 (33.3)	0
Positive SARS-CoV-2 test result after completed course	6 (50.0)	0
Time from completion of course to positive test result (d)	7 (2–10)	NA

COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; NA, not applicable.

Data are n, median (range), or n (%).

^*No patients reported high blood pressure or muscle aches.

^†No patients reported experiencing fever or chills, new loss of taste or smell, nausea or vomiting, diarrhea, abdominal pain, or mastitis.

Fig. 2.: A. Eleven individuals (91.7%) had any medication adverse effects. B. Six individuals (50.0%) had positive test results and four (33.0%) had a return of mild symptoms after the nirmatrelvir–ritonavir course. COVID-19, coronavirus disease 2019.

Three of five lactating respondents received a nirmatrelvir–ritonavir prescription; two opted to take the medication. One reported altered sense of taste. None reported subsequent COVID-19 rebound (Table 1).

The most common reported reason for avoidance of nirmatrelvir–ritonavir in both groups was lack of data and unknown risks. One participant expressed concern about rebound COVID-19 symptoms. Two participants declined nirmatrelvir–ritonavir because of mildness of symptoms (Appendix 2, available online at https://links.lww.com/AOG/D90).

There were no adverse events, no obstetric complications, and no hospitalizations for COVID-19. Of 12 pregnant individuals who completed the nirmatrelvir–ritonavir course, 10 had healthy term pregnancies without complications, one had a preterm twin delivery, and one remains pregnant.

DISCUSSION

In this cohort of vaccinated pregnant individuals, half were prescribed nirmatrelvir–ritonavir. Of those, 66.0% took the medication; most declined nirmatrelvir–ritonavir because of concerns about unknown risks in pregnancy. Nearly all who took nirmatrelvir–ritonavir had mild adverse effects, and half experienced mild COVID-19 rebound. There were no serious adverse events, and the medication was overall well tolerated, consistent with available data.⁶

Although pregnant status is a high-risk condition, we report low rates of nirmatrelvir–ritonavir prescription receipt. Patient uncertainty about this new medication is a barrier to treatment uptake, even after it is prescribed by a health care professional. The rates of medication adverse effects and COVID-19 rebound were higher than cited in nirmatrelvir–ritonavir clinical trials (5.6% and 1–2%, respectively) in nonpregnant or lactating individuals.¹ There may be bias in survey reporting in this small sample size; larger trials are needed.

Ritonavir is well studied and widely used in pregnancy and lactation, but the safety of nirmatrelvir is based largely on animal models⁷ and one series of 46 pregnancies.⁶ More research is needed to understand whether nirmatrelvir–ritonavir is protective against adverse COVID-19 outcomes in this population, including those who are vaccinated. Studies of nirmatrelvir–ritonavir efficacy are mostly in older individuals^1,8 and exclude pregnant or lactating individuals. Although our study was too small to infer true medication safety, until clinical trials are completed, this study provides early data on nirmatrelvir–ritonavir experiences in this population.