Congenital cytomegalovirus (cCMV) is a leading cause of sensorineural hearing loss and developmental disabilities in US children.1 In the USA, neither prenatal screening nor antiviral treatment for cytomegalovirus (CMV) infection during pregnancy are currently recommended.2 Several studies have found a lower rate of vertical transmission after primary CMV infection in the first trimester of pregnancy with high dose valacyclovir treatment (8 g daily), including a clinical trial conducted in Israel that was published in 2020.3–5 Valacyclovir is administered in a lower dose regimen (1–2 g daily) to treat or prevent recurrency of herpes simplex virus (HSV) infections during pregnancy. Using electronic health record data, our main objective was to assess if high dose valacyclovir had been dispensed to pregnancies with a CMV diagnosis in the USA.
We used HealthVerity, Inc. 2022 Quarter 4, Maternal Outcomes Masterset data, which contained data on 3 712 592 pregnancies with a documented live birth during 2018–2022 (Data S1; Table S1). We limited the study to pregnancies with a live birth in order to be able to link the pregnancies to the infants. We identified pregnancies with a CMV infection based on a combination of CMV diagnostic codes (B25.xx) and laboratory test results (positive polymerase chain reaction, culture or IgM, IgG seroconversion or low IgG avidity) (Data S1; Table S1). We also used diagnostic codes from the medical claims to identify immunocompromising conditions, HSV, and varicella zoster virus infections that could explain the use of antivirals. We identified valacyclovir, acyclovir, or famciclovir, using dispensed pharmacy claims (Data S1; Table S1). We also identified cCMV infection (P35.1) or CMV disease (B25.xx) within 45 days of birth to identify cCMV1 among linked live births. The project was reviewed by the Institutional Review Board and was determined to be exempted.
We identified 1884 (0.05%) pregnancies with CMV infection of which 1023 (54%) had diagnostic codes only, 654 (35%) had positive laboratory tests only, and 207 (11%) had both. The first CMV diagnosis was at median 25 weeks gestational age. Immunocompromising conditions and other herpes virus infections (all had HSV) were more common in pregnant people with CMV infection (114 [6%] and 261[14%], respectively) than those without (22 311 [1%] and 207 009 [6%]) (Table 1).
TABLE 1.
Selected characteristics of pregnancies with a live birth by CMV diagnosis.
| No. (%) of pregnancies | |||
|---|---|---|---|
| With CMV diagnosisa | |||
| Without CMV diagnosisa | All | With dispensed antiviral prescription | |
| Characteristics | n (%) | n (%) | n (%) |
| Overallb | 3 710 708 (99.95) | 1884 (0.05) | 185 (9.82) |
| Periodc | |||
| 2018–2020 | 2 782 495 (75) | 1219 (77) | 112 (9) |
| 2021–2022 | 928 213 (25) | 665 (23) | 73 (11) |
| Medical history | |||
| Immunocompromising conditiond | 22 311 (1) | 114 (6) | 13 (7) |
| Other herpes virus infection | |||
| HSV | 207 009 (6) | 261 (14) | 113 (61) |
| VZV | 2240 (0) | 4 (0) | 0 (0) |
| HSV and VZV | 403 (0) | 8 (0) | 1 (1) |
| None documented | 3 503 296 (94) | 1615 (86) | 71 (38) |
| Antiviral treatment | 182 012 (5) | – | 185 (10) |
| Valacyclovire | 130 291 (72) | – | 126 (68) |
| Acyclovir | 42 758 (23) | – | 32 (17) |
| Acyclovir and valacyclovir | 8454 (5) | – | 15 (8) |
| Other | 509 (0) | 12 (6) | |
| Gestational age when treatment first dispensed | |||
| Median (q1, q3) | 34 (20, 36) | – | 34 (29, 36) |
| First trimester (0–13 weeks) | 28 650 (16) | – | 4 (2) |
| Second trimester (14–27 weeks) | 33 341 (18) | – | 35 (19) |
| Third trimester (28–end) | 120 021 (66) | – | 146 (79) |
| Pregnancies linked to live births | 1 121 663 | 558 | – |
| Infants with a diagnosis of congenital CMV | 104f (0.01) | 71 (13) | 10 (14) |
Abbreviations: CMV, cytomegalovirus; HSV, herpes simplex virus; VZV, varicella zoster virus.
Among 1884 pregnancies identified with CMV infection, 1023 (54%) had a diagnostic code for CMV disease (B25.xx) and 861 (46%) had a positive CMV test (197 by polymerase chain reaction, 3 culture, 668 IgM, and 24 IgG seroconversion).
Percentages for the row with overall data reflect ROW percentages. The percentages calculated for pregnancies without and with a CMV diagnosis were among all 3 712 592 pregnancies. The percentage among those with a CMV diagnosis with dispensed antiviral prescription were calculated among the 1884 with a CMV diagnosis.
We examined the data before and after 2020, the year when the clinical trial that examined valaciclovir for prevention of vertical transmission of CMV after maternal primary infection during pregnancy was published.
Before or during pregnancy episode.
Valacyclovir was administered at median daily dose of 1000 mg for 30 days; 17 pregnancies with daily dose ≥8 g.
Among whom 50 (48%) had prenatal antiviral treatment.
Antiviral treatment, most commonly valacyclovir, was dispensed for 182 012 (5%) pregnancies without a CMV diagnosis and 185 (10%) pregnancies with a CMV diagnosis. In the latter group, 13 (7%) had a diagnosis of immunocompromising condition, and 114 (62%) had a diagnosis of other herpes virus infections (Table 1). Valacyclovir was first dispensed at a median of 34 weeks gestational age (146 [79%] in the third trimester), and at a median daily dose of 1000 mg for 30 days. There were 17 (9%) pregnancies with a daily dose of ≥8 g dispensed; all had CMV during pregnancy, seven (41%) in 2020 and 10 (59%) in 2021, though most received treatment during the second or third trimester and one (6%) was immunocompromised.
Among 558 (30%) pregnancies with a CMV diagnosis that were linked to live births, 71 (13%) of the infants had a diagnosis of cCMV. For the 71 infants, 10 (14%) of their mothers had documented antiviral treatment during pregnancy. Among 1 121 663 (30%) pregnancies without a CMV diagnosis that were linked to live births, 104 (0.01%) of the infants had a diagnosis of cCMV. For these 104 infants, 50 (48%) of their mothers had documented antiviral treatment during pregnancy. There was no difference in the median gestational age at initial treatment (both 34 weeks) or median daily dose (both 1000 mg) comparing pregnancies with and without CMV infection.
In this study, we found the characteristics of dispensed valacyclovir treatment (i.e., dosage, duration, and timing) and high proportion with HSV diagnosis suggested use for treatment or suppression of recurrent genital herpes in most cases with or without a CMV diagnosis recorded during pregnancy. Most pregnant people did not receive high dose valacyclovir. Although a few pregnant people had recorded high dose valacyclovir being dispensed during 2020–2021, most were after the first trimester of pregnancy. We only assessed pregnancies with live birth outcomes and diagnostic codes or treatment may have been missed or incorrect. We were also unable to examine potential side effects of treatment. These data are potentially useful in the future for monitoring trends in laboratory testing, diagnoses, and treatment for CMV infection during pregnancy. Reviewing the evidence on efficacy and safety of high dose valacyclovir treatment given early in pregnancy to prevent vertical transmission of CMV will be helpful to inform future guidance on prenatal CMV screening and treatment in the USA.
Supplementary Material
ACKNOWLEDGMENTS
We would like to acknowledge CDC Epidemiologist Lara Bull, PhD, for her valuable guidance and detailed technical review.
FUNDING INFORMATION
No financial support was received for this work.
Footnotes
CONFLICT OF INTEREST STATEMENT
The authors report no conflict of interest.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
DATA AVAILABILITY STATEMENT
The data that support the findings of this study were obtained from a third party vendor. Restrictions apply to the availability of these data, which were used under license for this study that do not allow sharing of this data.
REFERENCES
- 1.Leung J, Grosse SD, Hong K, Pesch MH, Lanzieri TM. Changes in valganciclovir use among infants with congenital CMV diagnosis in the United States, 2009–2015 and 2016–2019. J Pediatr. 2022;246:274–278. [DOI] [PubMed] [Google Scholar]
- 2.American College of Obstetricians and Gynecologists. Practice bulletin no. 151: cytomegalovirus, parvovirus B19, varicella zoster, and toxoplasmosis in pregnancy. Obstet Gynecol. 2015;125:1510–1525. [DOI] [PubMed] [Google Scholar]
- 3.Chatzakis C, Shahar-Nissan K, Faure-Bardon V, et al. The effect of valacyclovir on secondary prevention of congenital cytomegalovirus infection, following primary maternal infection acquired periconceptionally or in the first trimester of pregnancy. An individual patient data meta-analysis. Am J Obstet Gynecol. 2024;230(2):109–117.e2. [DOI] [PubMed] [Google Scholar]
- 4.Shahar-Nissan K, Pardo J, Peled O, et al. Valaciclovir to prevent vertical transmission of cytomegalovirus after maternal primary infection during pregnancy: a randomised, double-blind, placebo-controlled trial. Lancet. 2020;396(10253):779–785. [DOI] [PubMed] [Google Scholar]
- 5.Zammarchi L, Lazzarotto T, Di Tommaso M, et al. Valacyclovir for prevention and treatment of fetal CMV infection: inclusion in the law 648/96 list and launch of the Italian multicentre observational prospective study “MEGAL-ITALI”. Infez Med. 2021;29(2):299–303. [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study were obtained from a third party vendor. Restrictions apply to the availability of these data, which were used under license for this study that do not allow sharing of this data.