Severe Haematologic Toxicity Is Rare in High Risk HIV-Exposed Infants Receiving Combination Neonatal Prophylaxis

The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord


HIV Medicine. 2019;20(5):291-307. 

In This Article

Abstract and Introduction


Objectives: Combination neonatal prophylaxis (CNP) is recommended in high-risk situations for the prevention of mother-to-child HIV transmission, although data on its safety are limited. The aim of the study was to identify whether neonatal prophylaxis (NP) type is associated with the risk of severe anaemia or neutropaenia.

Methods: An individual patient data meta-analysis was conducted within six European cohorts, in infants at high risk for acquiring HIV infection. Adjusted logistic regression models were used to assess the risk of National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) grade 3–4 anaemia/neutropaenia at ages 0–6 months. Mixture models of haemoglobin (Hb) level and log10-transformed neutrophil count (NC) were used to explore associations with NP type at ages 0–18 months.

Results: Of 1836 infants, 25% were preterm, 1149 (63%) had antenatal combination antiretroviral therapy (cART) exposure and 395 (22%) received NP (125 received CNP with three drugs). Overall, 117 (6.7%) infants had grade 3–4 anaemia at age 0–6 months and 140 (9.1%) had grade 3–4 neutropaenia. The presence of grade 3–4 anaemia or neutropaenia was not associated with NP type [adjusted odds ratio (aOR) 1.04 for one-drug NP and 1.60 for three-drug NP versus two-drug NP (P = 0.879 and P = 0.277, respectively) for anaemia; aOR 1.33 for one-drug NP and 1.98 for three-drug NP versus two-drug NP (P = 0.330 and P = 0.113, respectively) for neutropaenia], but was associated with preterm delivery. Overall, 7746 Hb and NC results were available for 1836 infants up to age 18 months; no significant differences in predicted Hb level or NC were apparent by NP type.

Conclusions: A small proportion of infants experienced grade 3–4 haematological adverse events; risk of anaemia or netropenia was not associated with type of NP.


Universal antenatal HIV testing, combination antiretroviral therapy (cART) during pregnancy, labour and delivery, neonatal antiretroviral prophylaxis (NP), elective caesarean section (CS) for women without optimal viral suppression near delivery and the avoidance of breast feeding have led to a dramatic decline in the number of perinatally HIV-infected children: currently, in the USA as well as in Western Europe, mother-to-child transmission (MTCT) rates are < 1%.[1–3] However, there remain missed opportunities for prevention of MTCT (PMTCT) in these settings, including late diagnosis of HIV infection in pregnant women and failure to control viral replication during pregnancy as a consequence of inadequate or lack of cART, and low adherence.[2,4,5]

In most cases, NP consists of zidovudine (ZDV) monotherapy for 4–6 weeks.[6] International guidelines recommend the use of combination NP (CNP) with two or three antiretroviral drugs (ARVs) in specific high-risk situations.[6] However, the optimal prophylactic regimen and the additional efficacy of CNP in reducing MTCT risk in such situations are not well understood. CNP was found to be superior to one-drug NP in a randomized trial conducted in exclusively formula-fed infants born to women who had not received ARVs during pregnancy,[7] but data in other high-risk situations are limited. Furthermore, there is some controversy regarding whether high-risk newborns should receive therapeutic rather than prophylactic doses of ARVs. This is based on increasing evidence of the benefits of very early cART initiation in perinatal infection with respect to restricting the viral reservoir.[8–10]

We previously showed that the use of CNP in high-risk situations is increasing in Europe.[4] Data regarding the safety of NP, particularly CNP, are limited in both term and, concerningly, preterm infants. Haematological toxicity associated with in utero or early life exposure to ARVs has been well established, with some studies demonstrating that infants exposed in utero to cART have lower haemoglobin (Hb) levels and neutrophil counts (NCs) than those exposed to ZDV monotherapy or without ART exposure.[7,11–16] In the HPTN 040 trial, in which infants had no in utero ART exposure, neutropaenia (grade 2 or above) was more common in the three-drug arm than in the ZDV/nevirapine (NVP)- or ZDV-only arms, although there was no significant difference with respect to anaemia.[7]

In an individual patient data meta-analysis of data collected from a European cohort collaboration, our aim was to examine haematological toxicity in infants born to women with HIV infection at high risk of MTCT, and specifically to identify whether NP type was associated with (1) the presence of severe or potentially life-threatening anaemia or neutropaenia within the first 6 months of life and (2) haemoglobin level and NC at ages 0–18 months.