This prospective study was conducted at Hospital Federal dos Servidores do Estado (HFSE) and Hospital Geral de Nova Iguaçu (HGNI), both located at Rio de Janeiro State, Brazil from February 2005 to May 2006. This study was approved by the IPEC-FIOCRUZ institutional review board. Participant eligibility criteria were: (1) pregnant women older than 18 years; (2) gestacional age between 14 and 30 weeks; (3) HIV diagnosis confirmed by serology or HIV RNA viral load; (4) use of at least one dose of any ARV during pregnancy; (5) having had at least one medical appointment after the pregnancy diagnosis.

Women were classified according to antiretroviral therapy (ART) status at pregnancy diagnosis: ARV experienced (ARTexp) or ARV-naïve (ARTn); these two groups were analyzed separately. Women were followed up from pregnancy diagnosis until delivery.

Data were collected by two trained health professionals (one physician and one pharmacist) on the study procedures and definitions. The medical records of all patients included in the study were reviewed in a weekly basis until the end of the follow-up period, in order to update clinical information, focusing on ADR. Standardized forms to collect demographic, clinical, ART and ADR data were designed and piloted before study initiation.

Demographic and clinical characteristics at baseline included: age (years), race (white or non-white), number of previous pregnancies (0, 1–2, ≥3), number of living children (0, 1–2, ≥3), HIV exposure category (sexual, injecting drug use, or unknown), previous AIDS-defining illness, time until HIV diagnosis (months), nadir CD4+ lymphocyte T-cells< or ≥200cels/μL, baseline CD4+ lymphocyte T-cell, highest and lowest CD4+ lymphocyte T-cells during pregnancy, baseline HIV RNA viral load (copies/mL), HIV RNA viral load>1000copies/mL during pregnancy, gestational age at study entry, route of delivery (vaginal route or cesarean section), pregnancy outcome (term birth, preterm birth and abortion), ART use during pregnancy (weeks), ARV modification (at least one ARV of the regimen modified) and type of ART: non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitors (PI), NNRTI+PI, or nucleoside reverse transcriptase inhibitor (NRTI) only.

ADR related to ARVs were classified according to information collected from the medical charts, and were grouped as follows: gastrointestinal (GI) (diarrhea, vomiting, nausea, belly cramps), cutaneous (exanthema, pruritus), hematologic (anemia, neutropenia, and thrombocytopenia), hepatic, and constitutional symptoms (asthenia).

The most frequent ADR related to ARVs (gastrintestinal, cutaneous, hematologic and hepatic) were graded according to the DAIDS Table for Grading the Severity of Pediatric Adverse Events5 on intensity (mild, moderate and severe). Causality between ADR and ARV was assessed according to6 and defined as definitely, probably and possibly ARV-related. Other caractheristics related to the ADR were also assessed: serious (yes or not), outcome (resolved or ongoing), type of ART (NNRTI and PI), time to ADR onset (weeks), and ADR duration (weeks).

Incidence rate and confidence interval for each ADR was estimated by Poisson model and reported it as the number of occurrences per 1000 person-months. The statistical software R, version 2.14.1 (www.r-project.org) was used for all statistical analyses.

For the ARTexp group, median time from ART initiation until labor was 23.7 months (IQR6.4–66.4).

Eighteen women (50%) were using an Efavirenz (EFV) based regimen when they became pregnant and have been switched to the following ARVs in order to avoid teratogenic effects: lopinavir/ritonavir (LPV/r) in three cases, nevirapine (NVP) in eleven cases, and nelfinavir (NFV) in four cases. Mean gestational age at the time of EFV discontinuation was 16 weeks (SE+0.8). No obstetric complications during labor were observed and no infants were born with low birth weight or had congenital malformations diagnosed. EFV use was significantly associated with neither abortion nor premature birth (p=0.825).

After the EFV switch, 16 women were using an NNRTI-based regimen, all of them were receiving Nevirapine (NVP); 19 women were using a PI-based regimen, nine with LPV/r, eight with NFV, and one with saquinavir plus ritonavir (SQV/r); one woman was taking an NNRTI+PI containing regimen (LPV/r+NVP). Mean time of exposure to the new ART after EFV switch was 29.8 weeks (SE+1.2).

Six women modified at least one ARV during gestation due to virological failure, three were in use of NVP (switched to NFV) and three were taking NFV (switched to LPV/r). Mean time of exposure to the new ART after virological failure was 4.2 weeks (SE+0.4).

Ten adverse medical events not related to ART were observed: hypertension (4), hepatitis C (HCV) co-infection (1), syphilis (1), ischemic heart disease (1), genital warts (1), pyelonephritis (1), and seizure in a patient with previous epilepsy diagnosis (1). Twenty-six women (77.8%) had no complication whatsover during prenatal period.

Overall, only one obstetric complication was verified, a fetal distress caused by preeclampsia. Only one child had low birth weight (2420g).

Six undesirable pregnancy outcomes occured: two induced miscarriage and four premature births. All pregnant women who gave birth prematurely had a nadir CD4+ T lymphocyte>200cells/μL, two were on NVP and two on PIs. The rate of preterm birth was not different in pregnant women on PI or on NNRTI (p=1.00). Mean baseline CD4+ T lymphocyte count was 563cells/μL (IQR 377.25–749.75) and 291.5cells/mm3 (IQR 188.5–291.5) in women who had premature birth and in those who gave birth at term, respectively.

No ADR during pregnancy were observed for all 36 women.

A total of 178 ARTn patients were included in this study. NVP was prescribed to all 73 patients (41.0%) who were started on NNRTI-based regimen. For PI-based regimens, 93, eight, and two pregnant women received NFV, LPV/r, and atazanavir (ATV), respectively. Two patients received NRTI-only based regimen, one received zidovudine (ZDV) monotherapy and one received a combination of ZDV, lamivudine (3TC) and abacavir (ABC). Eleven women (6.2%) modified at least one ARV during pregnancy, and all modifications were toxicity-driven.

Twenty adverse events (AE) not related to ART occurred among 10 women: hypertension (3), genital herpes (3), syphilis (3), oral candidiasis (2), upper respiratory tract infection (1), conjunctivitis (1), gestational diabetes diagnosed before ART initiation (1), facial cellulitis (1), herpes zoster (1), pyelonephritis (1), sinusitis (1), bacterial vaginosis (1) and scabies (1). Six women (3.4%) had obstetric complications during pregnancy and labor: ruptured membranes (3), perinatal asphyxia and uterine atony leading to hysterectomy (1), failure to progress in labor (1) and placental abruption (1). Only one child was born with low birth weight (2120g). A hundred sixty-two women (91.0%) had no complications during prenatal period.

No statistically significant difference in the rate of preterm delivery in pregnant women according to ART-based regimen was observed. No difference was found in preterm delivery according to the ART regimen received.

Two children (1.1%) were born with congenital malformations diagnosed at birth, both with hemangioma, one on the face and one on chest, and these were not attributed to the ARV exposure.

Among those women who developed ADR, mean ART exposure was 16.3 weeks. The frequency and incidence of ADR among the 178 pregnant women enrolled as ARV-naïve are depicted in Table 2. Thirty-six (20.2%) women developed 48 events classified as ADR. Overall ADR frequency was 27% (48/178) and overall ADR incidence was 70.8 episodes per 1000 person-months. Twenty-six, eight and two women experienced one, two or three ADR, respectively. No potential fatal ADR was reported.

ADR intensity, relationship to ARV, evolution, duration and outcome on women enrolled as ARV-naïve are shown in Table 3.

Eleven women (6.2%) permanently discontinued at least one ARV due to the following ADR: moderate anemia related to ZDV (1); diarrhea related to NFV (one moderate and one severe); moderate hepatitis (1) and rash (7) related to NVP. ZDV was replaced by stavudine (d4T), NFV by NVP and vice versa. Among women starting ART with NVP, 9.6% (7/73) had to permanently discontinue it.

GI events were the most frequent ADR observed and most of them were observed one week after ART initiation. Twenty-four women developed 29 GI ADR episodes (16.3%), including diarrhea (9.5%), vomiting (3.4%), nausea (2.8%) and belly or abdominal cramps (0.6%), with an overall incidence of 42.8 episodes per 1000 person-months. These women were more frequently having a comorbidity during pregnancy (p=0.034), used PI-based regimen (p=0.016), and were in a more advanced gestational age at prenatal care initiation (p=0.014). Mild GI ADR was observed in 89.6% and one woman had a serious ADR. Almost half of these events (44%) were resolved without interrupting ART and in most cases they persisted until labor. Almost all GI ADR (96.5%) occurred in women using a PI-based regimen and only two women had to discontinue their ARV regimen. All episodes of diarrhea were related to NFV (18.3%).

Cutaneous ADR occurred in 6.2% women, including pruritus (3; 1.7%) and exanthema (8; 4.5%), representing an incidence of 16.2 episodes per 1000 person-months. There were three cases of mild pruritus, which were resolved without ART discontinuation. These women were using ATV (1) and NVP (2) in combination with ZDV/3TC. Most cases of rash ranged from moderate to severe (87.5%), but none of them were classified as serious. The only case of mild intensity was resolved without ART discontinuation. All cases of rash occurred in pregnant women using a NVP-based regimen, with an overall frequency of 10.9%. Cases of rash were identified earlier than a week after ART initiation and rapidly improved after NVP discontinuation.

Anemia occurred in four women (2.2%), representing an incidence of 5.9 episodes per 1000 person months. No other hematological ADR (neutropenia or thrombocytopenia) occurred in our study population. All women who had anemia were using ZDV/3TC, two of them in combination with NVP, one with LPV/r, and one with NFV. Anemia occurred for a mean time of 2.3 weeks and it was diagnosed at a mean time of 2.2 weeks after ART initiation. Almost all episodes of anemia were mild to moderate. One case which required hospitalization and blood transfusion was classified as serious, being resolved after ZDV discontinuation in all cases. Anemia persisted until delivery and only one woman had ART interrupted.

Three women (1.7%) had hepatitis, representing an incidence of 4.4 episodes per 1000 person-months. Hepatitis occurred 0.7 weeks after ART initiation and lasted for 4.1 weeks. All cases were mild or moderate and none of them evolved to a severe outcome. Two women were using an NVP-based regimen (overall frequency 2.7%) and one in a NFV-based regimen, both combined with ZDC/3TC. NVP was permanently discontinued in one woman. The other two cases of hepatitis were mild and persisted until delivery.

One case (0.6%) of asthenia was observed in a woman in use of ZDV+3TC+NFV, representing an incidence of 1.5 episode per 1000 person-months. This event started one week after ARV onset and persisted until delivery.