Abstract
Background: The mother-to-child transmission of HIV, which accounts for 90% of infections in children, has been reduced markedly through the use of antiretroviral drugs by pregnant women and their newborns. Changes to the World Health Organization guidelines support further extension of the prevention of mother-to-child transmission programs with increased risk of toxicity on the fetuses.
Aim: To determine the hematological indices at birth of infants exposed in utero to maternal antiretroviral drugs.
Method: A comparative analytical study of 126 neonates whose blood samples were analyzed to determine their hematological indices.
Result: The hemoglobin, hematocrit, the total white blood cell (WBC) count and absolute neutrophil count (ANC) were significantly lower in infants of HIV-positive mothers. The total WBC and ANC were also significantly lower in the highly active antiretroviral therapy. HAART group and those exposed to maternal drugs for <1 year.
Conclusion: There are significant changes in the hematological indices of infants of HIV-positive mothers at birth.
Keywords: hematological indices, birth, infants, HIV-infected mothers
INTRODUCTION
The HIV/AIDS pandemic is one of the most important challenges of global health today. By the end of 2009, about 33.3 million people worldwide were estimated to be living with HIV [1]. Women of the child-bearing age account for nearly 50% of the people living with HIV/AIDS [2], leading to an estimated 2 million infants exposed yearly to HIV-1 during pregnancy and delivery [3].
Efforts have been made to introduce and expand programs to prevent mother-to-child transmission of HIV. These include prevention of HIV infection in women of reproductive age and the prevention of unintended pregnancy. It also includes the use of antiretroviral therapy (ART) in HIV-infected mothers during pregnancy and also in their infants [4].
Perinatal ART has reduced the risk of transmission of HIV to infants of infected mothers but is associated with side effects [5]. Increased use of antiretroviral (ARV) drugs for the prevention of mother-to-child transmission (PMTCT) of HIV is associated with the risk of several adverse effects, including hematological toxicity in the mother and infant. The extent of risk to the mother, and fetus/infant varies according to the exposure timing, duration and the number of drugs to which the woman and infant are exposed [6, 7]. Several ARVs, most importantly zidovudine and other nucleoside reverse transcriptase inhibitors, are known to cause anemia in adults and children [8–13].
Concerns about the short- and long-term hematological toxicities caused by transmission prophylaxis have prompted several studies that addressed issues of their safety and possible side effects. Some short-term studies are reassuring [14], while others suggest that effects on hematopoiesis can last up to 18 months following perinatal exposure [15, 16].
PMTCT programs have become widespread in Nigeria with more neonates of HIV-infected mothers being exposed to ARV, especially zidovudine or HAART in utero. The effect of ARV on infant’s hematological parameters in south-east Nigeria has not been explored. This study therefore set out to find if HIV-exposed uninfected neonates have lower hematological parameters when compared with the unexposed ones.
METHODS
A comparative analytical study that lasted for 9 months (February to October 2011), during which neonates of consenting HIV-negative or -positive mothers were enrolled consecutively within 0–72 h of birth. It was carried out in the University of Nigeria Teaching Hospital (UNTH) Ituku/Ozalla in Enugu, South-east Nigeria, a referral center with clinics for HIV/AIDS and a PMTCT follow-up among many other general/specialist medical services. The PMTCT follow-up clinic provides services that include continuation of ARV medications, Pneumocystis jirovecci pneumonia prophylaxis, growth monitoring, infant feeding counseling, general care and early infant diagnosis of HIV infection.
The inclusion criteria for the neonates of HIV-infected mothers were the use of ART by their mothers during pregnancy, labor and/or delivery in addition to being term at birth. Term neonates of consenting HIV-positive mothers matched for sex with those of HIV-negative mothers were enrolled within 72 h of birth. The exclusion criteria for both groups, were pre/postmature newborns, presence of fever and absence of PMTCT services (in HIV-infected mothers). A sample size of 63 pairs of neonates was used based on known sample size calculation of means for comparative studies [17].
The characteristics of the mothers and neonates were obtained and entered into a data questionnaire. The time at which the diagnosis of retroviral disease was made, use of ART and type of drugs used in pregnancy were obtained from the HIV-infected mothers. The postexposure prophylaxis adopted for the neonates was documented, while the mode of delivery, gender, and birth weight were recorded. The HIV-infected mothers received different combinations of zidovudine-based HAART or zidovudine monotherapy and were categorized into two groups; HAART and zidovudine monotherapy.
The hematological indices {hematocrit [Hct], hemoglobin [Hb] concentration, red blood cell indices; [mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV)], leukocytes count; total and differential, platelet count and reticulocyte count} of the neonates were measured using 1–2 ml of venous blood in EDTA, collected within 72 h of birth. The samples were analyzed with the KX21N Sysmex auto hematology analyzer (XT2000i, 2001, Japan) using the protocol described by the manufacturers.
The reticulocyte count was determined manually according to standard laboratory procedure described by the World Health Organization expert panel on cytometry [18].
Ethical approval was obtained from the Health Research and Ethics Committee of UNTH. Universal aseptic procedures were adopted in sample collections.
DATA PRESENTATION AND ANALYSIS
Data analysis was with SPSS version 15 (IBM corporation, Chicago, IL 2007). Descriptive statistics was used to characterize the study population. Hematological parameters were summarized by their means, standard deviations and 95% confidence intervals. Independent t-test was used for statistical significance between the hematological parameters of the exposed uninfected neonates and unexposed neonates, HAART/zidovudine exposure and duration of ARV drugs in the mother (<1 year/≥1 year). p value of <0.05 was adopted for limit of significance.
RESULTS
Eight hundred and thirty-six singleton live babies were delivered by mothers during the period, and 79 HIV-infected mothers consented to the study. Of the consenting participants, 16 of the HIV-exposed neonates did not meet the entry criteria. Sixty-three of these HIV-positive mother/neonate pairs and 63 sex-matched neonates of HIV-negative mothers were enrolled, giving 126 participants. Forty-three (68.3%) of HIV-infected mothers received HAART, while 20 (31.7%) received zidovudine monotherapy. Twenty-two (34.9%) mothers had received ART for <1 year; Table 1.
Table 1.
General characteristics of study participants
| Characteristics of mothers | HIV positive | HIV negative |
|---|---|---|
| N = 63 | N = 63 | |
| Marital status | ||
| Married | 55 (87.3%) | 62 (98.4%) |
| Widowed | 3 (4.8%) | 1 (1.6%) |
| Single | 4 (6.3%) | 0 |
| Separated | 1 (1.6%) | 0 |
| ART used | ||
| HAART | 43 (68.3%) | |
| Zidovudine monotherapy | 20 (31.7%) | |
| Duration of ART in mother | ||
| <1 | 22 (34.9%) | |
| ≥1 | 41 (65.1%) | |
| Characteristics of the neonates | ||
| Gender | ||
| Male | 32 | 32 |
| Female | 31 | 31 |
| Birth weight mean (SD) | 2.9 ± 0.8 kg | 3.3 ± 0.6 kg (p = 0.04) |
The neonates were composed of 64 males and 62 females, giving a male:female ratio of 1.03:1. The mean birth weight was 2.9 ± 0.8 kg for the HIV-exposed neonates and 3.3 ± 0.6 kg for the unexposed neonates; Table 1.
The mean Hb concentration and Hct of the neonates of the HIV-positive and that of HIV-negative mothers at birth were 14.1 ± 2.4 g/dl vs. 15.4 ± 2.3 g/dl (p = 0.003) and 41.2 ± 6.6% vs. 44.3 ± 6.2%, respectively (p = 0.007); Table 2. The MCV was higher in the exposed neonates [101.9 ± 17.4 fl vs. 95.9 ± 11.2 fl (p = 0.02)] than in the unexposed neonates, while the reticulocyte count was lower in the HIV-exposed neonates compared with the unexposed ones [0.9 ± 1.4% vs. 2.5 ± 2.9%, (p = 0.001)].
Table 2.
Hematological parameters of HIV-exposed neonates at birth (0–72 h) compared with controls
| Parameters | HIV exposed | HIVunexposed | Meandifference | 95% confidence interval of the mean difference | p value |
|---|---|---|---|---|---|
| N = 63 | N = 63 | ||||
| Mean (SD) | Mean (SD) | ||||
| Hb (g/dl) | 14.1 ± 2.4 | 15.4 ± 2.3 | − 1.2 | − 2.1 to −0.4 | 0.003 |
| Hct (%) | 41.2 ± 6.6 | 44.3 ± 6.2 | − 3.2 | −5.4 to −0.9 | 0.007 |
| MCHC (g/dl) | 35.5 ± 2.7 | 35.3 ± 1.9 | 0.2 | −0.6 to 1.1 | 0.622 |
| MCV (fl) | 101.9 ± 17.4 | 95.9 ± 11.2 | 5.9 | 0.7 to 11.1 | 0.024 |
| Reticulocytes (%) | 0.9 ± 1.4 | 2.5 ± 2.9 | −1.6 | −2.4 to –0.8 | 0.001 |
| WBC × 109/l | 8.5 ± 3.9 | 13.1 ± 5.1 | −4.5 | −6.13 to −2.9 | 0.001 |
| ANC × 109/l | 3.2 ± 2.3 | 7.1 ± 4.2 | − 3.9 | −5.1 to −2.9 | 0.001 |
| Lymphocyte × 109/l | 5.1 ± 2.4 | 5.6 ± 2.3 | −0.6 | −1.43 to 0.2 | 0.16 |
| Eosinophil × 109/l | 0.2 ± 0.2 | 0.1 ± 0.2 | 0.1 | −0.0 to 0.1 | 0.17 |
| Basophils × 109/l | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.0 | −0.0 to 0.0 | 0.15 |
| Monocyte × 109/l | 0.1 ± 0.1 | 0.1 ± 0.2 | − 0.1 | −0.1 to −0.0 | 0.01 |
| Platelets × 109/l | 282.5 ± 114.8 | 172.9 ± 70.2 | 109.6 | 76.0 to 143.2 | 0.001 |
The total respective white blood cell (WBC) count and the absolute neutrophil count (ANC) for the exposed and unexposed neonates were [8.5 ± 3.9 × 109/l vs. 13.1 ± 5.1 × 109/l (p = 0.001)] and [3.2 ± 2.3 × 109/l vs. 7.1 ± 4.2 × 109/l (p = 0.001)], respectively. The mean platelet count was 282.5 ± 114.8 × 109/l in the exposed neonates compared with 172 ± 70.2 × 109/l in the controls (p = 0.001); Table 2.
The Hb concentration in the neonates whose mothers were on HAART was 14.0 ± 2.4 g/dl compared with 14.4 ± 2.6 g/dl (p = 0.5) in those whose mothers were exposed to zidovudine. The Hct level in HAART group was 40.7 ± 6.4% compared with 42.7 ± 7.1% (p = 0.4) in the zidovudine group; Table 3. An MCV value of 105.3 ± 12.5 fl was seen in the HAART group compared with 94.7 ± 23.8 fl (p = 0.02) in those exposed to zidovudine.
Table 3.
Mean haematological values at birth of neonates whose mothers received HAART compared with those whose mothers received zidovudine monotherapy
| Parameters | HAART | Zidovudine | Mean difference | 95% confidence interval of the mean difference | p value |
|---|---|---|---|---|---|
| N = 43 | N = 20 | ||||
| Mean (SD) | Mean (SD) | ||||
| Hb (g/dl) | 14.0 ± 2.4 | 14.4 ± 2.6 | −0.4 | −1.7 to 0.9 | 0.51 |
| Hct (%) | 40.7 ± 6.4 | 42.7 ± 7.1 | −1.4 | −4.9 to 2.2 | 0.42 |
| MCHC (g/dl) | 35.7 ± 2.9 | 35.2 ± 2.3 | 0.5 | −1.0 to 1.9 | 0.50 |
| MCV (fl) | 105.3 ± 12.5 | 94.7 ± 23.8 | 10.6 | 4.6 to 1.5 | 0.02 |
| Reticulocytes (%) | 0.9 ± 1.5 | 0.8 ± 1.2 | 0.2 | −0.6 to 0.9 | 0.6 |
| WBC × 109/l | 7.8 ± 2.8 | 9.9 ± 5.3 | −2.2 | −4.2 to −0.1 | 0.03 |
| ANC × 109/l | 2.8 ± 1.8 | 4.2 ± 3.1 | −1.4 | −2.6 to −0.2 | 0.02 |
| Lymphocyte × 109/l | 4.7 ± 1.8 | 5.7 ± 3.3 | −0.9 | −2.6 to 0.7 | 0.13 |
| Eosinophil × 109/l | 0.2 ± 0.2 | 0.2 ± 0.2 | −0.1 | −0.2 to 0.1 | 0.31 |
| Basophils × 109/l | 0.0 ± 0.0 | 0.0 ± 0.0 | −0.0 | −0.0 to 0.0 | 0.49 |
| Monocyte × 109/l | 0.06 ± 0.09 | 0.08 ± 0.12 | −0.02 | −0.07 to 0.04 | 0.46 |
| Platelets × 109/l | 279.4 ± 113.7 | 289.4 ± 119.7 | −9.9 | −72.55 to 52.5 | 0.75 |
The total WBC count and the ANC in the HAART group were 7.8 ± 2.8 × 109/l and 2.8 ± 1.8, respectively, while in the zidovudine group, they were 9.9 ± 5.3 × 109/l and 4.2 ± 3.1 × 109/l, respectively; Table 3.
Neonates whose mothers had received ARV for < 1 year, had a mean MCV value of 95.8 ± 22.7 fl compared with 105.4 ± l2.6 fl in those with maternal treatment for > 1 year. The respective mean values of total WBC and ANCs for maternal drug treatment of <1 year or ≥1 year were 9.9 ± 4.9 × 109/l and 4.2 ± 3.1 × 109/l and 7.7 ± 2.8 × 109/l and 2.7 ± 1.6 × 109/l; Table 4.
Table 4.
Mean hematological values of HIV-exposed infants at birth according to duration of ART in their mothers
| Parameters | Use of ART for <1 year | Use of ART for ≥1 year | Mean difference | 95% confidence interval of the mean difference | p value |
|---|---|---|---|---|---|
| N = 22 | N = 41 | ||||
| Mean (SD) | Mean (SD) | ||||
| Hb | 14.3 ± 2.5 | 14.1 ± 2.4 | 0.2 | − 1.1 to 1.5 | 0.77 |
| Hct (%) | 41.7 ± 6.7 | 40.8 ± 6.6 | 0.9 | −1.6 to 4.4 | 0.62 |
| MCHC (g/dl) | 35.1 ± 2.1 | 35.8 ± 2.9 | −0.74 | −2.2 to 0.7 | 0.33 |
| MCV (fl) | 95.8 ± 22.7 | 105.4 ± 12.6 | −9.6 | −18.5 to –0.8 | 0.03 |
| Reticulocytes (%) | 0.9 ± 1.5 | 0.9 ± 1.4 | 0.0 | −0.7 to 0.8 | 0.82 |
| WBC × 109/l | 9.9 ± 4.9 | 7.7 ± 2.8 | 2.3 | 0.3 to 4.2 | 0.02 |
| ANC × 109/l | 4.2 ± 3.1 | 2.7 ± 1.6 | 1.5 | 0.3 to 2.7 | 0.01 |
| Lymphocyte × 109/l | 5.6 ± 3.3 | 4.7 ± 1.7 | 0.9 | −0.3 to 2.2 | 0.12 |
| Eosinophil × 109/l | 0.2 ± 0.3 | 0.2 ± 0.2 | 0.1 | −0.5 to 0.2 | 0.25 |
| Basophils × 109/l | 0.0 ± 0.0 | 0.1 ± 0.0 | 0.0 | −0.0 to 0.0 | 0.59 |
| Monocyte × 109/l | 0.1 ± 0.1 | 0.1 ± 0.1 | 0.0 | −0.0 to 0.1 | 0.46 |
| Platelets × 109/l | 282.7 ± 118.2 | 282.4 ± 114.2 | 0.3 | −60.2 to 60.9 | 0.99 |
DISCUSSION
Various hematological parameters in this study were significantly lower at birth in neonates who were exposed to ARVs in utero compared with those that were not. This finding is similar to the reports from France [15], Europe [19], USA [20], Germany [21], the Netherlands [22] and South Africa [23]. Though Schramm et al. documented higher basophil counts and percentage, it was not so in the present study. Few basophils were found in the peripheral blood of both exposed and unexposed neonates, and these cells are known to constitute <1% of circulating leukocytes in normal peripheral blood. Blood samples in both studies analyzed within the same time frame, so the likely cause of this difference is unknown. Taha et al. [24] did not find any difference between the parameters of the exposed neonates and the controls. This may be because of the short exposure to ARVs among mothers in their study. The lower mean Hb and Hct seen at birth in the index study as well as the low total WBC counts and ANC among the HIV-exposed neonates could be because of the effect of maternal drugs on the erythroid and myeloid cell lines as shown by other workers [25–28]. These drugs are known to suppress the pluripotent blood cell lines, with high impact on the WBC lines [29–30]. It has been demonstrated that fetal ARV drug blood level can be 50–100% of that of the mother.
There were no documented leukopenia and/or neutropenia, although the absolute values were still lower in the exposed neonates. Although Slogrove and colleagues [31] have shown that HIV-exposed uninfected children were two times more likely to be hospitalized for severe infections, the frequency of infections was not different among the groups. Bunders and co-workers [22] also reported that there was no increased risk of infection or antibiotic use among the exposed uninfected infants.
An expectedly higher mean MCV value was found in the exposed infants as was also demonstrated by other researchers [21]. It may be from the effect of zidovudine and /or zidovudine-based ART on the synthesis of heme protein, possibly by the inhibition of DNA polymerase [32]. The reports of researchers on the platelet counts are varied. While some reported low platelet counts [20, 25], others found no difference or even higher counts at birth between the exposed and unexposed infants [21, 22, 33]. This study found normal platelet count at birth in both groups, although the values were significantly higher in the exposed infants. Miguez-Burbano et al. [34] demonstrated thrombocytosis in a cohort of patients receiving ARV drug and suggested an immunological mechanism as a possible cause. This was buttressed by the inverse relationship between the platelet counts and the natural killer (NK) cells. The present study did not assay the plasma level of the NK cells, but the mechanism may not be far from the mechanism suggested by Miguez-Burbano et al. [34].
The combination of zidovudine and lamivudine (in HAART) appeared to have affected the myeloid precursors compared with zidovudine, as leukocyte counts were significantly lower in neonates who were exposed to maternal HAART. This is similar to the reports from other studies [22–24] but different from the findings of Bae and colleagues in Botswana [35], who noted similar parameters among neonates exposed to HAART and zidovudine, respectively. The difference between the index study and that done in Botswana may be difficult to explain, as both participants were exposed to maternal HAART for about the same duration. It is possible that the additive effect of all the three drugs contributed to the marked effect on some of the hematological parameters studied. Zidovudine therapy is known to cause bone marrow suppression, and although lamivudine is relatively safe, in combination with zidovudine can cause pure red cell aplasia [36].
The duration of ART in the mothers appeared to have had a significant impact on the ANC and total WBC count. Some workers have demonstrated a relationship between maternal hematological indices and those of their infants [37]. However, our inability to measure corresponding maternal hematological indices may limit the interpretation and hence is a limitation of the study.
CONCLUSION
In utero exposures to ARV drugs are associated with adverse effects on the hematological parameters (particularly the white cells), and these effects are more among the neonate exposed to maternal HAART.
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