Sinha, Gita MD*; Choi, Tou J MBBS, MHS*; Nayak, Uma PhD*; Gupta, Amita MD, MHS*; Nair, Sandeep MPH†; Gupte, Nikhil MSc, PhD‡; Bulakh, Pandurang M MSc†; Sastry, Jayagowri MD, MPH‡; Deshmukh, Sanjay D MD§; Khandekar, Medha M MD†; Kulkarni, Vandana MSc‡; Bhosale, Ramesh A MD†; Bharucha, Kapila E MD∥; Phadke, Mrudula A MD¶; Kshirsagar, Anandini S MSc, PhD#; Bollinger, Robert C MD* ; on behalf of the Maternal Infant Transmission (MIT) Study in Pune, India
In India, more than 50% of pregnant women present for antenatal care with clinically significant anemia.1 Anemia in pregnancy is defined in India by a hemoglobin level <10 g/dL or loss of >25% of hemoglobin levels over the course of pregnancy.2,3 In India, similar to other resource-limited settings, anemia during pregnancy is attributed to iron and/or folate deficiency, plasma volume expansion, or acute blood loss.1 These factors have been linked to adverse birth outcomes, including preterm labor, low newborn birth weight, and fetal demise.4-7
Compared with HIV-negative women, HIV-positive women have higher rates of anemia, including during pregnancy.8-11 Many women in India are diagnosed with HIV during pregnancy and need appropriate therapy for prevention of maternal-to-child transmission (PMTCT) and effective continuing antiretroviral therapy.12,13 Similar to other established protocols, India's HIV treatment guidelines have endorsed using zidovudine for PMTCT.14,15
Zidovudine is known to cause and exacerbate anemia.16,17 Given the high background prevalence of anemia, it is unclear whether zidovudine could cause or exacerbate clinically significant anemia or associated adverse birth outcomes in HIV-positive pregnant Indian women, thereby limiting its initiation or continuing use.
The objectives of our study were to determine the prevalence of anemia, the characteristics of zidovudine initiation and use, and the subsequent anemia-related maternal delivery and newborn birth outcomes in HIV-positive pregnant women in India who present for antenatal care.
This study was conducted using data from antenatal care attendees enrolled in a PMTCT infant therapy trial conducted in Pune, India. Details of this trial can be accessed at www.clinicaltrials.gov using the identifier NCT00061321. Between August 16, 2002 and January 30, 2006, pregnant women presenting for antenatal care at Sassoon General Hospital, a large urban tertiary care government hospital in Pune, India, were screened for HIV and anemia. HIV-positive women with a serum hemoglobin level >7.5 g/dL and minimum gestational age of 28 weeks were enrolled in the parent trial.
All enrolled women were concurrently provided standard antenatal care and HIV PMTCT therapy according to Indian clinical guidelines, and their babies were subsequently randomized to PMTCT study therapies. At initiation of the parent PMTCT trial, Indian antenatal care guidelines included prescribing micronutrient supplements containing iron and folic acid to all pregnant women. Additionally, the guidelines endorsed administering single-dose nevirapine at delivery, with or without zidovudine, beginning at 36 weeks of gestational age. The endorsed zidovudine regiment was based on the short-course third-trimester zidovudine regimen demonstrated and used in Thailand as a feasible PMTCT regimen for resource-limited settings.18,19 All HIV-positive pregnant women were clinically evaluated for their eligibility to receive zidovudine as part of their PMTCT regimen. Exclusion criteria for zidovudine administration included gestational age <36 weeks, serum hemoglobin level <7.5 g/dL, uncontrolled hypertension and/or pre-eclampsia episodes, alanine aminotransferase level >120 IU/L, serum creatinine level ≥1.2 g/dL, obstetric complication history, history of disseminated intravascular coagulation, fetal abnormalities, history of alcohol or illicit drug use, benzodiazepine use, or voluntary refusal to take zidovudine.
The records of a subset of enrolled women with complete antenatal medication and laboratory records were assessed for zidovudine use, changes in hemoglobin level, CD4 cell count, maternal delivery-associated complications, and newborn birth outcomes, including hemoglobin level.
Assessment of HIV Status
HIV status was ascertained through voluntary counseling and testing using 2 previously validated rapid tests.20 Discordant results were re-evaluated with enzyme-linked immunosorbent assays (ELISAs) and Western blot assays. CD4 cell count was measured at enrollment into the study using standard flow cytometry methods.
Assessment of Zidovudine Use
Antenatal clinic patients who met clinical eligibility criteria and consented to receive zidovudine for PMTCT were prescribed the standard dose of 300 mg administered orally twice daily beginning at a minimum of 36 weeks of gestational age. Pharmacy dispensing records noted the number of tablets dispensed for each subject. To assess the total number of zidovudine doses administered, the number of tablets remaining at delivery was noted and the difference from the number dispensed was calculated. From this calculation, duration of zidovudine use was classified into <2 weeks and ≥2 weeks.
The time of enrollment in the study was defined as the calendar time from enrollment to delivery in days. During this period, all women, regardless of anemia status, were prescribed the micronutrient supplement Autrin (Wyeth/India, Mumbai, India), containing 300 mg of ferrous fumarate (conferring 30 mg of elemental iron per day), 1.5 mg of folic acid, and 15 μg of vitamin B12, according to Indian and international guidelines.21
Assessment of Anemia
Hemoglobin levels were measured at screening, at enrollment into the PMTCT trial, and within 2 weeks before or at delivery. Grade of anemia was categorized based on hemoglobin values as follows: severe anemia, <8 g/dL; mild to moderate anemia, 8 to 10 g/dL; and no anemia, >10 g/dL.
The primary endpoint for this analysis was hemoglobin value at delivery. The change in hemoglobin from enrollment to delivery was separately calculated for subjects who had both values available.
The analyses were focused on subjects presenting with mild to moderate anemia. This focus was chosen because women in India are more likely to present with this level of anemia and would be subject to consideration for zidovudine initiation, continuing use, and its effects.1 Additionally, the analysis excluded women who received zidovudine for <2 weeks and focused on comparing hemoglobin levels, maternal delivery outcomes, and birth outcomes for babies of women receiving zidovudine for ≥2 weeks compared with no zidovudine. This focus was chosen because zidovudine's dose-related clinically relevant effect on anemia is thought to occur after at least 2 weeks of daily dosing and/or in utero exposure.17
All comparisons were stratified by anemia category. The χ2 test was used for categoric data, and two-sample t testst test(s) used if possible. --> were used to compare continuous data. Group proportions within specific anemia categories were compared using 2-sample binomial testing. Statistical analysis was performed using SAS, version 9.1 (SAS Institute, Cary, NC).
Antenatal Screening for Anemia and HIV
A total of 24,105 women presented for antenatal screening, of whom 906 (3.8%) were HIV-positive (Table 1). HIV-positive women had lower mean hemoglobin values compared with HIV-negative women (10.47 vs. 10.73 g/dL, respectively; P < 0.01). Of the screened women, HIV-positive women were more likely to be anemic (hemoglobin <10 g/dL) compared with HIV-negative women (38.7% vs. 28.4%, respectively; P < 0.01). Thirty-six percent of HIV-positive women and 27% of HIV-negative women had mild to moderate anemia (hemoglobin value of 8-10 g/dL).
Zidovudine Use and Anemia Status
Of the 467 enrolled pregnant women with complete medication administration and laboratory test records, 232 (49.7%) received prenatal zidovudine with or without nevirapine. Initially, women who received any zidovudine were compared with women who received no zidovudine (Table 2). These 2 groups of women did not significantly differ in age, gestational age, or trimester at presentation for antenatal care; anemia prevalence at screening or enrollment; or maternal delivery or newborn birth outcomes. Compared with women who received zidovudine, women not receiving zidovudine were enrolled for a shorter duration in the study, received a shorter duration of concurrent micronutrient supplementation (24.8 vs. 40 weeks, respectively; P < 0.01), and had a higher prevalence of anemia at delivery (32% vs. 16.9%, respectively; P < 0.01). Preterm births, at <37 weeks of gestational age, were more prevalent among women not receiving zidovudine compared with women who did receive zidovudine (21% vs. 8%, respectively; P < 0.01). Additional reasons reported for the 235 women not receiving zidovudine included not meeting predefined clinical eligibility criteria based on abnormal laboratory values or obstetric complications (17%), lack of follow-up from study enrollment until onset of labor and delivery (11.5%), and voluntary refusal to take zidovudine (55%) (data not shown).
Of the 232 women receiving prenatal zidovudine, 96 (41%) received <2 weeks of zidovudine and 136 (59%) received ≥2 weeks of zidovudine. Women receiving ≥2 weeks of zidovudine were administered an average of 44 doses, whereas women receiving <2 weeks of zidovudine were administered an average of 13.7 doses.
Based on the association of clinically significant anemia with ≥2 weeks of zidovudine use, the analysis was focused on comparing women receiving ≥2 weeks of zidovudine with women receiving no zidovudine (Table 3). CD4 cell count and gestational age at screening did not significantly differ between women receiving ≥2 weeks of zidovudine compared with women receiving no zidovudine. Compared with women receiving no zidovudine, women receiving ≥2 weeks of zidovudine had similar mean hemoglobin values at screening and enrollment but higher mean hemoglobin values at delivery (11.8 vs. 11.3 g/dL, respectively; P = 0.02). Regardless of whether they received zidovudine, and regardless of their baseline anemia status at enrollment, all women had net increased hemoglobin levels from enrollment to delivery. Mild to moderately anemic enrolled women receiving ≥2 weeks of zidovudine had a significantly greater net increase in mean hemoglobin compared with anemic women receiving no zidovudine (1.26 vs. 0.60 g/dL; P = 0.04).
At screening and enrollment, women with mild to moderate anemia had comparable odds for receiving zidovudine for ≥2 weeks versus no zidovudine (see Table 3). At enrollment, there was no difference in the odds of anemic women receiving zidovudine versus no zidovudine for PMTCT. Of the 120 enrolled women with mild to moderate anemia, 29 (24.2%) were prescribed ≥2 weeks of zidovudine compared with 64 (53.3%) prescribed no zidovudine (odds ratio [OR] = 0.70, 95% confidence interval [CI]: 0.42 to 1.16; P = 0.70). Women who received ≥2 weeks of zidovudine were 70% less likely to subsequently show persistent or worsened anemia at delivery, however, compared with women receiving no zidovudine (P < 0.01).
Concurrent Anemia Treatment
All antenatal care attendees received concurrent micronutrient supplements containing iron and folic acid at initial presentation for antenatal care, in accordance with Indian guidelines. To assess the potential effect of micronutrient supplementation on zidovudine-associated anemia outcomes, we compared the duration of iron and folic acid supplementation in the different zidovudine treatment groups. Based on study enrollment duration, women who received ≥2 weeks of zidovudine received concurrent iron and folate for a longer duration compared with enrolled women who received no zidovudine (48 vs. 24.3 days, respectively; P < 0.01).
CD4 Cell Level and Anemia Status With Zidovudine Use
Because CD4 cell count is known to have an impact on anemia in HIV-positive pregnant women, we evaluated the association of zidovudine treatment on anemia outcome based on CD4 cell count category (data not shown). At enrollment, women with a CD4 count ≤200 cells/mm3 had a higher prevalence of anemia compared with women with a CD4 count >200 cells/mm3 (47.6% vs. 23.7%, respectively; P < 0.01). Anemic women with a CD4 count ≤200 cells/mm3 were as likely to receive zidovudine compared with anemic women with a CD4 count >200 cells/mm3. Of women who received ≥2 weeks of zidovudine, women with a CD4 count ≤200 cells/mm3 received a similar duration of micronutrient supplements for anemia compared with women with a CD4 count >200 cells/mm3 (45.1 vs. 48.3 days, respectively; P = 0.65). All women, regardless of CD4 cell count, had a net increase in serum hemoglobin from enrollment to delivery. At delivery, however, of women receiving zidovudine for ≥2 weeks, women with a CD4 count ≤200 cells/mm3 had a higher prevalence of anemia compared with women with a CD4 count >200 cells/mm3 (36.4% vs. 9.1%, respectively; P < 0.01) and were almost 6 times more likely to have anemia at delivery (OR = 5.71, 95% CI: 1.02 to 27.02; P < 0.01).
Women who received at least 2 weeks of zidovudine had lower rates of pallor at delivery and new-onset anemia at delivery compared with women receiving no zidovudine (Table 4). No women receiving zidovudine had delivery-related bleeding complications of postpartum hemorrhage or shock or required blood transfusion.
Newborn Birth Outcomes
Birth outcomes and anemia characteristics were compared for babies born to mothers receiving ≥2 weeks of zidovudine versus no zidovudine, excluding those with <2 weeks of zidovudine exposure. Babies born to mothers receiving ≥2 weeks of zidovudine had a mean gestational age of 39 weeks compared with 38 weeks for those receiving no zidovudine (P < 0.01). Babies born to mothers receiving zidovudine were almost 90% less likely to be preterm compared with babies born to mothers not receiving zidovudine (2.7% vs. 21%, respectively, OR = 0.11, 95% CI: 0.03 to 0.35; P < 0.01; see Table 4). Despite having lower hemoglobin values at birth, 2 weeks, and 4 weeks of age, babies of mothers receiving ≥2 weeks of zidovudine did not have clinically defined anemia at any of these time points. Babies of mothers receiving ≥2 weeks of zidovudine compared with no zidovudine did not differ in mean birth weight or proportion with low birth weight (see Table 4). One baby of a zidovudine-receiving mother had intrauterine growth retardation, and 1 was stillborn. Overall, there were no clinically significant complications in babies associated with maternal use of zidovudine.
This study confirms that HIV-positive pregnant women in an urban Indian setting present for antenatal care with more prevalent and higher grade anemia compared with HIV-negative Indian pregnant women. Mild to moderately anemic HIV-positive Indian women given zidovudine for PMTCT do not have persistent or worsened anemia, new-onset anemia, or maternal or infant birth complications at a higher frequency than women not receiving zidovudine, however.
In women presenting with mild to moderate anemia at enrollment, the zidovudine administration rate for ≥2 weeks was low (24.2%). Despite the low zidovudine initiation rate in mildly anemic women in this study, the subsequent trend in hemoglobin in these women shows that zidovudine does not seem to worsen or impede recovery from anemia. Strikingly, regardless of anemia status at enrollment, women who received ≥2 weeks of zidovudine had lower odds of anemia at delivery compared with women who did not receive zidovudine.
Compared with women not receiving zidovudine, women receiving ≥2 weeks of zidovudine had concurrent anemia treatment with iron and folic acid for longer periods. The continuing use of iron and folic acid in this Indian setting may help to explain how the high background anemia prevalence was mitigated over the course of antenatal care.
Several randomized trials of zidovudine use for PMTCT have demonstrated low levels of anemia toxicity and associated pregnancy outcomes in women and infants. Early PMTCT trials using zidovudine, including the Pediatric AIDS Clinical Trials Group (PACTG) 076 trial, demonstrated no significant long-term impact on maternal anemia or delivery outcomes.22,23 Subsequent trials in Africa and Thailand similarly demonstrated little impact of zidovudine on maternal anemia or its sequelae.24-27 Similar to our study, other zidovudine-containing PMTCT trials demonstrate that infants exposed to zidovudine in utero show lower hemoglobin levels compared with unexposed infants but that these declines do not persist or lead to adverse clinical outcomes.24-30
An important difference between this Indian study and prior zidovudine PMTCT trial populations includes the higher pretherapy anemia prevalence among Indian study participants. Although 26% of the Indian women had clinically significant anemia before initiating zidovudine PMTCT therapy, other trials document lower pretherapy anemia rates, including 15% of Thai women enrolled in a zidovudine/lamivudine PMTCT trial.28 This Indian study's pregnant HIV-positive population, even with a higher prevalence of pretherapy anemia, did not seem to have more frequent anemia outcomes or associated adverse effects on maternal delivery or newborn birth outcomes compared with other zidovudine PMTCT trial populations.
Another important distinction between this Indian study and prior zidovudine PMTCT trials is the use of a relatively short course of zidovudine for PMTCT, beginning at 36 weeks of gestational age, as endorsed at initiation of the parent PMTCT trial, rather than at 28 weeks of gestational age, which is the most recent 2006 Indian PMTCT guideline.15 It is important to note that most HIV-positive women in this Indian study were initially screened at <28 weeks of gestational age. Under current guidelines, they could have received zidovudine earlier in pregnancy. Continuing studies of anemia toxicity are necessary as Indian clinical practice shifts to earlier zidovudine administration for PMTCT.
A limitation of this study was that pregnant women were administered zidovudine based on clinical judgment and practice rather than being randomized for treatment allocation. The clinical judgment-based administration of zidovudine could lead to additional unobserved factors that influenced zidovudine administration and its associated outcomes. We noted that women not receiving zidovudine were enrolled in the study for shorter durations compared with women who did receive zidovudine. Although our data indicate that neither gestational age at initial presentation for antenatal care nor baseline anemia prevalence in this study was different between the 2 groups, factors that may have prevented administration of zidovudine to otherwise clinically eligible women included preterm delivery at <37 weeks of gestational age and lack of follow-up for pregnancy care until delivery, which led to missing the window of opportunity to enroll women at appropriate gestational ages into the study and, subsequently, to administer zidovudine for PMTCT.
Additionally, a significant proportion of otherwise clinically eligible women voluntarily refused zidovudine. Previous PMTCT feasibility studies conducted by the National AIDS Control Organization in India report that HIV-positive pregnant women refused zidovudine because they intended to complete their pregnancies at locations away from the antenatal care setting, such as their maternal home, or that they and/or their family members voluntarily refused the medication.31 In addition to these reasons, in this study, variability in clinical counseling regarding whether to use a short course of zidovudine in addition to single-dose nevirapine at delivery may have led otherwise eligible women to opt out of using zidovudine for their PMTCT regimen. Now that clinical guidelines discourage using single-dose nevirapine, and as clinical practice shifts to initiating zidovudine earlier in the Indian HIV-positive pregnant population, there may be factors other than anemia or other clinical factors, including continuity of antenatal care utilization, that influence the use of zidovudine for PMTCT, and its associated clinical outcomes. Although our study seems to illustrate some of these potential factors, further study is necessary to validate these initial findings.
This study had relatively small numbers of women with CD4 counts ≤200 cells/mm3. When CD4 cell count is taken into account, however, women with a CD4 count ≤200 cells/mm3 receiving ≥2 weeks of zidovudine had a higher prevalence of anemia at delivery compared with women with a CD4 count >200 cells/mm3. This may reflect the higher baseline anemia prevalence in HIV-positive pregnant women who present for antenatal care with a CD4 count ≤200 cells/mm3 and/or zidovudine impeding recovery from anemia in women with lower CD4 cell counts.
An additional limitation includes the fact that the subjects are all part of a research study-enrolled population, thereby limiting generalizing results to the community-based clinical setting. Even in this study, however, anemia management is based on clinical guidelines that also apply in the community. If such guidelines are followed, similar outcomes should be expected in the community setting. Additionally, the study lacks data regarding adherence to the concurrent micronutrient supplements. Although we internally validated zidovudine adherence by checking the reported duration of zidovudine administration pharmacy records-based tablet administration, we did not collect similar data for other medications.
Improvement in anemia in HIV-positive pregnant women receiving zidovudine may reflect efforts to treat other sources of anemia concurrently with micronutrient supplements. In the Indian community setting, compared with women in this study, HIV-positive pregnant women may present at later stages of pregnancy, later stages of HIV, and lower CD4 cell counts and with a higher frequency of clinically significant anemia. Screening for HIV and anemia as early as possible in pregnancy is important in this population. With early and continuing treatment for correctable anemia sources such as nutritional deficiencies, however, zidovudine can and should be initiated for PMTCT without major concern for worsening anemia or associated adverse outcomes.
The authors thank all the Johns Hopkins University-Byramjee Jejeebhoy Medical College Maternal Infant Transmission study participants and clinical staff.
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© 2007 Lippincott Williams & Wilkins, Inc.