Tuberculosis (TB) is a major cause of morbidity and mortality for HIV-infected persons [
A cohort of 1995 HIV-infected adults was enrolled at eight clinics located in Francistown and Gaborone, Botswana, from 2004 to 2006. Details of enrolment are provided elsewhere [
Severe hepatitis was defined as elevation of liver enzymes to >5 times the upper limit of normal. Severe rash was defined as generalized erythroderma, eruption, or desquamation covering ≥50% of body surface area. Adverse events were determined by a blinded, independent committee to be possibly, probably, definitely, or not associated with the study medication. We defined adverse pregnancy outcome (AO) as any of the following: preterm delivery (estimated gestational age (EGA) ≤37 weeks at birth), low birth weight (<2500 g), stillbirth (delivery of an infant with no signs of life at ≥28 weeks EGA), spontaneous abortion (spontaneous termination of pregnancy <24 weeks EGA), neonatal mortality (death of term infant within 28 days of delivery), or any noted congenital abnormality. We defined ART as therapy with ≥3 antiretroviral drugs from ≥2 classes provided for treatment of HIV disease. The pregnancy outcomes analysis included only the first-born infant of the first pregnancy experienced by women during the trial pregnancies completed by February 19, 2009, and only included women who registered for PMTCT.
We performed univariate, bivariate, and multivariable analysis to investigate associations between AO, isoniazid exposure, and ART exposure in pregnancy. Continuous variables were compared using
All participants provided informed consent. The protocol was approved by Botswana and Centers for Disease Control and Prevention (CDC) ethics committees. The trial was registered at
Seventy-two percent of the 1995 enrollees were female; their median age was 32 years; their median CD4+ count was 297 cells/mm3, and 47% initiated ART during the 36-month period of observation. Of the 1436 women in the study, 721 (50.2%) were randomized to 6 months of IPT; 715 women (49.8%) were randomized to 36 months of IPT. A total of 268 pregnancies were observed during the trial. We excluded 29 women who were still pregnant at the time the dataset was closed or who exited the trial prior to the end of pregnancy, 23 repeat pregnancies, and 20 women without PMCT regimen data, leaving a total of 196 pregnancies in the analysis dataset (98 per arm). Some participants received placebo after 6 months of IPT or stopped taking isoniazid while remaining under observation in the trial, resulting in some women not receiving isoniazid while pregnant. Of women in the 6-month isoniazid arm, 20 were exposed to isoniazid during pregnancy, and 39 were exposed to ART. Of women in the 36-month isoniazid arm, 83 were exposed to isoniazid in pregnancy, and 34 were exposed to ART.
Overall, 103/196 (52.6%) women were exposed to isoniazid during some part of pregnancy, with 102 beginning in the first trimester, and 68% of these women had continuing exposure throughout pregnancy (Table
Selected characteristics of subjects experiencing pregnancy during the Isoniazid Preventive Therapy Trial, Botswana, 2005–2008 (
No. | % or range | |
---|---|---|
Characteristic ( |
||
Age (median, range) | 28 | 19–39 |
CD4+ lymphocyte count nearest LNMP (median, range) in cells/mm3 | 368 | 41–1231 |
CD4+ lymphocyte count near LNMP <200 cells/mm3 | 31 | 16% |
Maternal BMI (median, range) | 22.9 | 15.6–36.2 |
Maternal BMI <18.5 near LNMP | 17 | 19% |
Pregnancy outcome date range | Nov 26 2005 to Feb 19 2009 | |
Antiretroviral regimen in Pregnancy | ||
Antiretroviral therapy (≥3 drugs from ≥2 classes) | 73 | 37% |
AZT or AZT/3TC only | 123 | 63% |
| ||
Antiretroviral therapy exposure ( |
||
Number of women on ART prior to pregnancy | 47 | |
Time on ART before pregnancy (median, range) in days* | 347 | 21–2221 |
Timing of ART exposure during pregnancy | ||
First, second, and third trimesters | 45 | |
First and second trimesters only | 7 | |
Second and third trimesters only | 8 | |
Third trimester only | 8 | |
Timing unknown | 5 | |
| ||
Isoniazid exposure ( |
||
Time on isoniazid before pregnancy (median, range) in days | 341 | 1–1095 |
Exposed to isoniazid in pregnancy | ||
First trimester only | 11 | 11% |
First and second, trimesters only | 21 | 20% |
First, second, and third trimesters | 70 | 68% |
Second trimester only | 1 | 1% |
Any trimester (total) | 103 | 100% |
| ||
Pregnancy outcome ( |
||
Live birth | 124 | 63% |
Stillbirth | 11 | 6% |
Spontaneous (“inevitable”) abortion | 6 | 3% |
Neonatal death | 4 | 2% |
Premature | 42 | 21% |
Term low birth weight | 8 | 4% |
Congenital abnormality | 1 | 1% |
Maternal death | 0 | 0% |
3TC: lamivudine; ART: antiretroviral therapy; AZT: zidovudine; BMI: body mass index; IPT: isoniazid preventive therapy; LNMP: last normal menstrual period.
*Among women with ART start date prior to LNMP (
All women were exposed to antiretroviral drugs during pregnancy: 73 (37%) received ART, and the remainder received either short-course zidovudine (121) or zidovudine/lamivudine (AZT/3TC) (2). Of 73 women receiving ART during pregnancy, the most (64/73, 88%) received AZT/3TC and nevirapine; 3 received lopinavir/ritonavir-based regimens; 6 received other combinations. Women taking ART had significantly lower CD4+ T-cell counts than those taking short-course prophylaxis (median CD4+ count 239 versus 452, Wilcoxon rank-sum
Two pregnant women developed TB symptoms during their pregnancies. One started anti-TB treatment 3 months after having a live birth, and the other initiated anti-TB treatment a month after her LNMP and sustained a stillbirth 7 months later. Both successfully completed standard 6-month anti-TB treatment.
Final outcomes of the 196 pregnancies were 124 (63%) term live births; 42 (21.4%) premature deliveries, 8 (4%) low-birth-weight term infants, 11 (6%) stillbirths, 6 spontaneous abortions (3%), 4 neonatal deaths (2%), and 1 congenital abnormality (talipes equinovarus, Table
In bivariate analysis (Table
Association between adverse pregnancy outcomes and isoniazid and/or antiretroviral therapy during pregnancy in HIV-infected women, Isoniazid Preventive Therapy Trial, Botswana, 2005–2008 (
Characteristic | Adverse outcome |
No adverse outcome |
uOR | 95% CI | aOR | 95% CI |
---|---|---|---|---|---|---|
Isoniazid exposure in pregnancy | ||||||
Yes | 32 (31.1) | 71 (68.9) | 0.6 | 0.3–1.1 | 0.6 | 0.3–1.1 |
No | 40 (43.1) | 53 (57.0) | 1.0 | 1.0 | ||
Antiretroviral therapy regimen in pregnancy | ||||||
Antiretroviral therapy (≥3 drugs from ≥2 classes) | 34 (46.6) | 39 (53.4) | 2.0 | 1.1–3.5 | 1.8 | 0.9–3.6 |
Zidovudine or zidovudine/lamivudine only | 38 (31.0) | 85 (69.1) | 1.0 | 1.0 | ||
Maternal CD4+ lymphocyte count nearest LNMP | ||||||
<200 cells/mm3 | 13 (41.9) | 18 (58.1) | 1.3 | 0.6–2.8 | 1.0 | 0.4–2.5 |
≥200 cells/mm3 | 59 (35.8) | 106 (64.2) | 1.0 | 1.0 | ||
Maternal BMI near LNMP | ||||||
Underweight <18.5 | 9 (52.9) | 8 (47.1) | 2.0 | 0.7–5.5 | 2.4 | 0.8–7.1 |
Not underweight ≥18.5 | 63 (35.8) | 113 (64.2) | 1.0 | 1.0 | ||
Maternal age (years) | — | — | 1.1 | 1.0–1.1 | 1.1 | 1.0–1.2 |
BMI: body mass index; aOR: adjusted odds ratio (adjusted for all variables shown); CI: confidence interval; uOR: unadjusted odds ratio; LNMP: last normal menstrual period.
In a multivariable model including all variables in Table
We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in 103 women receiving isoniazid during pregnancy and/or immediately postpartum. Generally, isoniazid hepatitis occurs in the first months of treatment, as it did in the Botswana clinical trial [
Extensive use of isoniazid during pregnancy has indicated that although it readily crosses the placental barrier, the drug is not teratogenic even when given during the first trimester [
In this study we did not observe increased odds of adverse pregnancy outcomes among women receiving ART in pregnancy compared to women receiving short-course antiretroviral regimens. Previous studies offered mixed evidence of such an association. Studies from Europe found an association between ART (especially with protease inhibitor-based ART) exposure in pregnancy and preterm delivery [
This study provided a unique opportunity to examine pregnancy in the context of long-term INH exposure. Chief among its limitations was the small sample size, which limited the power of the study. Also, as antiretroviral medication use was not randomized, we were unable to rule out the existence of unmeasured confounders in our analysis of antiretroviral use and AO.
In summary, long-term prophylaxis with IPT appeared to be safe in this small secondary analysis, even when pregnancy was experienced by HIV-infected women during therapy and was not associated with adverse pregnancy outcomes.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.