AZT and Pregnant Women and Children

“Despite many unresolved physiopathological questions, there are coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to zidovudine [AZT], alone or in combination with lamivudine [3TC]. This effect may be transitory or persistent. Although, the clinical significance of the various biological and/or histopathological mitochondrial anomalies found at birth in NA-exposed animals or children has not been formally established, the high incidence of mitochondrial neurological diseases observed in the French cohort has not been contradicted to date in other cohorts.”

“Recently, we performed a study that examined HIV-1- infected children who began a combination of one or two NRTI [Nucleoside Reverse Transcriptase Inhibitors aka Nucleoside Analogs] plus efavirenz and nelfinavir. Of note, children receiving didanosine were found to have lower mitochondrial DNA to nuclear DNA ratios than children receiving other NRTI. However, of the five NRTI drugs that we evaluated, both in vivo and in vitro, zidovudine was one of the ones that had the least effect on mitochondrial DNA and RNA levels [Note that AZT is known to have a serious effect on mitochondria so this might mean that other drugs are worse].”

“ZDV [AZT] does not usually have any serious adverse effects in women or babies or children [no citation is given for this amazing statement]”

“you are justified in sounding a warning against the long-term therapeutic use of AZT, or its use in pregnant women, because of its demonstrated toxicity and side effects. Unfortunately, the devastating effects of AZT emerged only after the final level of experiments were well underway, that is the experiments which consisted of giving AZT to large numbers of human patients over a long period of time. Your effort is a worthy one…I hope you succeed in convincing your government not to make AZT available [Anthony Brink quoting Richard Belz, the first person to synthesize the drug AZT]”

“Zidovudine [AZT] administered during the perinatal period may result in a small but significant and durable effect on hematopoiesis [blood production] up to the age of 18 months.”

“An exhaustive study in a large prospective cohort with predetermined algorithm of the unexplained symptoms compatible with mitochondrial dysfunction. A total of 2644 of 4392 children were exposed to antiretrovirals…All the children with ‘established’ or ‘possible’ mitochondriopathy [mitochondrial damage] diagnosed in this study had been exposed to antiretroviral drugs. One of these children was treated with zidovudine [AZT] only during the prenatal period and received no treatment after birth…For the other children, the treatment was administered in the pre, per- and post-partum periods. It was zidovudine alone in five cases, a combination of zidovudine-lamivudine in 14 cases and another combination in one. 20 of the mothers received zidovudine by intravenous perfusion during labor.”

“children of HIV+ mothers are at risk for mitochondrial damage [mitochondria are the energy regulating organelles essential to every living cell, and that have their own DNA] that is further increased in infants of mothers receiving AZT during pregnancy”

“A total of 38 subjects were enrolled from June 1997 through June 1999 [1 was later excluded]…Zidovudine [AZT] was generally well tolerated in this high-risk population. The percent of patients who had selected adverse events is shown in Table II [32%-Anemia grade >=2; 11%-Neutropenia; 13%-Thrombocytopenia; 45%-Received transfusion; 26%-Received erythropoetin; 11%-HIV infection; 8%-Died] Slightly more than half of the subjects had anemia severe enough to require a transfusion [giving new meaning to the term 'well tolerated']…Three infants (8%) died at 3, 23, and 31 weeks of age. All 3 were born at <=26 weeks’ GA [gestation age] and each death was thought to be related to a complication of prematurity”

“The subjects were 37 infants [group C (C)] who were born to antiretroviral drug naïve HIV-1 infected mothers (MC) and 80 infants [group Z (Z)] who were born to HIV-1 infected mothers (MZ) that received a short-course ZDV [AZT] regimen…Of the whole cohort, there were 12 HIV-1 infected infants, seven in group Z [mothers were given AZT during pregnancy] (Z11, Z13, Z24, Z27, Z44, Z48, and Z51) and five in group C [mothers did not take AZT] (C3, C10, C13, C21, and C46)…The clinical category of all 12 infants was classified as EN [without any symptoms] at the age of 1–2 months. There were 6/12 (50%) infants who developed symptoms at the age 6 months. Of these rapid disease progression, five (83.3%) were infants in group Z [whose mothers used AZT] (Z11, Z24, Z44, Z48, and Z51) and one was in group C (C10). This revealed that more infants in group Z (5/7; 74%) than in group C (1/5; 20%) developed symptoms by 4–6 months (P=0.02). The clinical symptoms of these infected infants included oral thrush (4/6), dermatitis (1/6), splenomegaly [enlarged spleen] (5/6), hepatomegaly [enlarged liver] (5/6), and lymphadenopathy (3/6).”

“In univariate analysis, maternal peripartum zidovudine [AZT] had no effect on mortality up to day 230, but a negative effect beyond 8 months of age. Neonatal anaemia [quite possibly due to the maternal AZT], a diagnosis of HIV-1 infection on or before day 12 and between days 13 and 45, paediatric AIDS, a maternal CD4 lymphocyte count of less than 200/cubic mm, and a high maternal plasma viral load were risk factors for child death…The 18 month mortality rate in these HIV-1-infected children was 590 per 1000 in the zidovudine group and 510 per 1000 in the placebo group…The 18 month mortality rate in these HIV-uninfected children was 53 per 1000 in the zidovudine group and 78 per 1000 in the placebo group [meaning that AZT makes HIV-infected children sicker, but HIV-uninfected children healthier!]…11 of the 51 deaths of the HIV-1-infected children were attributed to a cause belonging to the AIDS clinical syndrome”

“In our study, we found a slightly higher risk for disease progression among ZDV[AZT]-exposed, HIV-infected children during the 18-month follow-up period [as compared to HIV-infected children whose mothers were given a placebo], although this difference was not statistically significant.”

“[Table 3 shows that congenital abnormalities occurred in 7% of infants when both mother and child had the long course of AZT (long-long), and only 1% when both had the short course (short-short). Neutropenia and leukopenia occurred in 7% of infants on the long-long course and 2% on short-short. Infections or other HIV-related events occurred in 43% on long-long and 33% on short-short. Neonatal or other obstetrical events occurred in 22% on long-long and only 14% on short-short. Number of deaths, severe anemia were similar (although severe anemia occurred significantly less (0%/1%) in the long-short and short-long treatment arms). Mothers who received the long AZT treatment had a higher rate of stillbirth (8% vs. 4%), severe anemia (7% vs 4%), infection or other HIV events (20% vs 17%), events related to pregnancy or delivery (24% vs 17%) than mothers who received the short course, although fewer died (3% vs 8%)]”

“Other factors associated with lower cumulative survival included suppressed CD4 cell counts, a history of zidovudine therapy [Table 1 shows that children who had taken AZT had a 37.5% risk of death over the study period versus 22.8% for those who had not. There was a 97% probability that this increase was not due to chance], and Pneumocystis carinii pneumonia diagnosed before the initial echocardiogram.”

“Infants with early positive HIV-1 cultures demonstrated a notable decrement in neurodevelopmental functioning within the first 30 months of life. They achieved motor developmental scores that were increasingly and significantly discrepant [worse] both from the average and from scores achieved by late HIV-1-positive children over the course of the study period. Those children with early HIV-1-positive cultures also demonstrated a trend toward a similar decline in mental functioning over time...The mothers of infants with early [HIV] positive cultures were more likely to receive ZDV [AZT] treatment during pregnancy, and their infants were more likely to receive ZDV treatment prophylactically during the first 6 weeks of life...Because antiretroviral therapy has been shown to improve neurodevelopmental function in children whose CNS has been affected by the HIV-1 virus...Infants with early HIV-1 culture positivity should be treated with multiple drugs with well-established CNS penetration to reduce the likelihood that resistance will develop in the CNS compartment [translation: this study showed that one drug may negatively affect neurological development, so multiple drugs must do the opposite!]”

“In a multicenter observational cohort study of 325 HIV-infected children born during 1986-1997, clinical progression was compared among infected children exposed or unexposed to Zdv [AZT] during prenatal and perinatal periods. Zdv exposure was associated with 1.8-fold (95% confidence interval, 1.02-3.11) increased risk of progressing to AIDS or death after adjusting for year of birth, maternal CD4 cell count, maternal AIDS diagnosis, and subsequent antiretroviral therapy of the child. Mean log10 viral copies at 712 weeks were higher among Zdv-exposed children (P = .004).”

“Children of study women who were prescribed ZDV [AZT] had increased adjusted odds of any anomaly (adjusted odds ratio [OR], 1.55; 95% CI, 1.01-2.29) [i.e. more than one-and-one-half times the risk of a birth anomaly than the HIV+ population being studied in general]...The prevalence of major anomalies in the full cohort based on definition 1 was significantly higher than that observed in the general New York State population...the SMR [Standardized Morbidity Ratio] adjusted for race, gender, and location suggests that the risk of a major anomaly in the study cohort was 2.79 times greater than the general population...the lack of data on potential adverse effects of this therapy is still a concern...we compared anomaly rates of subgroups defined by ZDV exposure history within the cohort of HIV-infected mothers. Babies whose mothers had ZDV exposure during pregnancy had a greater incidence of major malformations than those whose mothers did not.”

“The Antiretroviral Pregnancy Registry (APR), originally established in 1989 as the Zidovudine in Pregnancy Registry, was begun by the pharmaceutical industry, in conjunction with the U.S. Centers for Disease Control and Prevention, as a means of gathering sufficient data to measure incidence of structural anomalies in antiretroviral-exposed pregnancies. Despite its being an international registry, this effort had prospectively registered and closed only 392 ZDV monotherapy-exposed pregnancies by the end of 1997. Further, 20% of these were closed due to loss-to-follow-up, leaving only 317 pregnancies with data available for analyses.”

“Objective: To investigate zidovudine prophylaxis with caesarean section to reduce mother-to-infant HIV transmission. Interventions: Elective caesarean section before labour, usually at 36–38 weeks of gestation, plus a short oral course of zidovudine, normally starting at week 32, intravenous zidovudine before caesarean section and for 10 days for the neonate (the reduced Berlin regimen).

Results: Of 179 mother–infant pairs 104 received no antiretroviral prophylaxis or therapy (control group), 48 received the reduced Berlin prophylaxis regimen, 18 received combination therapy and nine received only part of the prophylaxis regimen. Of the antiretroviral group, 68 were delivered by elective caesarean section. The HIV transmission rate was zero in the antiretroviral group [95% confidence interval (CI) 0– 4.7] and 12.6% (6.4–19.0) in the control group. The reduction in vertical transmission was 90% for the Berlin regimen, with an 80 and 70% reduction in risk associated with antiretroviral treatment and caesarean section, respectively. Maternal CD4 cell count but not viral load had some confounding effect on the reduction in risk attributed to caesarean section and the prophylactic regimen. Neonatal haematological abnormalities associated with antiretroviral intervention lasted for up to 7 weeks. Weight and length, although significantly lower at birth, were normal by 6–8 weeks.

Conclusion: A much reduced three-arm regimen of zidovudine prophylaxis in combination with caesarean section before labour is highly effective in reducing the risk of vertical HIV transmission and is safe for the infant.”

“[Human Use of AZT] In the United States each year approximately 7000 pregnant women infected with the Human Immunodeficiency Virus (HIV-1) are treated with Highly Active Antiretroviral Therapy (HAART), either for their own disease or to inhibit maternal-fetal viral transmission. The HAART combinations of drugs typically include two nucleoside analogs and a protease inhibitor, and the nucleoside analogs zidovudine (AZT) and lamivudine (3TC) are used most frequently in combination in human pregnancy. Originally (1994) the CDC recommended that AZT be given orally for the last 6 months of pregnancy, by infusion to the mother during labor, and orally to the infant for the first 6 weeks, as standard-of-care for inhibition of vertical HIV-1 transmission.

[Animal Models]In 1997 AZT was reported to be a moderately-strong transplacental carcinogen in offspring of pregnant mice given the drug during the last week of gestation. Drug-induced tumor incidences in lung, liver, reproductive organs and skin from mice at 1 year of age were 2-8-fold higher than those observed in unexposed controls. Incorporation of AZT into nuclear and mitochondrial DNA (7.7-100.9 molecules AZT/106 nucleotides) of liver, lung and skin, and shortened telomeres in lung, brain and liver, were found at birth in mice exposed in utero to tumorigenic AZT doses. In addition, HPRT somatic mutation frequencies in spleen and thymus of similarly-exposed mice necropsied at 15 days of age increased in a dose-related fashion.

Subsequent modeling of human exposures in pregnant Erythrocebus patas monkeys, using human equivalent protocols for AZT or the combination AZT/3TC, demonstrated that full-term fetal monkey organs contained AZT-DNA levels higher than those found in the mouse tumor study. In addition, the combination of AZT/3TC, given for the last half of the patas monkey gestation, caused both drugs to become incorporated into fetal organ DNA and to shorten telomeres in almost every fetal organ examined. Based on animal studies and in vitro indicators of genotoxicity, the International Agency for Research on Cancer declared AZT a ‘possible human carcinogen’.

In order to explore transplacental nucleoside analog genotoxicity in human pregnancies we have examined cord blood leukocyte DNA from infants of HIV-1-infected women taking AZT or AZT/3TC. We found that 68% of infant cord blood leukocytes (n=22) were positive for AZT-DNA incorporation, with positive values ranging from 22 to 451 molecules of AZT/106 nucleotides In addition, a correlation was found between AZT-DNA incorporation and levels of intracellular AZT-triphosphorylated metabolite in cord blood leukocytes from 9 infants

Mutagenesis, presumed to be a consequence of AZT-DNA incorporation, was examined in infant cord blood leukocytes at the glycophorin A (GPA) and HPRT loci. The mean frequency of GPA N/N somatic mutant variants in umbilical cord blood erythrocytes was 2-3 fold higher in infants exposed in utero to AZT or AZT/3TC (n=27), compared to unexposed infants in the same study (n=30) or literature values for newborns (n=156). Infants exposed to AZT alone had half the induced N/N mutant frequency as infants exposed to the combination AZT/3TC (7).

The HPRT mutant frequency in cord blood lymphocytes of 66 unexposed children was half that of 37 children exposed to the combination of AZT/3TC, and sequence analysis indicated that the formation of single-base transversion substitutions was >2-fold higher in the treated group. HPRT mutant frequency increases with age in unexposed populations, and the mean mutant frequency of newborns in the AZT/3TC group was similar to that seen in adolescents, while ~30% of these infants had values comparable to adults. At 1 year of age, 30% of children exposed in utero to AZT/3TC (n=18) had HPRT mutant frequencies similar to values reported for children 6-17 years, while unexposed children (n=17) had mutant frequencies comparable to children < 6 years of age.

[Conclusions] Overall, the data indicate that children of HIV-1-infected women, exposed in utero to nucleoside analog drugs, may sustain significant genotoxic insult and should therefore be subjected to long-term surveillance”

“After adjusting for prematurity and maternal clinical characteristics, RPD [rapid disease progression] was three times more likely to occur in infants born to [mothers] treated [with AZT] compared with findings in untreated mothers (RR=2.8; p = .021).”

“All women [in this study] received oral zidovudine [AZT] prior to delivery and/or intravenous zidovudine at delivery...Of 42 subjects...24 had a CVL [cervicovaginal lavage] taken...Of these 24 women, 7 transmitted HIV-1 to their infants and 17 did not...In the CVL samples, 41% yielded culturable HIV-1, 67% were PCR positive for proviral HIV-1 DNA, 30% were positive for cell-free HIV-1 RNA and 45% were positive for cell-associated HIV-1 RNA. Peripheral CD4 cell counts did not correlate with levels of HIV-1 in the CVL by DNA or RNA PCR or by amount of genital tract inflammation...Although all subjects in our study received zidovudine therapy in the third trimester, the high rate (29%) of HIV-1 perinatal transmission in this data set does not agree with the largest prospective, randomized study addressing this question, ACTG 076 [in fact, this rate is higher than the transmission rate in the placebo arm of ACTG 076]”

“Eight children with mitochondrial dysfunction were found...the first patient presented with visual impairment...[and] died aged 13 months because of respiratory and cardiac-rhythm disorders...The second patient, from age 4 months until until death at 11 months, had refractory epilepsy and deterioration of cognitive and psychomotor abilities...At age 8 months...patient three had a seizure...At age 4 years, the child’s cardiac function was normal, but moderate muscular deficit persisted...In the fourth patient...between ages 14 and 27 months, the child had four episodes of febrile seizures...From age 7 months until 15 months, patient five had repeated seizures...at age 16 months...large necrotic lesions of the [brain]...At age 3-1/2 years the child had severe sequelae and microcephaly [abnormally small head]. Patient 6 was symptom-free until age 14 months, but persistent biochemical abnormalities were seen on standard follow-up...Patient 7 was symptom-free until age 4 months, at which time he became hypotonic [low muscle tone] [and stopped breathing]...The eighth child was symptom-free. Persistent hepatic and pancreatic abnormalities were seen from birth...At age 20 months, biological abnormalities persisted...electroretinography...was abnormal, and cerebral NMR imaging...showed abnormalities of the periventricular white matter...No child was infected with HIV-1 [but because their mothers were HIV-positive] all children were treated after birth with zidovudine [AZT] alone or with zidovudine and lamivudine [also a nucleoside analog]. Treatment continued for 6 weeks in four children and was stopped prematurely because of haematological or biochemical intolerance in four children...The observation of several cases [of mitochondrial abnormalities] in a population of about 1700 exposed children [as compared with 1/5,000 to 1/20,000 in normal populations] strongly suggests an acquired mitochondrial dysfunction...Pregnant women should be informed of the potential effects associated with these treatments during pregnancy.”

“The UK's Committee on Safety of Medicines has issued a warning to doctors about the risk of mitochondrial dysfunction in infants born to HIV infected mothers treated with zidovudine (AZT) to prevent vertical transmission...The warning comes in advance of the publication of data from a French study in which it was discovered that 8 out of approximately 200 infants developed mitochondrial dysfunction following exposure to zidovudine, with or without 3TC treatment, for the prevention of vertical transmission of HIV infection.”

“The data show that AZT crosses the human placenta and becomes rapidly incorporated into DNA of placental tissue in a dose-dependent fashion, suggesting that even short exposures to this drug might induce fetal genotoxicity and might also inhibit maternal-fetal viral transmission.”

“Incorporation of ZDV [AZT] into DNA was detected in most of the samples from ZDV-exposed adults and infants. Therefore, the biologic significance of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be further investigated in large cohorts of HIV-positive individuals.”

“Comparison of HIV-1-infected children whose mothers were treated with ZDV [AZT] with children whose mothers were not treated showed that the former group had a [1.8 times] higher probability of developing severe disease or severe immune suppression [2.4 times higher risk] and a lower survival (72.2% versus 81.0%).”

“transplacental exposure studies demonstrated that AZT is a moderate to strong transplacental carcinogen in mice...Since AZT-DNA incorporation in human placenta occurs rapidly by 2 hr of AZT perfusion, infants exposed to AZT even for short periods of time during gestation may sustain genotoxic damage. In previous studies AZT has been shown to produce both, large scale DNA damage and point mutations...the consequences of any fetal exposure to a nucleoside analog, in utero, remain unknown”

“…these two [HIV+ babies taking AZT+3TC] died of an extremely rare disease caused by genetic damage to the mitochondrial DNA - which is found in the cell body rather than in the nucleus with the genes. One died at 11 months and one died at 13 months, both from severe brain damage. Blanche [of the French medical research institute INSERM] told the meeting that there was no proof the drugs caused the damage. But he said there was also no evidence the babies had inherited abnormalities, and HIV drugs are known to cause mitochondrial damage.”

“At present, data regarding the effects of ZDV use on vertical transmission rates are inconclusive and incomplete. In addition, the long-term effects of ZDV use during pregnancy and after birth on the woman and any resulting child are yet to be discovered…the possibility has not yet been ruled out that this “risk-reducing” measure may not be effective and may prove detrimental to the health of both mother and child.”

“Conclusions: In HIV-infected pregnant women treated with two RTI [nucleoside analogs, of which AZT was the most common] with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies.”

“Similar levels of AZT-DNA incorporation were detected in peripheral blood from HIV-1-positive mothers and cord blood from their infants and tissues from newborn mice exposed to tumorigenic [cancer-causing] doses of AZT in utero. Therefore, the biologically effective dose (i.e. the amount of AZT that incorporated into DNA) was similar in both species even though the mouse daily dose of AZT was much higher than that received by humans.”

“We present two cases of severe PCP [pneumocystis carinii pneumonia] in infants who were perinatally exposed to HIV [and AZT] but who were uninfected with HIV…Both children had a transient decrease in their CD4 cell counts that was concomitant with the acute PCP episode…A survey of healthy 4-year-old children showed that the seroprevalence of PCP was ~67%. Thus, children with PCP usually have asymptomatic infection. It has been suggested that immunosuppression allows P. carinii to progress to serious disease. The two children described herein were not significantly immunosuppressed, and it is unclear if any of the recognized antecedents (a mother with AIDS and severe immunosuppression, zidovudine [AZT] treatment, and concomitant herpesvirus infection) set the stage for PCP”

“Anemia occurred in 22% of the infants who received zidovudine”

“The authors selected six patients who were HIV positive and who had requested termination of pregnancy to study the passage of zidovudine through the placenta...1 gram of zidovudine [AZT] was given in five doses of 200 mg each orally...At a mean age of 17.5 weeks [into the pregnancy], samples were taken from the mothers’ blood, from the amniotic fluid and from the fetal blood...The concentrations of [AZT] in the [amniotic fluid] and in the fetal blood were higher or equaled those found in the maternal blood...The drug remains contraindicated in pregnancy”

“Treatment of HIV-infected pregnant women with anti-HIV therapeutics may, therefore, inadvertently expose many uninfected and healthy fetuses to these maternally administered and potentially toxic drugs.”

“AZT and/or its metabolites were found in every [macaque ape] fetal tissue examined, including plasma and amniotic fluid. The greatest amount of AZT-derived compound was found in the fetal kidney,”

“Initiation of ZDV [AZT] therapy during pregnancy did not result in a significant decrease in viral load at delivery when controlling for the effect of pregnancy…Mother-to-child transmission of HIV-1 occurred in one of 27 (4%) ZDV-treated women and in two of 16 (12.5%) untreated women.”

“Six women (three in each group [AZT/placebo]) discontinued their treatment [with AZT] because of toxic effects. Thirty-five women (18 in the zidovudine group and 17 in the placebo group) had anemia of more than moderate severity, neutropenia, or thrombocytopenia, and 15 women (8 in the zidovudine group and 7 in the placebo group) had abnormalities of serum electrolytes and liver function of more than moderate severity. Toxic effects were defined according to standard toxicity tables modified for pregnancy and defined in the protocol. The majority of the adverse effects were judged to be related to labor and delivery. None of the mothers died during the study. [These numbers, particularly of anemia, are suspicious, as both pairs are 1 higher in the AZT group than placebo, especially given the known association of AZT with anemia]”

“In reviewing the frequency of birth defects in this population [of HIV+ women taking AZT during pregnancy] we noted eight birth defects (10%) out of 80 live births [and 8 spontaneous fetal losses, for a total of 17% abnormal pregnancies]”

“Treatment with trimethoprim-sulfamethoxazole and zidovudine [AZT] was started earlier and was more frequent among the 16 children born to mothers with class IV disease [AIDS]. At 18 months,…13 had received zidovudine [81%], as compared with…81…of the 130 children [62%] born to mothers with class II [HIV+, without symptoms] or III disease [swollen glands].”

“Children treated with zidovudine continued to have bacterial and opportunistic infections. The effect of the drug on the frequency of these events could not be assessed because of the lack of control groups...One or more episodes of hematologic toxicity occurred in 54 children (61 percent)—anemia (hemoglobin level, <75g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, <0.75X10^9 per liter) in 42 (48 percent)”

“The concentrations of the drug [AZT] in the liquor and in the fetal blood [of 6 aborted human fetuses] were higher or equaled those found in the maternal blood...The drug remains contraindicated in pregnancy.”