Combination antiretroviral therapy in 100 HIV-1-infected pregnant women

A.M. Bucceri1,3, E. Somigliana1, R. Matrone1, G. Ferraris2, G. Rossi1, E. Grossi1 and M. Vignali1

1 II Department of Obstetrics and Gynecology, and 2 Cattedra di Patologia Neonatale, Clinica L. Mangiagalli, University of Milan, Milano, Italy


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
BACKGROUND: In recent years, combination antiretroviral therapy has substantially improved the prognosis of human immunodeficiency virus type-1 (HIV-1) infection. However, at present, information regarding the effects of these regimens during pregnancy is limited. METHODS: Side-effects, vertical transmission rate and neonatal outcome associated with different combination therapies were evaluated retrospectively in a consecutive series of 100 women who attended the II Department of Obstetrics and Gynecology for the management of HIV-1 infection in pregnancy. RESULTS: Antiretroviral treatment was initiated at a median of 16 weeks gestation with a range from pre-pregnancy until 31 weeks gestation. Twentythree women continued their pre-pregnancy therapy during the first trimester of gestation. Protease inhibitors were incorporated in 23 of the final therapeutic regimens. Twentyfive women did not receive zidovudine. Most women (97) delivered by Caesarean section and none breast-fed. Prematurity rate for the entire series was 19%. When women who actively used illicit drugs were excluded, only seven of 69 (10%) women were found to deliver prematurely. The use of protease inhibitors was limited by an elevated frequency of severe gastrointestinal disturbances. The rate of congenital malformations did not appear to differ significantly from that reported in the literature for the general population. Only one of 102 live newborns was found to be HIV-1-infected (1.0%, 95% confidence interval; 0.3–4.6%). CONCLUSIONS: The present findings confirm the remarkable efficacy of combination antiretroviral therapy, Caesarean section and refraining from breast-feeding in lowering the rate of vertical HIV-1 transmission. Moreover, they are suggestive that combination antiretroviral therapy may not be related to major neonatal toxicity. The necessity to discontinue the therapy during the first trimester of pregnancy and to systematically incorporate zidovudine into combination regimens is discussed.

Key words: combination antiretroviral therapy/HIV-1/pregnancy/vertical HIV-1 transmission


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Risk of mother-to-child transmission of human immunodeficiency virus type-1 (HIV-1) can be reduced by prophylactic zidovudine use during pregnancy, delivery and in the neonatal period, by elective Caesarean section and by avoiding breast-feeding (Stringer et al., 1999Go; Cohen, 2000Go). The combination of these three interventions has been accompanied by a remarkable decline in perinatal transmission rate in industrialized countries (The International Perinatal HIV Group, 1999). However, simultaneously to the establishment of these obstetrical measures aimed to prevent vertical transmission of the virus, in recent years, substantial advances have been made in the general treatment of HIV-1 disease (Gulick et al., 1997Go; Palella et al., 1998Go). Specifically, such progress has resulted in changes in standard antiretroviral therapy so that, nowadays, more aggressive combination drug regimens are recommended (Centers for Disease Control and Prevention, 1998Go). Therefore, at present, the zidovudine monotherapy, which is highly recommended to prevent vertical transmission during pregnancy, is considered suboptimal for treatment of the disease. Moreover, considering the potential benefit of the current standard antiretroviral therapies in term of maternal health, pregnancy should not preclude the use of these regimens. In this context, it is not surprising that a consistent number of women are now taking combination therapy during pregnancy (Fiscus et al., 1999Go).

However, information regarding the effects of combination antiretroviral therapies during pregnancy is limited (Lorenzi et al., 1998Go; McGowan et al., 1999Go; O'Sullivan et al., 1999Go; Stek et al., 1999Go; Morris et al., 2000Go; Mandelbrot et al., 2001Go). Although these combined regimens seem to be highly efficacious in preventing vertical transmission of the virus, questions remain regarding their potential adverse effects. In particular, exposure to antiretroviral therapy in fetal and/or early life has been suggested to be associated with an increased risk of premature delivery (Lorenzi et al., 1998Go; European collaborative study and the Swiss Mother + Child HIV Cohort Study, 2000Go) and, in rare cases, with mitochondrial abnormalities (Blanche et al., 1999Go). Furthermore, evidence is lacking regarding appropriate timing of initiation of these therapies, specific drugs to be used and whether prophylactic Caesarean delivery may be considered a protective adjunct in preventing vertical transmission of HIV-1.

In this study, we report a series of 100 consecutive pregnant women who received combination therapy. Side-effects during pregnancy, vertical transmission rate and neonatal outcome are analysed and discussed.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
During a 45 month period, from January 1998 to September 2000, records of all women who attended the II Department of Obstetrics and Gynecology, Clinica L. Mangiagalli for the management of HIV-1 infection in pregnancy were reviewed. The results of this examination led to the identification of 100 women who had delivered by September 30, 2000 and who were treated with combination antiretroviral therapy. During this same period five patients received zidovudine monotherapy after they refused combination regimens. The known and unknown short- and long-term benefits and risks of antiretroviral therapy, of elective Caesarean section and breast-feeding were always discussed with the patient.

According to the protocol used in our department, antiretroviral-naive women whose immune system is not severely compromized are prescribed zidovudine-lamivudine combination unless the drug is not indicated. The efficacy of this combination in lowering viral load and improving outcome in HIV-infected patients is well established (Mandelbrot et al., 2001Go). On the other hand, a comprehensive and personalized approach taking into consideration clinical findings, biochemical parameters (viral load, number of CD4 cells) and the pharmacological history (drug resistance, side-effects) is used for antiretroviral-experienced patients. The opportunity to introduce zidovudine in regimens which did not include this agent was always carefully evaluated and discussed with the women. Laboratory and clinical data were extracted from detailed patients' charts. Abstracted data included demographic information; medical and obstetrical history; previous antiretroviral treatment; AIDS-defining conditions before and during index pregnancy; illicit drug and/or methadone use; clinical events and abnormal laboratory values (complete blood biochemical evaluation was performed every 4–6 weeks); detailed information regarding prenatal, intrapartum and newborn antiretroviral treatment; other non-antiretroviral concomitant treatments; plasma maternal CD4 cell count and HIV-RNA viral load; and breast-feeding. Moreover, data extracted from newborn charts included gestational age at delivery, Apgar score, weight, height, head circumference, adverse clinical events; results from newborn HIV-1 DNA polymerase chain reaction (PCR) assays.

Elective Caesarean section was defined as an abdominal delivery performed before the onset of labour and/or rupture of membranes. This procedure was performed to prevent HIV-1 transmission and/or for obstetrical reasons. Preterm birth was defined as the birth of an infant before 37 completed weeks gestation. Gestational age at delivery was based on the last menstrual period if the last menstrual period and findings at first ultrasonographic assessment agreed within 10 days. If not, the earliest ultrasonographic measurement was used to define the gestational age. Antiretroviral therapy failure was defined as one of the following: viral load was not efficiently suppressed within 4–6 months of initiating therapy, there was an unexplained increase in viral load after initial suppression or a persistently declining CD4 cell count.

After delivery, all newborns were examined in the Neonatology department by a neonatologist. Zidovudine prophylaxis to the newborn was prescribed only if the antiretroviral therapy failed and/or the mother delivered before 34 weeks gestation. The decision not to routinely administer zidovudine to the newborn was based on the lack of data about the long-term effects of the treatment and has been previously discussed (Zuccotti et al., 1999Go). Small for gestational age at birth was defined as newborn birth weight <10th percentile for gestational age according to the normogram employed in our clinic (Società Italiana di Neonatologia, 1996Go). The surveillance protocol consisted of transfontanellar cerebral echography, cardiological evaluation, ultrasonography of the abdomen (including liver, pancreas, gallbladder, kidneys and bladder), specialistic evaluation of audiological and oculistic functions, cytomegalovirus (CMV) saliva and urine samples and assessment of plasma glucose, haemoglobin, haematocrit, bilirubin and calcium. The infants were evaluated according to this protocol during the first week of life. A child who had a positive culture of urine and/or saliva at birth or a positive PCR result on urine at a later age was considered CMV-infected (Kovacs et al., 1999Go). PCR for HIV-1 DNA was performed on peripheral blood mononuclear cell obtained from each newborn within 48 h of birth, and at 2, 3 and 6 months of age. Infants were said to be uninfected when two negative HIV-1 PCR test results were available with at least one of them being at >=3 months of age.

Data are expressed as median and range or as mean ± SD. Differences were determined by paired Student's t-test, Wilcoxon signed-rank test or {chi}2 test as appropriate. Probability < 0.05 was considered as statistically significant. A binomial probability distribution model was used to calculate the 95% confidence limits of the vertical transmission rate of HIV-1.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Baseline characteristics of the 100 patients who received combination antiretroviral therapy are shown in Table IGo. Eighteen women had previously delivered 21 HIV-1-exposed newborns; two of them were HIV-1-infected. Forty-six patients were antiretroviral-naive and 43 were receiving therapy when they became pregnant. In this latter group, 20 women (47%) decided to discontinue the therapy as soon as they became aware of pregnancy. The remaining 23 women continued their previous treatment during the first trimester of pregnancy (Table IIGo).


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Table I. Characteristics of the 100 HIV-infected women who received combination antiretroviral therapy during pregnancy
 

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Table II. First trimester and pre-delivery antiretroviral therapy combinations
 
The median (range) time of combination antiretroviral therapy during pregnancy for the entire cohort was 21 (4–36) weeks. These regimens were initiated at a median of 16 weeks gestation with a range from pre-pregnancy until 31 weeks. They were modified in 18 women during pregnancy because of therapeutic failure (eight), prior decision to use a zidovudine-containing regimen (two) and unacceptable side effects (eight). Specifically, in this last group, six out of 27 women who initially received protease inhibitors discontinued their use because of gastrointestinal disturbances. Final combination antiretroviral therapies are listed in Table IIGo. Forty out of 46 (87%) antiretroviral-naive women received zidovudine-lamivudine combination. Nine out of the 23 AIDS-affected women received a regimen including at least one protease inhibitor agent (Table IGo). Twenty-five final regimens did not include zidovudine. The reasons for this therapeutic choice were treatment failure and unacceptable side-effects during pre-pregnancy use of zidovudine in 18 and two women respectively. Moreover, three patients had severe anaemia before initiation of therapy and were therefore considered not eligible for zidovudine use. Thus, these 23 women did not receive this drug at all during pregnancy. Finally, two subjects discontinued zidovudine use during pregnancy because severe anaemia developed.

In two women, AIDS-defining conditions developed during pregnancy: one had clinical cytomegalovirus chorioretinitis and pancitopenia and the second had Candida esophagitis. Moreover, four cases of bacterial pneumonia, six cases of oral candidiasis, five cases of recurrent symptomatic genital herpes, eight cases of diffuse genital warts, one case of dorsal herpes zoster and one case of severe facial herpes simplex infection were observed. Anaemia (haemoglobin <10 g/dl) was detected in 24 women; in six of them haemoglobin levels were <8 g/dl. Persistent elevated serum liver transaminases were observed in 13 women and were presumed to be related to exacerbation of hepatitis C virus infection in 11 cases and to intrahepatic cholestasis of pregnancy in two cases. However, it cannot be excluded that liver toxicity of reverse transcriptase inhibitors may also play a role in determining the increase of serum liver transaminases in these patients. Finally, three cases of hypertensive disorders, three cases of renal colic, two cases of placenta previa and one case of intrauterine death at 24 weeks gestation were observed. This latest patient received zidovudine-lamivudine-nelfinavir from 14 weeks gestation; no important abnormalities were observed at autopsy.

In those women in whom data were available, an increase in CD4 cell count and a decline in HIV-1 viral load were observed throughout pregnancy (Table IIIGo).


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Table III. Maternal immunological and virological data
 
Most women (97) delivered by Caesarean section and only three by normal spontaneous delivery. Specifically, 72 underwent elective prophylactic Caesarean section whereas 25 had a non-elective Caesarean; in 18 of these latter women, surgery was performed due to spontaneous preterm labour (in five cases Caesarean was performed after premature rupture of membranes). None of the mothers breast-fed. There were no maternal deaths. Considering that, in this series, there were three twin pregnancies and one intrauterine death, information was available on 102 newborns. Infant outcomes are shown in Tables IV and VGoGo. Only two infants were born before 32 completed weeks gestation. Protease inhibitors did not seem to display a major effect on prematurity as six of 21 women in this group delivered before 37 weeks gestation compared with 12 out of 75 in the group of patients who received only reverse transcriptase inhibitors (P = not significant). Nine of these 102 infants received prophylactic zidovudine for the first 6 weeks of life. Opiate withdrawal syndrome was observed in 19 out of the 27 infants who were born to active illicit drug and/or methadone users. In regard to congenital malformations, urogenital tract anomalies were observed in two infants. One of them, who was exposed to stavudine-lamivudine-nevirapine from 15 weeks gestation, had a complete right ureteric duplication with a severe vesicoureteral reflux and had to undergo surgery to repair the defect. The second, who was diagnosed a bilateral hydrocele, received zidovudine-lamivudine-nelfinavir throughout pregnancy. A case of atrial-ventricular communication was observed in an infant with Down's syndrome who was exposed to zidovudine-lamivudine from 18 weeks gestation. One infant who had an interatrial communication and a concomitant asymptomatic partial corpus callosum agenesia, necessitated a surgical repair of the cardiac defect; this newborn had been exposed in utero to zidovudine-lamivudine from 15 weeks gestation. A case of asymptomatic, non-life-threatening, intracranial haemorrhage was detected by transfontanellar cerebral echography in an infant born at 36 weeks gestation who was exposed to stavudine-lamivudine-nelfinavir.


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Table IV. Newborn outcomes: prematurity and low birth weight
 

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Table V. Newborn outcomes: anaemia and infective complications
 
Vertical HIV-1 transmission was assessed in all infants; only one of them was HIV-1-infected (1.0%, 95% confidence interval; 0.3–4.6%). This infant was a male born by Caesarean section at 36 weeks and weighed 2500 g. His mother, a 34 year old illicit drug user, HIV-1 infected from at least 14 years of age, initiated combination antiretroviral therapy with zidovudine-lamivudine at 29 weeks gestation. She was probably poorly adherent. Caesarean section was decided because of spontaneous preterm labour and was performed before rupture of membranes. HIV-1 viral load at 26 weeks gestation (before initiating the therapy) was 29 000 cop/ml; no other data regarding the viral load was available. CD4 cell counts were 138 and 328 cell/ml at 26 weeks and before delivery respectively.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
This study describes a large series of HIV-1-infected women receiving combination antiretroviral therapy during pregnancy and, to the best of our knowledge, this is the largest consecutive series ever reported in this field. Prophylactic measures to control vertical transmission employed in this study were the use of combination therapy during pregnancy, elective Caesarean section and refraining from breast-feeding. The efficacy of all these measures in preventing vertical transmission of HIV-1 has been previously documented (O'Sullivan et al., 1999Go; Stek et al., 1999Go; Cohen, 2000Go; Morris et al., 2000Go; Nduati et al., 2000Go; Ricci et al., 2000Go; Mandelbrot et al., 2001Go). The present study confirms the remarkable efficacy of these three prophylactic procedures since only one out of 102 newborns was found to be infected (1.0%, 95% confidence interval; 0.3–4.6%).

Although the value of combination therapies in terms of preventing vertical transmission appears to be ascertained, relatively little is known about their short- and long-term safety for both the mother and the fetus or infant. In particular, a possible association with premature delivery has been suggested (Lorenzi et al., 1998Go; European collaborative study and the Swiss Mother + Child HIV Cohort Study, 2000Go). Similarly, the prevalence of preterm birth in our study also appeared to be elevated; 18 out of 96 (19%) singleton pregnant women delivered before 37 completed weeks gestation. However, it has to be considered that a link between illicit drug use and prematurity in both HIV-1-infected and non-infected pregnant women is well-established (Boer et al., 1994Go; Mauri et al., 1995Go; Bucceri et al., 1997Go). When subjects who actively used illicit drugs and/or methadone were excluded, only 7/69 (10%) women in our study were found to deliver prematurely. This percentage does not seem to significantly differ from the reported prevalence of this complication which is said to occur in about 11% of all pregnancies (McCormick, 1985Go). Our data are in line with the three other current available series on this topic (McGowan et al., 1999Go; Morris et al., 2000Go; Mandelbrot et al., 2001Go).

Considering the use of protease inhibitors, gastrointestinal disturbances were a significant problem in our series. Indeed, six of the 27 women who received these drugs discontinued their use due to these symptoms. This problem was surprisingly not reported in the largest study published on this topic (Morris et al., 2000Go). Larger trials are required to assess whether the use of protease inhibitors during pregnancy could be severely limited by an increased occurrence of gastrointestinal disturbances. On the other hand, since insulin resistance is a well known side-effect of protease inhibitors, an increased risk for pregnancy-associated hyperglycaemia has been hypothesized (Centers for Disease Control and Prevention, 2000Go). We failed to detect this complication among women receiving these drugs in our study. Similarly, Morris et al. did not report an increased risk of gestational diabetes mellitus among women using protease inhibitors in their series (Morris et al., 2000Go).

In the present study, the rate of congenital abnormalities observed in infants did not seem to be significantly different from that reported in the literature for the general population. Considering that congenital heart defects are estimated to occur in 0.88% of live birth, the frequency of cardiac abnormalities (two cases, 2%) detected in our study did not appear to be significantly increased (Hoffman and Christianson, 1978Go). One of these two cardiac malformations occurred in an infant with Down's syndrome for whom an increased frequency of congenital heart disease has been reported (Hoffman and Christianson, 1978Go). Similar conclusions can be drawn considering the congenital urinary tract anomalies, the asymptomatic partial corpus callosum agenesia and the asymptomatic intracranial haemorrhage (Reece et al., 1998Go). However, it should be noted that the sample size of our study does not allow the exclusion of the risk for some kind of adverse events which may, at least to some extent, be increased in women receiving combination antiretroviral therapy. Furthermore, since the present study has only a short neonatal follow-up, there is no data on the effects of perinatal exposure to combination antiretroviral drugs on the subsequent health of children. Further efforts should be directed toward the evaluation of any potential difference among the several antiretroviral and/or combination drugs currently available.

The decrease in HIV mortality and disease progression and the remarkable decline in perinatal transmission rate is increasing the number of HIV-infected women who elect to give birth. Since a host of antiretroviral medications has become available, most of these women are receiving complex antiretroviral regimens when they become pregnant. In our series, 10 different agents and 21 different regimens were used. In this context, an emerging priority for those caring for HIV-1-infected pregnant women is to evaluate the antiretroviral regimen that these women are receiving when they become pregnant. At least two major problems have to be considered Firstly, should these women discontinue the therapy during the first trimester of pregnancy? Secondly, is it necessary to systematically add zidovudine to combination regimens?

In regard to the first query, no definitive data are currently available. Theoretically, discontinuation of therapy could induce a rebound in viral load resulting in the decline of the immune status and the occurance of drug resistance. On the other hand, the maintenance of the treatment may expose the fetus to the teratogenic effect of drugs whose action during pregnancy has been poorly investigated (Centers for Disease Control and Prevention, 2000Go). In our study, women were counselled regarding these benefits and potential risks of antiretroviral therapies and nearly half (47%) of them decided to temporarily discontinue their use during the first trimester of pregnancy. None of the infants whose mother discontinued the therapy were HIV-1-infected and only one case of bilateral hydrocele was observed in women who did not interrupt therapy.

Considering the use of zidovudine, 25 out of 100 women in our series did not receive zidovudine-including regimens and none of their newborns were HIV-1-infected. Current Public Health Service Task Force Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women indicate that, to prevent perinatal transmission, zidovudine chemoprophylaxis should be incorporated into the antiretroviral regimens (Centers for Disease Control and Prevention, 2000Go). On the other hand, these same American Guidelines underline that therapies of known benefit should not be withheld during pregnancy unless adverse effects outweigh the benefit to the woman (Centers for Disease Control and Prevention, 2000Go). This poses doubts about the need to systematically incorporate zidovudine in therapeutical regimens. It should also be considered that the lower the level of HIV-1-RNA, the lower the risk of transmission becomes (Garcia et al., 1999Go). Therefore, it might be speculated that combination regimens able to maximally suppress viral replication should reduce the risk of vertical transmission. On this basis, we believe that pregnancy should not preclude the use of optimal therapeutic regimens in order to introduce zidovudine. However, since to date only a few cases of women receiving combination antiretroviral therapy without zidovudine have been studied, future large studies and specific registry are required to address this important issue.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The authors wish to gratefully acknowledge Dr Paola Viganò for critical reading of the manuscript and helpful discussions.


    Notes
 
3 To whom correspondence should be addressed at: II Dept of Obstetrics and Gynecology, Clinica L. Mangiagalli, Via Commenda 12, 20122, Milano, Italy. E-mail: dadosomigliana{at}yahoo.it Back

Submitted on February 15, 2001; resubmitted on August 6, 2001


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
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accepted on November 2, 2001.