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Antiretroviral therapy, pregnancy, and birth

defects: a discussion on the updated data

This article was published in the following Dove Press journal:

HIV/AIDS – Research and Palliative Care
31 July 2013
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Luiz Euribel Prestes- Abstract: An increasing number of HIV-infected women of childbearing age are initiating
Carneiro 1–2 antiretroviral therapy (ART) worldwide. This review aims to discuss updated data of the eligible
ART regimens and their role in inducing birth defects in utero. Zidovudine and lamivudine plus
1
Immunology Department, University
of Oeste Paulista, Presidente a non-nucleoside reverse-transcriptase inhibitor or protease inhibitor (PI) is the first-line regimen
Prudente, São Paulo, Brazil; 2Infectious applied. The role of zidovudine exposition monotherapy or associated with other ART in inducing
Diseases Department, Hospital
Ipiranga, São Paulo, SP, Brazil
birth defects remains inconclusive. The main organ systems involved are genitourinary and
cardiovascular. For HIV-infected pregnant women, World Health Organization (WHO) guidelines
up to 2010 recommend the same group of drugs that are prescribed to nonpregnant women. The
exception is efavirenz, which has been associated with an increase in the risk of teratogenicity.
Increased rates of birth defects were found in large cohorts and computational studies conducted
recently in infants exposed to efavirenz-containing regimens. The combination of zidovudine
and lamivudine and lopinavir/ritonavir is one of the most used ART regimens for prevention of
mother-to-child-transmission. Conflicting data about the role of PI exposure in utero and birth
defects have been reported. However, a reduced number of studies evaluating the role of PI
in inducing birth defects in women are available. An association between prematurity and PI
exposure in pregnancy was extensively described. Some questions arise due to the tendency of
initiating ART early in the life of HIV-infected individuals or those at risk of infection. Long-
time exposure to different ART regimens and the potential effect of birth-defect induction in
pregnancy are not completely understood. Developing regions harbor the highest numbers of
women of reproductive age exposed to ART. Most of the largest and expressive data come from
developed countries, and could not be sufficiently representative of pregnant women living in
developing countries.
Keywords: antiretroviral therapy, pregnancy, birth defects

Background
Globally, 34.0 million people were living with HIV at the end of 2011, and most of
the new infections were transmitted heterosexually. Mode of HIV transmission is
sexual for most people who are newly infected. Women represent about half of all
people living with HIV, the main cause of death among women of reproductive age.
Correspondence: Luiz Euribel Prestes-
Carneiro Particularly in developing countries, women make up a vulnerable population, being
Immunology Department, University at risk at a reproductive age.1 At the end of 2011, there were 3.3 million children living
of Western São Paulo, 700 Rua José
Bongiovani, Cidade Universitária, with HIV around the world and 330,000 new infections among children, most of them
Presidente Prudente, São Paulo living in sub-Saharan Africa. This dramatic scenario is mainly a result of mother-to-
19050-680, Brazil
Phone/fax +55 18 229 1013
child transmission (MTCT).1 In the absence of any intervention, the risk of MTCT is
Email [email protected] 15%–45%, with a risk of 15%–30% during pregnancy and delivery and an additional

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http://dx.doi.org/10.2147/HIV.S15542 which permits unrestricted noncommercial use, provided the original work is properly cited.
Prestes-Carneiro Dovepress

risk of 10%–20% postpartum via breastfeeding.2 The risk HIV-infected, ART-treated, pregnant women. According to
can be reduced to less than 2% through the combination of predefined inclusion criteria, articles that appeared to be
preventive interventions. One of the most important measures potentially relevant were identified by the reviewer after
is antiretroviral therapy (ART). Treatment of mothers living reviewing titles and abstracts.
with HIV benefits not only the mothers themselves but also
their children.1,2 Results
In 1994, the landmark Pediatric AIDS Clinical Systematic review
Trials Group study 076 (PACTG076), promoted a rapid On the basis of a review of the abstracts of the articles,
implementation and a significant reduction in perinatal 107 studies were initially identified as being potentially
HIV transmission in the US and other developed countries. eligible for inclusion. After abstract and full-text analysis, 66
Zidovudine monotherapy given orally to pregnant women fulfilled the inclusion criteria and 41 were discarded.
and to newborns promoted a reduction of 70% in MTCT.3
Since then, a significant reduction has been noted in Treatment and prophylaxis of MTCT
developed and developing countries. In 1998, the US In 2006 the World Health Organization (WHO) guidelines
Public Health Service recommended the use of combined recommended regimens involving three different
ART for treating pregnant women and preventing MTCT drugs – zidovudine, lamivudine, and nevirapine – resulting
of HIV.4 This review aims to discuss updated data of the in increased rates of MCTC reduction than monotherapy.5,6
eligible ART regimens and their role in inducing birth In 2010, the WHO revised MTCT guidelines and defined
defects in utero. two strategies: (1) long-term first-line ART regimens for
HIV-infected women in need of treatment for their own
Methods health, which is also safe and effective in reducing MTCT
Study selection of HIV, and lifelong treatment should start as soon as
This review summarizes studies identified by systematic possible during pregnancy (Table 1); and (2) short-term
literature searches of both Medline and PubMed. The ART prophylaxis to reduce MTCT during pregnancy,
following combinations of search terms were used: “anti- delivery, and breastfeeding for HIV-infected women not in
retroviral therapy and pregnancy” and “birth defects”. need of treatment. For short-term ART, the 2010 guidelines
Additionally, hand searches of the reference lists of all include two options, both of which should start earlier in
included articles identif ied during the search period pregnancy: at 14 weeks or as soon as possible (Table 2).2,7
were performed to locate any additional relevant stud- Worldwide, zidovudine/lamivudine with a non-nucleoside
ies. Requirements for inclusion criteria were descriptive reverse-transcriptase inhibitor (NNRTI) or a protease
studies written in English, published from January 1995 inhibitor (PI) is the eligible combination regimen in ART-
through March 2013, with sample sizes higher than 100 naive pregnant women. However, for women who are

Table 1 Antiretroviral treatment options recommended for HIV-infected pregnant women who are eligible for treatment

Maternal ART + infant ARV prophylaxis

Mother
Meternal antepartum daily ART, starting as soon as possible irrespective of gestational age, and continued
during pregnancy, delivery and thereafter. Recommended regimens include:
AZT + 3TC + NVP or
AZT + 3TC + EFV* or
TDF + 3TC (or FTC) + NVP or
TDF + 3TC (or FTC) + EFV*
Infant
Daily NVP or twice-daily AZT from birth until 4 to 6 weeks of age (irrespective of the mode of infant feeding).
Note: *Avoid use of EFV in the first trimester and use NVP instead. For all exposed infants, regardless of infant feeding, reprinted with permission World Health Organization
(Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants, 2010 version. Available from: http://whqlibdoc.who.int/publications/2010/9789241599818_
eng.pdf. Accessed March 20, 2013).7
Abbreviations: ART, antiretroviral therapy; ARV, antiretroviral; AZT, zidovudine; NVP, nevirapine; TDF, tenofovir; EFV, efavirenz; 3TC, lamivudine; FTC, emtricitabine;
XTC, 3TC lamivudine.

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Dovepress Birth defects and pregnancy

Table 2 ARV-prophylaxis options recommended for HIV-infected pregnant women who do not need treatment for their own
health

Maternal AZT + infant ARV prophylaxis Maternal triple ARV prophylaxis

(Option A) (Option B)
Mother Mother
Antepartum twice-daily AZT starting from as early as Triple ARV prophylaxis starting from as early as 14
14 weeks of gestation and continued during weeks of gestation and continued until delivery, or, if
pregnancy. At onset of labour, sd-NVP and initiation of breastfeeding, continued until 1 week after all infant
twice daily AZT + 3TC for 7 days postpartum. exposure to breast milk has ended. Reecommended
regimens include:
(Note: If maternal AZT was provided for more than 4
AZT + 3TC + LPV/r or
weeks antenatally, omission of the sd-NVP and
AZT + 3TC + ABC or
AZT + 3TC tail can be considered; in this case,
AZT + 3TC + EFV or
continue maternal AZT during labour and stop at
TDF + 3TC (or FTC) + EFV
delivery).
Infant Infant
For breastfeeding infants Irrespective of mode of infant feeding
Daily NVP from birth for a minimum of 4 to 6 weeks, Daily NVP or twice-daily AZT from birth until 4 to 6
and until 1 week after all exposure to breast milk has weeks of age.
ended.
Infants receiving replacement feeding only
Daily NVP or sd-NVP + twice-daily AZT from birth until
4 to 6 weeks of age.

Notes: Single-dose NVP and AZT + 3TC can be omitted if mother receives .4 weeks’ AZT antepartum. Begin as early as 14 weeks’ gestation (second trimester) or as
soon as possible thereafter. Reprinted with permission World Health Organization (Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants,
2010 version. Available from: http://whqlibdoc.who.int/publications/2010/9789241599818_eng.pdf. Accessed March 20, 2013).7
Abbreviations: ARV, antiretroviral; AZT, zidovudine; ART, antiretroviral therapy; NVP, nevirapine; LPV, lopinavir; ABC, abacavir; EFV, efavirenz; 3TC, lamivudine;
FTC, emtricitabine; SD, single dose; TDF, tenofovir.

intolerant to zidovudine due to severe anemia or who have The use of ART is one of the main steps for HIV-infected
developed resistance to the drug, alternative regimens can pregnant women, both for their own treatment and for MTCT.
be used. For ART-naive pregnant women with CD4 cell The main ART regimens used worldwide are grouped into
lymphocyte counts ,250 cells/mm3, nevirapine would be four categories: nucleoside analog reverse-transcriptase
the preferred NNRTI. However, the drug should not be inhibitor (NRTI) only; NRTI and NNRTI; combination of
given to naive women with CD4 cell counts .250 cells/mm3 NRTI and PI; or a combination of NRTI, NNRTI, and PI.
due to the risk of nevirapine toxicity. An increased risk of Highly active antiretroviral therapy (HAART) is defined as
symptomatic and possible fatal rash and hepatic toxicity regimens including three or more drugs.8 For initiating an
should be considered.8 According to the Recommendations ART regimen in a pregnant HIV-infected woman, the choice
for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected should be individualized and must be based on discussion
Women for Maternal Health and Interventions to Reduce about the available data from the individual drugs. The history
Perinatal HIV Transmission in the United States, the and evolution of the infection should be taken into account,
main alterations induced in animal models or humans as should whether the treatment is indicated for own health
by ART are clastogenic (causing disruption or breakages or only for MTCT, the presence of comorbidities, and access
in chromosomes), mutagenic (inducing or capable of and drug availability. Moreover, some HIV-infected women
inducing genetic mutation), genotoxic (damaging to genetic have never received ART previously or may not be receiving
material such as DNA and chromosomes), or carcinogenic ART at the time they are pregnant. With an increasing
(producing or tending to produce cancer). Some agents, number of pregnant HIV-infected women receiving ART
such as certain chemicals or forms of radiation, are both worldwide, concerns have been raised over the possible
mutagenic and clastogenic. Teratogenic (any agent or factor side effects linked to exposure in early pregnancy, mainly
that induces or increases the incidence of abnormal prenatal in the first trimester. This trimester is the period of greatest
development).8 susceptibility to teratogens, since it is when germ-layer

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formation and organogenesis occur, defined as up to and that registers ART regimens and pregnancy outcomes
including 12 gestational weeks.8–10 worldwide. Created in 1989, the APR collects data on
Congenital abnormalities were classified according birth defects after ART exposure in pregnancy. It estimates
to WHO criteria as any major structural or chromosomal the risk of birth defects against different classes of ART,
abnormality, or any cluster of two or more minor (conditional) including case-report retrospective and prospective studies.
abnormalities, occurring in fetuses of at least 20 weeks of The data are compared with rates from a population-based
gestational age (polydactyly, malformed ear, abnormalities surveillance system, and first-trimester exposure is compared
in the feet, minor mouth abnormalities, undescended testes, with second-/third-trimester exposure.11 Preclinical data
accessory nipple, spinal hairy patch, strawberry nevi, skin tag, include both in vitro and in vivo results of animal screening
and subclinical subependymal cysts). Similar criteria are used tests for carcinogenicity, clastogenicity/mutagenicity, and
by the APR11 and by the Metropolitan Atlanta Congenital reproductive and teratogenic effects. Data on the risk of
Defects Project.12 birth defects after ART exposure are limited and conflicting,
with some studies showing risk similar to a population-
In utero ART exposure and birth defects based surveillance and others finding increased risks after
Data on the potential teratogenic effect of ART drugs include specific exposure.
animal toxicity data, anecdotal experience, cohort studies,
case reports, and data from such agencies as the PACTG,13 Nucleoside analog reverse-transcriptase
European Collaborative Study,14 Pediatric European Network inhibitors and birth defects
for Treatment of AIDS,15 National Institute of Child Health Since the hallmark study of PACTG076,3 zidovudine has
and Human Development International Site Development become routine for most HIV-infected pregnant women for
Initiative (NISDI), 16 and the APR, the largest agency preventing MTCT. However, rising concerns of congenital

Table 3 Results of major studies associated with birth defects on zidovudine monotherapy and zidovudine-containing regimen exposure
in utero
Study Antiretroviral Number Number (%)* Rates compared to controls
therapy enrolled exposed
Sperling et al4 ZDV 437 437 0.7 Lower than APR and US pediatric
population
Mandelbrot et al21 ZDV 1344 1344 3 Similar to newborns in Paris (2.7%)
ZDV + 3TC
Patel et al22 ZDV 3740 1973 1.6 Similar compared to controls not
ZDV + 3TC + HAART exposed (1.4%)
Watts et al23 ZDV 2527 2527 3.5 Similar to US pediatric population (2.7%)
ZDV + NRTI
ZDV + NRTI + NNRTI
Townsend et al24 ZDV 8242 8242 2.8 Similar to Europe newborns (2.2%)
ZDV + 3TC
ZDV + NRTI + NNRTI
Gibb et al30 ZDV 1867 226 3 Similar to international data (1.4%–3.9%)
ZDV + NRTI
Nielsen-Saines et al29 ZDV 236 236 7.6 High compared to international data
ZDV + NRTI + NNRTI
Newschaffer et al10 ZDV 1932 1917 10.5 2.79 times higher than New York
newborns
Joao et al25 ZDV 974 954 6.0 High compared to newborns of Rio de
Janeiro, Brazil (2.2%)
Brogly et al26 ZDV 2202 33 5.5 High compared to APR (2.9%)
Watts et al27 ZDV 1414 1113 3.5 High compared to CDC (2.2%)
ZDV + NRTI
ZDV + NRTI + PI
Knapp et al28 ZDV 1112 944 5.5 High compared to APR (2.9%)
Note: *Prevalence per 100 live births.
Abbreviations: ZDV, zidovudine; NRTI, nucleoside analog reverse-transcriptase inhibitor; NNRTI, non- nucleoside analog reverse-transcriptase inhibitor; 3TC, lamivudine; PI,
protease inhibitor; HAART: highly active antiretroviral therapy, APR, antiretroviral pregnancy register; US, United States; CDC, Centers of Disease Control and Prevention.

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malformations, including potential cancers, mitochondrial of heart defects, increasing with advancing maternal age,
disease, and heart, hematological, and genitourinary although these findings were based on a small number of
abnormalities, appeared from animal models and clinical cases. An association of zidovudine and septal heart defect
trials performed in developing and developed countries due was previously reported in litarature.26,27 Among the 80 organ-
to zidovudine exposure.17–20 Zidovudine plus lamivudine is system anomalies identified in the International Maternal
a recommended dual-NRTI regimen for pregnant women.21 Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT)
Zidovudine is classif ied by the FDA as category C, protocol P1025, cardiovascular (n = 33), musculoskeletal
indicating that the drug may have teratogenic effects; (n = 15), renal (n = 9), genitourinary (n = 6), craniofacial
however, the available information is insufficient.7,8 One of (n = 4), and central nervous system (n = 2) were included.28
the first scientific studies on the role of ART in congenital In a multisite study conducted in infants exposed to ART
abnormalities, particularly to zidovudine, was the perinatal from Africa, India, Thailand, and Brazil, 18/236 (7.6%)
cohort trial PACTG 076.4 The main results of major studies showed congenital defects/inborn errors of metabolism, of
exploring the role of zidovudine monotherapy or zidovudine- which 17 were from Thailand.29 Summarizing, in zidovudine
containing regimens in inducing birth defects in utero are monotherapy or zidovudine-containing regimens, the main
summarized in Table 3.4,10,21–30 The sequence follows the organ systems involved are genitourinary and cardiovascular.
time course over which the studies were published. Among In the selected studies, no increase in birth defects was found
the eleven selected studies, six showed similar rates of between first and second/third trimester of in utero exposure
birth defects in zidovudine monotherapy or zidovudine- to zidovudine/lamivudine or PIs. The role of zidovudine alone
containing regimens compared to the Centers for Disease or associated with other ART exposure in utero in inducing
Control and Prevention, APR, or the European pediatric birth defects in HIV-infected pregnant women or in women
population. In addition, the risk was not significantly higher at childbearing age remains sparse.
for mothers in the first trimester compared with second-/third-
trimester exposure. Furthermore, the presence of congenital Non-nucleoside reverse-transcriptase
abnormalities was not associated with the use of monotherapy inhibitors and birth defects
(zidovudine), dual therapy (zidovudine/lamivudine), Millions of HIV-infected women in developed and developing
or HAART regimens. Two of them were conducted in the countries are in need of safe and effective ART.30 Except for
US,4,10,21–30 three in Europe,21,22,24 and one in Africa.30 In the efavirenz, which has been associated with a potential increase
US Women and Infants Transmission Study,23 an association in the risk of teratogenicity in women of childbearing age,
between first-trimester exposure to zidovudine and a tenfold-
increased risk of hypospadias among male newborns was Table 4 Results of major studies associated with birth defects on
described, although birth-defect rates were not different from efavirenz-containing regimen exposure in utero
the general US pediatric population. The same observation Study Number Number (%)* Rates compared
was reported by Townsend et al,24 including twelve cases of enrolled antenatal to controls or
hypospadias in infants exposed to zidovudine-containing exposure international data

regimens. Bera et al37 623 623 2.6 Similar to

international data
Conflicting results are described, showing higher levels (1.4%–3.9%)
of birth defects in infants exposed to zidovudine alone or in Townsend 8242 205 2.4 Similar to Europe
combined regimens. Five major studies showing increased et al24 newborns (2.2%)
rates of birth defects associated with zidovudine or zidovudine- Ford et al32 8295 1132 3.0 Similar to APR
(2.9%)
containing regimens in utero were selected. According to a Antiretroviral 679 679 2.7 Similar to US
study by Joao et al25 carried out in Brazil and Argentina, one Pregnancy newborns (2.0%)
possibility of the higher prevalence of birth defects found Register11
Ekouevi et al36 344 213 0 Lower than APR
in this study than rates from the US and Europe could be
Brogly et al26 105 5 15.6 Higher than APR
attributed to the prospective model of the study. In addition, and CDC data
small cohorts destined to determine the prevalence of birth Knapp et al38 1112 56 10.7 Higher than APR
defects were designed in Latin America, and rates ranged and CDC data
Note: *Prevalence per 100 live births.
from 0.4% in Vitoria (Brazil) to 8.4% in Chile.25 In PACTG Abbreviations: APR, Antiretroviral Pregnancy Register; CDC, Centers for Disease
219 and 219C, zidovudine exposure exerted a higher risk Control and Prevention.

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guidelines up to 2010 recommend the same group of drugs pregnancy, the rate was 77.26 events per 100,000 women.
that are prescribed to nonpregnant HIV-infected mothers. They concluded that efavirenz exposure was associated with
In 2005, the drug was classified by the US FDA as a a small (4.8 per 100,000 women) increased risk of teratogenic
class C drug (drugs in which risk cannot be ruled out). This events.39 Another HIV computer simulation model was also
recommendation is based on animal studies with cynomolgus applied in Côte d’Ivoire to analyze the results of either
monkeys, in which significant malformations (anencephaly, efavirenz or nevirapine as an ART regimen in women of
anophthalmia, and cleft palate), were observed in three childbearing age in a cohort of 100,000 women. Similarly,
out of 20 infants (15%) receiving efavirenz during the first it was concluded that initiating ART with efavirenz instead
trimester. The plasma levels of the drug are comparable to of nevirapine induces a smaller potential number of birth
systemic human therapeutic exposure.7,8 The first trimester defects compared to women with no efavirenz-containing
of pregnancy is the critical time for neural tube formation. regimens.40 In most of these studies, the prevalence of birth
Subsequently, due to retrospective and prospective case defects was not significantly different between the first
reports of neural tube defects in humans with first-trimester and second/third trimester of efavirenz exposure or even
exposure to efavirenz, the FDA reclassified the drug as compared with exposure to other ART. However, according
class D (there is positive evidence of human fetal risk to the APR, although some data provide sufficient numbers
based on studies in humans, but potential benefits may of first-trimester exposures to rule out a twofold or greater
warrant use of the drug in pregnant women despite potential increase in the risk of overall birth defects, the low incidence
risks).8,31–35 Although the FDA recommends other ARTs than of neural tube defects in the general population means that
efavirenz for childbearing women or HIV-infected pregnant a larger number of exposures are still needed to make it
women in the first trimester, in 2010, WHO guidelines possible to rule out definitively an increased risk of this
recommend the use of efavirenz as first line for developed specific defect.11
and developing countries: zidovudine/lamivudine/efavirenz
or tenofovir/lamivudine (or emtricitabine)/efavirenz.7 The Protease inhibitors
role of efavirenz-containing regimens in inducing birth Several national guidelines recommend the combination of
defects in HIV-pregnant women remains inconclusive. Seven antiretroviral regimens for prevention of MTCT of HIV and
major studies were selected,11,24,26,32,36–38 and the results are for the treatment of maternal HIV infection. In HIV-infected
summarized in Table 4. pregnant women, the combination of zidovudine, lamivudine,
Classified by organs, in the study of Townsend et al,24 and a PI is one of the most used regimens for both preventing
undescended testes, hip dislocation, and hypertrophic and MTCT and treatment of HIV infection itself. In the US, ten
pyloric stenosis were the most prevalent. In the multisite US PIs are available based on several clinical trials in human
cohort PATCTG protocols 219 and 219C, the defects included pregnancy.8 There are a lot of data available for lopinavir/
laryngomalacia, meningomyelocele with Arnold–Chiari ritonavir, atazanavir, nelfinavir, ritonavir, and saquinavir. Not
malformation type II, hypospadias, varus feet, hypertonicity many data are available for darunavir, fosamprenavir, and
of extremities, and cleft palate.26 Bussmann et al described indinavir. Very limited data are available for tipranavir.8,41,42
in pregnant women on efavirenz-containing regimens in Although experience is more limited with these regimens,
Botswana, polydactyly, umbilical hernia, shortening of the depending on the side effects, resistance to ART, and other
right lower extremity, and one live birth showing shortened limiting circumstances, alternative PIs include ritonavir-
right femur with midshaft cortical thickening, absence of boosted atazanavir or saquinavir regimens. Nelfinavir and
right femur head epiphysis, and dysplastic right fibular indinavir can be considered for prophylaxis of perinatal
head.38 In a computer simulation model, investigators from transmission in ART-naive women who cannot tolerate
the Cost-Effectiveness of Preventing AIDS Complications alternative agents. However, indinavir has been associated
(CEPAC) used literature-based rates of live births and with renal stones developing. Darunavir can also be used, but
teratogenic reports of HIV-infected women to calculate the there are few studies showing the role of the drug exposition
risk of teratogenic events. Simulations were conducted for in in utero and birth defects. Fosamprenavir and tipranavir
women both receiving efavirenz and non-efavirenz-based can also be considered for women who are intolerant to
regimens. For women without efavirenz exposure during other agents.8,41,42 Overwhelmingly, the combination of
pregnancy, the rate of teratogenic events was 72.46 events zidovudine + lamivudine and lopinavir/ritonavir is one of the
per 100,000 women. For women exposed to efavirenz during most widely used worldwide ART regimens for prevention

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Dovepress Birth defects and pregnancy

of MTCT of HIV, especially in ART-naive pregnant are exposed to multiple risk factors, such as undernutrition,
women.1,2,5,11 anemia, increasing number of pregnancies and conceptions
Conflicting data are reported about the role of PI early in life, unsure treatment access, and irregular use of
exposition in in utero and birth defects. However, a ART.47 The role of such interactions in induction of birth
reduced number of studies of pregnant women in use of defects is not completely understood. (2) Developing regions
PI are available. In the European Collaborative study, such as sub-Saharan Africa and Latin American countries
3740 mother–infant pairs were enrolled, and 1973 infants harbor the highest numbers of women of reproductive age
were exposed to ART in utero, 789 received HAART in exposed to ART.1,25,47,48 Most of the largest and expressive
the first trimester of pregnancy, and no increase in birth data comes from retrospective, prospective, and case-report
defects were found between children exposed to lopinavir/ studies carried out in developed countries and could be
ritonavir and nonexposed infants.9 The NISDI group found not sufficiently representative of pregnant women living in
in the first extensive prospective study of birth defects in developing countries. Both extensive cohorts and expressive
Latin America a prevalence of 4.3% of birth defects in 94 studies in these populations are missing.47,48 In some of these
children exposed to two NRTIs + one PI.25 In studies in regions, higher rates of birth defects were found in small
Ireland and the UK between 1990 and 2006, the use of cohorts.25 (3) ART drugs not commonly used in standard
PIs in HAART regimens increased from 36.1% in 1999 to protocols are being used with increasing frequency in HIV-
73.2% in 2006, and birth defects were not higher in infants infected pregnant women or of childbearing age, mainly
exposed to PIs than in nonexposed ones. Of note, there in developing countries. At the moment, few studies are
are higher prematurity rates found in children exposed available to determine the role of these drugs alone or
to PIs than those on monotherapy or dual therapy.24 The associated with other ART in inducing birth defects.49
association between prematurity and PI exposition in Answers to these questions should be urgently addressed
pregnancy has been extensively described previously. by researchers.
Recently, Watts et al through the Pediatric HIV/AIDS Among the limitations of our updated review is that only
Cohort Study network’s Surveillance Monitoring for ART English-language articles were included. Furthermore, few
Toxicities showed that use of PIs early in pregnancy may studies conducted in poor-resource settings with limited
be associated with increased risk of prematurity.43 In the applicability due to the small number of enrolled participants
PACTP 219 and 219C cohorts, the rate of birth defects were selected.
was higher in children exposed to lopinavir/ritonavir in
the first trimester than in unexposed children, including Disclosure
hydronephrosis, supernumerary nipple, umbilical hernia, The author reports no conflict of interest in this work.
atrial septal defect, pyloric stenosis, ventricular septal
defect, and hemangioma.26
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