Article

Safety of efavirenz in the first trimester of pregnancy: An updated systematic review and meta-analysis

Centre for Infectious Disease Epidemiology and Research, University of Cape Town, Cape Town, South Africa.
AIDS (London, England) (Impact Factor: 5.55). 09/2011; 25(18):2301-4. DOI: 10.1097/QAD.0b013e32834cdb71
Source: PubMed

ABSTRACT

Evidence of the risk of birth defects with efavirenz use is limited. We updated a meta-analysis of birth defects in infants with first trimester efavirenz exposure up to July 2011. In 21 studies, there were 39 defects among live births in 1437 women receiving first trimester efavirenz [2.0%, 95% confidence interval (CI) 0.82-3.18]. The relative risk of defects comparing women on efavirenz-based (1290 live births) and nonefavirenz-based regimens (8122 live births) was 0.85 (95% CI 0.61-1.20). One neural tube defect was observed (myelomeningocele), giving an incidence of 0.07% (95% CI 0.002-0.39).

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Research Letter
AIDS 2011, 25:23012304
Safety of efavirenz in the first trimester of
pregnancy: an updated systematic review and
meta-analysis
Nathan Ford
a,b
, Alexandra Calmy
c
and Lynne Mofen-
son
d
Evidence of the risk of birth defects with efavirenz
use is limited. We updated a meta-analysis of birth
defects in infants with first trimester efavirenz
exposure up to July 2011. In 21 studies, there were
39 defects among live births in 1437 women receiv-
ing first trimester efavirenz [2.0%, 95% confidence
interval (CI) 0.823.18]. The relative risk of defects
comparing women on efavirenz-based (1290 live
births) and nonefavirenz-based regimens (8122 live
births) was 0.85 (95% CI 0.611.20). One neural
tube defect was observed (myelomeningocele),
giving an incidence of 0.07% (95% CI 0.0020.39).
Current antiretroviral treatment guidelines in resource-
limited settings recommend efavirenz or nevirapine as
first-line drugs [1]. Efavirenz is widely used because it is
well tolerated, easy to monitor, conveniently coformu-
lated as a once-daily pill and shows similar virologic
suppression to nevirapine. However, efavirenz use during
the first trimester of pregnancy is contraindicated due to
animal data and case reports indicating a potential
association with neural tube defects [2]. We previously
published a systematic review and meta-analysis that
found no increase in overall birth defects comparing first
trimester receipt of efavirenz-based and nonefavirenz-
based regimens, although the limited number of reports
prevented a definitive conclusion regarding the risk of
rare outcomes such as neural tube defects [3]. We updated
our systematic review to include data up to July 2011.
Using a predefined protocol (http://tinyurl.com/
3hzz5wo), we combined terms for efavirenz, pregnancy
and birth outcomes and searched the following databases
up to 1 July 2011 without language restrictions:
MEDLINE via PubMed; EMBASE; CINAHL and
PsycInfo; Cochrane CENTRAL; LILACS; Current Con-
trolled Trials; BioMedCentral and Public Library of Science;
and websites of major HIV conferences such as
International AIDS Society conferences up to July
2011 and Conferences on Retroviruses and Opportu-
nistic Infections up to February 2011. Data were
abstracted from the latest Antiretroviral Pregnancy
Registry (http://www.apregistry.com), and the following
treatment cohorts were contacted: the MTCT Plus
Initiative; Me
´
decins Sans Frontie
`
res; the International
Epidemiologic Databases to Evaluate AIDS in Southern
Africa (IeDA-SA); and the Reproductive Health
Research Unit (RHRU).
The primary endpoint was birth defects of any kind.
Unsystematic observations (case series or case reports)
were excluded. Point estimates and 95% confidence
intervals (CIs) were calculated for birth defects reported
among live bir ths for each study (spontaneous and
induced abortions and stillbirths were excluded).
Proportions were summarized using random effects
meta-analysis using a FreemanTukey arcsine transform-
ation of the raw proportions. The t
2
-statistic was
calculated to assess between-study heterogeneity. For
cohorts reporting birth outcomes of infants exposed to
ef avirenz vs. other antiretrovirals during the first
trimester, relative risks (RRs) and CIs were calculated
and data pooled using random effects method. Subgroup
analyses assessed potential effects on the pooled estimates
of study design, location, exposure duration and
publication status. All analyses were conducted using
Stata, version 11 (StataCorp LP, College Station, Texas,
USA).
The initial search yielded 798 publications and 885
conference abstracts, from which 32 studies were
reviewed as full text. Twenty-one studies were included
for analysis (among which 19 reported our primary
outcome), including 13 prospective studies. This updated
review found 181 additional live births with first trimester
ef avirenz exposure and birth defect data from five
additional cohorts [48], one updated study [9] of a
previous report [10], and the updated Antiretroviral
Pregnancy Reg istry [11].
Across the 19 studies reporting birth defects among 1437
live-born inf ants born to women receiving efavirenz in
the first trimester, birth defect prevalence ranged from 0%
[12] to 22.6% [13], with a 2.0% pooled prevalence (CI
0.823.18); heterogeneity between studies was low
(t
2
¼ 1.89). One neural tube defect was observed
(myelomeningocele) [11], giving an incidence pro-
portion of 0.07% (CI 0.0020.39) (Table 1) [49,
1123]. In a subgroup analysis, there was no difference
according to publication status (P ¼ 0.58), study design
(P ¼ 0.19) or exposure duration (P ¼ 0.96); prevalence
appeared higher in developed countries compared with
developing countries (P ¼ 0.015).
Eleven studies reported birth defects among infants born to
women receiving first trimester efavirenz-containing
regimens (38 defects among 1290 live births) and
DOI:10.1097/QAD.0b013e32834cdb71
ISSN 0269-9370 Q 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins
2301
Page 1
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
nonefavirenz-containing regimens (316 defects among
8122 live births), giving a nonsignificant RR of 0.85 (CI
0.611.20); heterogeneity was low (t
2
¼ 0) (Fig. 1). The
pooled estimate was not affected by subgroup analyses that
compared study setting (P ¼ 0.47), duration of efavirenz
exposure (P ¼ 0.78) or publication status (P ¼ 0.50).
The reporting of secondary outcomes varied across
studies. Eight studies reported spontaneous abortions,
with prevalence raging from 0% [6] to 16.05% [14]. The
prevalence of stillbirths, reported by eight studies, ranged
from 0% [19] to 13.3% (MTCT-Plus). The prevalence for
termination of pregnancy, reported by 10 studies ranged
from 0% [6] to 33.7% [24]. Three studies reported data on
termination of pregnancy (none based on prenatal
screening) for women exposed to efavirenz-containing
and nonefavirenz-containing regimens [9,19,24], giving a
RR of 2.81 (95% CI 0.948.36) for efavirenz-exposed
women. Finally, five studies reported on preterm delivery,
with prevalence ranging from 9.1% [19] to 18.2% [20].
The methodological quality of included studies was
judged to be moderate. The vast majority of reports were
from prospective cohorts (1364 live births), and only four
studies were composed of less than 10 patients with first
trimester efavirenz use. Ascertainment of birth defects
among stillborn/terminated births was only reported by
two studies (the prevalence of birth defects was consistent
with data reported for live births).
This expanded review confirms the previous meta-
analysis findings of no increased risk of overall birth
2302 AIDS 2011, Vol 25 No 18
Table 1. Description of reported birth defects in infants born to women with first trimester efavirenz exposure.
Study
Number of with
EFV exposure in
first trimester
Mean duration of
EFV exposure during
pregnancy
Number of
pregnancies
with live births
Number of
birth defects
(live births) Description of birth defects
Antiretroviral Pregnancy
Registry, [11]
623 623 17
a
Myelomeningocele (n ¼ 1),
anophthalmia with severe
oblique facial clefts and
amniotic band on arm
Ekouevi et al. [9] 203 59 days 147 0 NR
Phanuphak et al. [4] 7 NS 6 0 NR
Cressey et al. [5] 4 NS 4 0 NR
Westreich et al. [14] 60 NS 60 0 NR
Blood et al. [7] 2 NS 1
b
0NS
Areechokchai [6] 5 NS 5 0 NR
Bera et al. [15] 195 39 weeks 184 5
c
Arthrogryposis multiplex
congenital
d
, oesophageal
atresia with trachea
oesophageal fistula,
polysyndactyly
e
, postaxial
polydactyly, central lower
incisor
Townsend et al. [16] 205 NS 204 5 undescended testes (n ¼ 2),
hip dislocation (n ¼ 2),
hypertrophic pyloric
stenosis
Machado et al. [17] 19 Not reported 18 1 Undescended testes
Gonzalez-Tome et al. [13] 31 2 months 31 7 Renal dilatation (n ¼ 4),
angiomatosis, dermoid
cyst, acetabular dysplasia,
inguinal hernia
Oliveira [8] 17 NS 17 0 NR
Rossouw et al. [18] 37 NS 31 0 NR
Bussmann et al. [19] 38 43 days 22 1 Bone dysplasia
Floridia et al. [20] 39 NS 32 2 Bilateral clubfoot,
undescended testes
Joao et al. [12] 23 15 weeks (median) 21 0 NR
Jeantils et al. [21] 12 8 weeks 7 1
f
Right arm angioma
Patel et al. [22] 19 40 days 19 0 NR
Batallan et al. [23] 5 23.7 weeks 5 0 NR
EFV, efavirenz; NS, not specified; NR, not reported.
a
Detailed information on type of birth defects in the Antiretroviral Pregnancy Registry only provided for the two central nervous system defects.
b
One woman defaulted.
c
One additional birth defect was noted in stillbirth (trisomy 18).
d
Arthrogryposis multiplex congenita: birth defects included joint contractures, webbed limbs, pulmonary hypoplasia, absent sacrum and unilateral
cleft lip and palate.
e
Polysyndactyly, polysyndactyly with syndactyly: extra digits fully formed with phanges and nail, fingers were postaxial and toes were pre-axial
fused with big toe.
f
One additional birth defect was noted on autopsy of medically aborted fetus (multiple malformations including pulmonary segmentation, bicuspid
pulmonary value and accelerated skeletal maturation without genetic abnormalities).
Page 2
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
defects among women receiving first trimester efavirenz.
The pooled prevalence of birth defects for women
exposed to first trimester efavirenz (2.0%) is similar to that
for women exposed to nonefavirenz-based reg imens in
the antiretroviral pregnancy registry (2.9%) [11], and in
the general population (6%) [25]. Incidence of neural
tube defects remains low (0.07%), but this estimate is
derived from a small sample.
Strengths of this review include a broad search strategy
that identified data from the grey literature and
unpublished cohorts, and the inclusion of updated data
for several cohorts. Limitations include the inconsistent
reporting of secondary outcomes and the potential for
bias associated with selective abortion as a result of
prenatal screening that could result in a reduction of birth
prevalence. We consider such bias unlikely, given that
none of the studies reporting rates of termination of
pregnancy among women exposed to efavirenz used
prenatal screening to guide termination decisions and
note that in the Antiretroviral Pregnancy Registr y the
reported prevalence of birth defects among induced
abortuses of women exposed to antiretroviral therapy in
the first-trimester (2.5%) is consistent with the back-
ground prevalence [11]. The main limitation of this
review is the small sample size. It is notable that more than
80% of data come from just four studies in which
prospective reporting of birth outcomes has been
established [9,11,15,16]. The lack of systematic recording
of birth outcomes from women receiving antiretroviral
drugs during pregnancy persists, with reports of birth
outcome data for only 181 live births found by this review
in the last 18 months. Prospective surveillance systems
par ticularly in developing countries are needed to
improve data reporting and inform the assessment of
risk of rare defects.
Acknowledgements
The authors would like to thank Tim Cressey, Nittaya
Phanuphak and D. Heather Watts for providing additional
data, and Stephanie Bartlett and Catherine Kirby for
assistance with the preparation of the final repor t.
Conflicts of interest
There are no conflicts of interest.
a
Centre for Infectious Disease Epidemiology and
Research, University of Cape Town, Cape Town,
South Africa;
b
Me
´
decins Sans Frontie
`
res;
c
HIV Unit,
Service of Infectious Diseases, Geneva University
Hospital, Geneva, Switzerland; and
d
Pediatric,
Adolescent and Maternal AIDS Branch, Center for
Research for Mothers and Children, Eunice Kennedy
Research Letter 2303
Overall
Study
Gonzales−Tome et al.
Townsend et al.
Bera et al.
Patel et al.
Floridia et al.
Machado et al.
Ekouevi et al.
Phanupak et al.
Bussmann et al.
Antiretroviral pregnancy registry
Cressey et al.
Year
2010
2010
2010
2010
2010
2010
2011
2011
2010
2011
2011
Reference
13
16
15
22
20
17
9
4
19
11
5
0.85 (0.61, 1.20)
risk (95% CI)
0.65 (0.33, 1.26)
0.75 (0.30, 1.87)
0.90 (0.11, 7.43)
1.33 (0.08, 21.51)
1.22 (0.28, 5.31)
6.22 (0.41, 95.10)
(Excluded)
(Excluded)
0.75 (0.07, 7.78)
0.92 (0.56, 1.50)
(Excluded)
38/1290
Treatment
7/31
5/204
Events,
5/184
0/19
2/32
1/18
0/147
0/6
1/22
17/623
0/4
316/8122
Control
93/266
48/1478
Events,
1/33
14/770
10/195
1/112
0/102
0/180
2/33
147/4932
0/21
Relative
non−EFV EFV
10.05 0.1 0.5 1 5 10
Fig. 1. Relative risk of birth defects on efavirenz vs. nonefavirenz regimens. CI, confidence interval; EFV, efavirenz.
Page 3
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Shriver National Institute of Child Health and Human
Development, National Institutes of Health, Bethesda,
Maryland, USA.
Correspondence to Dr Nathan Ford, MPH, PhD,
Centre for Infectious Diseases Epidemiology and
Research, University of Cape Town, Anzio Road Cape
Town 7925, South Africa.
E-mail: nathan.ford@msf.org
Received: 5 August 2011; revised: 26 August 2011;
accepted: 7 September 2011.
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Page 4
  • Source
    • "re ineffective). ' It should be noted, however, that data supporting this classification are not supported by findings in cohorts of pregnant women exposed to EFV. In a meta-analysis, the incidence of neural tube defects and all congenital abnormalities among women exposed to EFV in the first trimester was similar to that of the general population. [53] WHO guidance is that EFV can be used throughout pregnancy; their review of current data on EFV safety and risk of teratogenicity is reassuring and, from a public health perspective, the need for simplicity and the toxicity associated with NVP are considered to outweigh concerns regarding unproven risks associated with EFV. [ 54] Studies"
    [Show abstract] [Hide abstract] ABSTRACT: These guidelines are intended as an update to those published in the Southern African Journal of HIV Medicine in 2012. Since the release of the previous guidelines, the scale up of antiretroviral therapy (ART) in southern Africa has continued. Cohort studies from the region show excellent clinical outcomes; however, ART is still being initiated late (in advanced disease) in some patients, resulting in relatively high early mortality rates. New data on antiretroviral drugs have become available. Although currently few, there are patients in the region who are failing protease-inhibitor-based second-line regimens. To address this, guidelines on third-line therapy have been expanded.
    Full-text · Article · Dec 2014 · Southern African Journal of HIV Medicine
  • Source
    • "ed with central nervous system defects in monkeys [15], and case reports of neural tube defects in human patients are concerning [16,17]. A recent meta-analysis has not shown increased risk of birth defects, including central nervous system defects, in newborns exposed to efavirenz during the first trimester of pregnancy (RR 0.85 (95% CI 0.61-1.20) [18]. This result was an important consideration by WHO recommendation for the use of efavirenz during pregnancy [19]. However new data about central nervous system defects published, beyond this meta-analysis, has been less reassuring in the consideration of the use of EFV during first trimestrer of pregnancy [14]. The continued surveillanc"
    [Show abstract] [Hide abstract] ABSTRACT: Antiretroviral therapy (ART) in pregnancy has resulted in a marked impact on reducing the risk of mother-to-child transmission (MCT) of HIV. However the safety of in utero ART exposure in newborns remains a concern. A multicenter prospective observational study of HIV-infected mother and their infants was performed in Madrid, Spain, from 2000 to 2009. Children had regular visits with clinical examination according to protocol until the age of 24 months. An abdominal ultrasound and an echocardiogram were scheduled during follow up. Birth defects (BDs) were registered according to European Surveillance of Congenital Anomalies (EUROCAT). A total of 897 live births from 872 mothers were included. Overall the birth defects prevalence observed was 6.9% (95% CI 5.4-9.1).The most commonly reported birth defects types were in genital organs and urinary system (19 cases, 30.6%) and cardiovascular system (17 cases, 27.4%). There was no increased risk for infants exposed in the first trimester to ARVs compared with unexposed infants. No significant associations were observed between exposure to any individual antiretroviral agent during pregnancy and birth defects A higher prevalence of BDs was observed, higher than previously reported. In utero exposure to ART was not proved to be a major risk factor of birth defects in infants. However the relatively small number of patients is a major limitation of this study.
    Full-text · Article · Dec 2014 · BMC Infectious Diseases
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    • "Although women in both arms reported high rates of adherence, pharmacokinetic analyses from this study and others suggest that lopinavir/ritonavir exposure may be inadequate antepartum [8,24,25]. Similar to other studies, hair antiretroviral concentrations were strong independent predictors of virologic suppression [ in humans have not demonstrated an increased risk of birth defects with efavirenz [31,32], a concern that arose from neural tube defects observed among efavirenz-exposed animals and retrospective case reports in humans. Women were enrolled in PROMOTE no earlier than 12 weeks gestation, following organogenesis; thus, we cannot comment on the impact of efavirenz exposure on birth defects in this cohort. "
    [Show abstract] [Hide abstract] ABSTRACT: Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4 cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda. Randomized clinical trial. We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ≤400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduces placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naïve pregnant women at 12-28 weeks gestation and any CD4 cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum. The median age of the 389 study participants was 29 years; median CD4 cell count was 370 cells/μl. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P < 0.001). At 48 weeks postpartum, 91.0% of women on efavirenz and 88.4% on lopinavir/ritonavir had viral suppression (P = 0.49). Grade 1 or 2 gastrointestinal adverse events were higher among women on lopinavir/ritonavir versus efavirenz. Only two infants acquired HIV (both in the lopinavir/ritonavir arm), and HIV-free infant survival was similar between study arms: 92.9% (lopinavir/ritonavir) versus 97.2% (efavirenz) (P = 0.10). Virologic suppression at delivery was higher with an efavirenz versus lopinavir/ritonavir-based regimen. However, women in both arms achieved high levels of virologic suppression through 1 year postpartum and the risk of transmission to infants was low.
    Full-text · Article · Nov 2014 · AIDS (London, England)
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