Perinatal/Neonatal Case Presentation

Encephalocele following a periconceptional exposure to efavirenz: a case report

Abstract

The use of Efaverinz in reproductive age women needs caution as its use in the first trimster of pregnancy is reportedly associated with an increased risk of neural tube defect (NTD) in the newborn. This concern is based on evidence from animal studies and two human case reports. We report here yet another case of encephalocele born from a mother who was taking efaverenze during conception and the first 8 weeks of gestation, the critical time in the pathogenesis of NTDs.

Introduction

Efavirenz (EFV) is a first-line anteretroviral drug used in the managment of HIV infection in many developing countries. Its use in reproductive age women, particularly in the first trimester, has been a concern as it potentially is associated with the development of neural tube defects (NTDs) in the exposed fetuses.

Case

A 35-year-old Para III known HIV-positive woman on HAART presented to the antiretroviral treatment clinic of Karamara Hospital for her scheduled visit. She complained of nausea and occasional vomiting of 2 weeks and amenorrhea of 2 months. A urine pregnancy test was positive. Gestational age calculated from last menstrual period was 8 weeks and 5 days.

The woman was diagnosed to be HIV positive 2 years prior to this pregnancy and with the assessment of WHO clinical stage 3, and CD4 count of 216 mm−3 was initiated on HAART at that time. The HIV treatment regimen included Zidovudine, Lamivudine and EFV. She was not in any form of contraceptives throughout the course of antiretroviral therapy.

EFV was switched to Neverapine the day pregnancy was confirmed and she was linked to an antenatal clinic. A comprehensive prenatal evaluation was done. She had no significant complaints except those mentioned above. All her previous pregnancies and deliveries were uneventful. On physical examination she had stable vital signs and the findings in all systems were unremarkable.

Initial prenatal laboratory tests were within normal limits and CD4 count was 321 mm−3. Ultrasound scanning was performed in the second trimester and revealed a 21-week gestation singleton viable intrauterine pregnancy with a heterogeneous occipital mass measuring 4.5 cm × 4.0 cm with a defect in the occipital bone, which was consistent with encephalocele.

The mother was counseled on the anomaly detected, the available postnatal management options, the prognosis and the possibility of termination of pregnancy. She decided to carry on with the pregnancy and continued follow-up.

At 34 weeks of gestation, the woman presented with decreased fetal movement of 1 week duration, and upon examination fetal heart beat was absent and fetal death was confirmed with ultrasound examination. The encephalocele had increased to 6.5 cm × 6.0 cm. The mother was informed and was counseled on the options of management and opted for immediate termination of pregnancy. After ripening of the cervix with misoprostol and induction of labor with oxytocin, she delivered a 2100 g female fresh stillborn with an occipital encephalocele measuring 7.0 cm × 6.0 cm (Figure 1). There were no other associated gross congenital malformations. The mother refused autopsy. She had an uncomplicated postpartum course and was discharged with an advice on contraception and preconception care before any planned future pregnancy.

Figure 1
figure1

The stillborn immediately after delivery showing the encephalocele.

Discussion

The association between the use of EFV during pregnancy and NTDs has not been established by human studies, as pregnant women are always excluded from any clinical trials during drug development.1 But teratogenic effects of EFV during pregnancy involving the NTDs have been suggested in animal studies, birth registries and retrospective case reports.

The first evidence came from a developmental toxicity study in primates, which reported anomalies in 3 out of 20 fetuses of cynomologus monkeys exposed to EFV from the 20th to the 150th days of gestation at therapeutic doses comparable to those used in humans. The anomalies observed were one case of anencephaly and unilateral anophthalmia, one case of microophthalmia and one case of cleft palate.2 Subsequently two human cases of NTDs (meningomyeloceles) were reported in neonates exposed accidentally to EFV in the first trimester, which were consistent with those reported in animal studies.3, 4

Following these case reports, EFV was reclassified by the United States Food and Drug Administration (FDA) from a category C (‘risk cannot be ruled out’) to a category D (‘evidence of human fetal risk’).5

However, data from prospective pregnancy registries on EFV are inconclusive. Four retrospective reports of findings consistent with NTDs, including meningomyelocele, were reported in the interim report of antiretroviral pregnancy registry.6 While most birth registries reported no increased risk of congenital anomalies after EFV exposure during pregnancy, none had adequate cases of exposed samples to draw firm conclusion on its safety in the first trimester.7 Subsequent systematic reviews and meta-analyses also showed no increased risk of overall birth defects, but none had adequate sample size for detection of rare outcomes such as NTDs.2, 8, 9

Despite this limitation of evidence, WHO in its recent technical update recommended that EFV should be considered as part of the preferred first-line treatment option, including among women of reproductive age and those in the early stages of pregnancy.10

In the face of such inconclusive evidence, one should be vigilant and report any cases of congenital malformations that are associated with in utero exposure to EFV. To the best of our knowledge, this is the third human case report in the literature of NTDs and the first case of encephlalocele following in utero exposure to EFV in the first trimester. Even though sporadic occurrence of encephalocele is a possibility, the fact that the exposure occurred in the critical period of organogenesis and neural tube closure might suggest EFV-induced teratogenicity.

In sub-Saharan countries the majority of women on HAART are in the reproductive age and a substantial proportion of these women will conceive while on EFV-containing regimens.2 Unfortunately, the neural tube closes within the first 28 days of gestation, thus, by the time pregnancy is recognized, the potential risk for EFV toxicity has already occurred. Hence, in reproductive age women not using contraceptives, EFV should only be used if there are no other effective alternative antiretroviral substitutes and its use in the first trimester of pregnancy should be avoided.

Conclusion

To date, none of the available prospective studies and pregnancy registries has been strong enough to prove the safety of EFV during the first trimester of pregnancy. Our case strengthens the concern expressed in previous similar case reports of the potential central nervous system teratogenicity of EFV use during the first trimester. Until conclusive evidence regarding the safety of EFV in the first trimester emerges, we recommend that its use should be avoided and reproductive age women on EFV-containing regimen should be counseled on the associated risks and be put on effective contraceptives.

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Correspondence to D Bekele.

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Gudu, W., Bekele, D. Encephalocele following a periconceptional exposure to efavirenz: a case report. J Perinatol 33, 987–988 (2013). https://doi.org/10.1038/jp.2013.121

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Keywords

  • efaverinz
  • neural tube defect
  • encephalocele

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