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CLINICAL SCIENCE

Bilateral oblique facial clefts and extremity anomaly in an infant after intrauterine efavirenz exposure and review of its teratogenic risk

Shanske, Alan L.

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doi: 10.1097/QAD.0b013e328356467a
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Abstract

Introduction

Congenital anomalies may be caused by genetic or environmental factors or a combination of both. It is felt that approximately 5% of congenital structural defects are caused by teratogens [1]. Oblique facial clefts are very rare congenital deformities and constitute 0.22% of all facial clefts [2]. The occurrence of facial clefts and an extremity anomaly suggests a common underlying cause. Lateral oro-ocular clefts do not occur along normal developmental planes. Along with so-called amniotic banding defects of an extremity, they may be part of the amnion disruption complex sequence. The incidence of the amniotic disruption complex sequence varies between 1 : 1200 and 1 : 15 000 live births [3]. Sometimes the acronym, ADAM (amniotic deformity, adhesions, mutilations), or amniotic band sequence is used to describe such patients with a broad spectrum of anomalies. The acronym was first used by Hermann and Opitz [4] to describe the sequence produced by aberrant amniotic bands, sheets or strands causing disruption of normal structures.

The amnion disruption complex sequence is a disruption complex sequence with a disputed pathogenesis. Streeter [5] proposed a primary defect in the germinal disc. Torpin [6] suggested that the fetal anomalies are secondary to a primary rupture of the amnion early in gestation. The amniotic cavity expands during the 12th week of gestation pressing against the chorion and obliterating the extraembryonic coelom. If this process is incomplete, lack of support of the chorion may cause the amnion to rupture resulting in compression or band defects. Our patient had both a compression defect of the forearm and band defects of the craniofacial region. The amniotic rupture sequence has not previously been reported in an HIV-exposed newborn. Additionally, it has not been associated with fetal antiretroviral exposure in the Antiretroviral Pregnancy Registry (APR) [7] (http://www.APRegistry.com/forms/interim_report.pdf) or fetal statin exposure [8].

Case report

The infant girl was the 2945 g product (25th percentile) of a 37-week gestation. The pregnancy was complicated by maternal HIV, hypercholesterolemia and gestational diabetes. She was delivered by normal spontaneous vaginal delivery to a 35-year-old mother who was diagnosed with AIDS in 1999 when she presented with cytomegalovirus esophagitis. Her viral load was undetectable during the pregnancy. Before this pregnancy her HIV disease and hypercholesterolemia were effectively treated with a once-daily single efavirenz–emcitribine–tenofavir antiretroviral combination pill (Atripla) along with the antihyperlipidemic agent, atorvastatin. She continued these agents until the diagnosis of pregnancy was made at 7 weeks estimated gestational age (or 5 weeks conceptional age) when she switched to combination lamivudine–zidovudine (Combivir) and nelfinavir. Gestational diabetes was diagnosed at 12 weeks gestation, and she was placed on insulin three times daily. A bilateral cleft lip and palate and swollen left forearm were noted by ultrasound. The newborn examination revealed bilateral oblique facial clefts (a Tessier cleft number 3 on the right and number 4 on the left) (Tessier [9]) and right microphthalmia with an ectopic right lacrimal duct protruding from the right inner canthus (Fig. 1). The head circumference was 33.5 cm (25th percentile). The skeletal defect was clinically apparent in the right lateral maxillary alveolus tranversing the maxilla to the infraorbital rim. A circumferential constriction band encircled the left forearm (Fig. 2). A gastrostomy tube was placed at 2 weeks because of feeding difficulties. The vision in the left eye is felt to be normal. She underwent repair of the facial clefts at 7 months with bilateral rotation advancements. The eyelid was repaired at the level of the tarsus and the lacrimal duct remnant was removed from the right eye. The constriction band was released at the same time by the use of multiple z-plasties. This was followed several months later by a second stage repair of the left orofacial ocular cleft and repair of left lower eyelid coloboma with lower lateral canthotomy and Tenzel flaps. A temporary tarsoraphy was placed at the lateral limbus. When last examined at 8 months, her weight was 6.97 kg (10th percentile), length 65 cm (10th percentile), and head circumference 43.5 cm (50th percentile) (Fig. 3). The outer canthal distance was 8 cm and the inner 2.5 cm. The facial clefts were repaired and wide bilateral palatal clefts remained. Her psychomotor development was appropriate. She was able to sit independently and stand supported. A three-dimensional computed tomography of the face with no contrast revealed a hypoplastic maxilla, bilateral clefts of the palate and floor of the nasal cavities (Fig. 4). The defect on the left extended to the anterior and medial walls of left orbit. The right globe was small.

Fig. 1
Fig. 1:
Patient at 3 months of age showing a Tessier cleft number 3 on the left and a number 4 on the right.
Fig. 2
Fig. 2:
Constriction band around left forearm.
Fig. 3
Fig. 3:
Patient at 8 months following surgery.
Fig. 4
Fig. 4:
Three-dimensional computed tomography scan showing clefts of nasal cavity, palate and orbit.

The antiretroviral pregnancy registry

The APR is a prospective exposure-registration cohort study designed to detect a potential increase in the risk of birth defects following antiretroviral drug use during pregnancy [7] (APR). Birth defect prevalence after first trimester exposure is compared to second/third trimester exposures and to the Centers for Disease Control's population-based surveillance data (Metropolitan Atlanta Congenital Defects Program) [10] during the period 1 January 1989 through 31 July 2011.

The pediatric aids clinical trials group

The Pediatric AIDS Clinical Trials Group protocols 219 and 219C were used to further estimate the independent association between in-utero antiretroviral exposure and birth defects [11].

Results

Between 1989 and July 2011, the ongoing APR [7], (http://www.APRegistry.com) has found no increase in birth defects in 5779 prospectively monitored first trimester exposures compared with second or third trimester exposures [7]. Prospective monitoring of 644 efavirenz-exposed pregnancies has not shown an increase in the prevalence of birth defects after first trimester exposure. However, one of these prospectively reported defects was a neural tube defect and our current case was described as a case of anophthalmia with severe oblique facial clefts and amniotic banding. This child represents the first association of the amniotic disruption complex sequence after antiretroviral exposure and was registered prospectively in the Registry (Table 1).

Table 1
Table 1:
Number of birth defects by trimester of earliest exposure to any ART or prospective registry cases with follow-up data closed through 31 July 2011.

There was a total of 5931 children enrolled in protocols 219 and 219C and 2202 that were enrolled before 1 year of age and were the study population. A total of 117 children had birth defects for a prevalence of 5.3% [confidence interval (CI): 4.4–6.3)]. The prevalence of birth defects was higher in this cohort than in other pediatric cohorts. The defect rate was even higher among children exposed to efavirenz during the first trimester at 15.6% [adjusted odds ratio = 4.31 (95% CI: 1.56–11.86)]. One of the five cases had a meningomyelocele and Arnold-Chiari malformation type II [11].

Discussion

Lateral oro-ocular clefts are not consistent with the normal embryologic development of the face and can occur as a result of amniotic bands (http://www.cdc.gov/ncbddd/bd/macdp.htm) [10]. The pathogenesis of amnion disruption is unclear and amnion rupture is rarely associated with teratogenic exposure. A prenatal history of febrile acute illness and vaginal bleeding during the first trimester were found as risk factors for the ADAM sequence [12]. Teratogenic exposure via some hypoxicemic mechanism has been reported in South American Indians living above 2000 m [13]. Sentilhes et al.[3] reported the amniotic band syndrome after mifepristone exposure in early pregnancy. Amniotic bands are found in three types of lesions: constrictive tissue bands, amniotic adhesions and the limb-body wall complex (LBWC) [14]. Therefore, facial clefts associated with amnion adhesions may not simply be a result of amnion rupture. They may be part of the LBWC due to an entirely different pathogenetic mechanism. Facial and pharyngeal anomalies in LBWC include oblique facial clefts. This hypothesis is supported by the observation that the amnion is intact in some cases. The suggested mechanism is an alteration of embryonic blood supply between 4 and 6 weeks gestation that leads to disruptive vascular defects to the developing embryo including facial clefts [15]. The amnion becomes adherent to the fetal areas made necrotic by decreased vascular supply.

Women of reproductive age with HIV/AIDS face unique challenges when considering the risks and benefits of first-line HIV treatment options. Efavirenz (Sustiva) is a highly potent nonnucleoside reverse transcriptase inhibitor in wide use. It is recommended as part of first-line combination treatment for HIV-1 infections. As part of the once-daily single pill efavirenz–emcitribine–tenofavir preparation (Atripla), it is highly popular among patients and caregivers alike due to its low toxicity and side effect profile, its unique convenience and high adherence rates. Women with hypercholesterolemia face similar challenges. Statin drugs have been associated with limb anomalies, but the significance of this association is controversial [8].

Because of a high number of craniofacial defects in cynomolgus monkeys in an unpublished but widely cited premarketing primate study [16] and retrospective reports of human central nervous system/neural tube defects after in-utero efavirenz exposure, it is the only antiretroviral drug that is rated by the FDA Pregnancy Category D and its use is not recommended during pregnancy [17] (Perinatal HIV Guidelines Working Group). The first case of a myelomeningocele after intrauterine exposure was reported by Fundaro et al. in 2002 [18]. The exposure occurred during the first 28 days of gestation. The second case of a myelomeningocele also after a first trimester intrauterine exposure was reported by Saitoh et al. in 2005 [19]. Anencephaly, anophthalmia, microophthalmia or cleft palate were observed in three of 20 treated cynolmogus monkey pregnancies in a developmental toxicity study [16]. No teratogenic findings were reported in studies of pregnant rabbits and rats treated with efavirenz probably because of different pharmacokinetics.

We do not offer an etiologic explanation here, but highlight the importance of prospective evaluation of first trimester exposures to potential teratogens. Shephard [20] outlined the required proofs of human teratogenicity as proven exposure to agent at a critical time, careful delineation of the clinical cases and three or more cases. The selection of three or more was apparently arbitrary. Certainly, it must be obvious that these criteria cannot be fulfilled unless the first two cases have been identified. In addition, there is an animal model of craniofacial anomalies in cynomolgus monkeys that supports the biologic plausibility of the defects. Carey et al.[21] propose a stringent evaluation of teratogenicity based upon the identification of three or more cases with a distinct pattern of embryopathy of rare occurrence in an uncommon pregnancy exposure. They suggest and I agree that less than three cases makes the association of the exposure and outcome tenuous. The amniotic disruption complex sequence is a rare pattern of multiple defects with fewer defects than one in 1000 births, and antiretroviral exposure is an uncommon pregnancy exposure. Furthermore, our observation is based upon a prospective study with a denominator of risk of one of 644 efavirenz-exposed or one of 5779 antiretroviral-exposed first trimester pregnancies.

By reporting and registering more cases, we will be able to better assess the risks such medications pose to the developing fetus. The publication of a single case report has the potential to contribute to our knowledge of the significance of prenatal exposure to antiretroviral drugs and other medications for common HIV-associated disorders. It also generates a hypothesis that can be tested with further clinical data, animal models and epidemiologic studies.

Acknowledgements

A.L.S. cared for and evaluated the patient and wrote the article.

Conflicts of interest

The author has no conflicting financial interest.

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Keywords:

amnion disruption complex sequence; antiretroviral; efavirenz; oblique facial clefts

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