Extremity Findings of Methotrexate Embryopathy

Abstract

Background: Methotrexate (MTX) is widely used as an immunosuppressant, chemotherapeutic, and abortifacient agent. It is also a potent teratogen, and intentional or unintentional exposure during pregnancy is associated with heterogeneous birth anomalies. Methods: We retrospectively reviewed a cohort of patients who presented to our clinic with limb anomalies in the setting of MTX embryopathy. Results: In our case series, we describe 7 cases of patients who had limb anomalies with heterogeneous functionality, from severely debilitating to completely asymptomatic. Most of the upper extremity anomalies in our group were managed conservatively. Conclusions: Methotrexate embryopathy is a rare but clinically important entity with phenotypic and functional variability. This series underscores the need for proper counseling of patients and raises concern regarding using this medication for the purpose of abortion.

Introduction

Methotrexate (MTX), a derivative of aminopterin, has been used to treat malignancies, autoimmune diseases, dermatologic conditions, ectopic pregnancies, and voluntary early fetal terminations.^1-3 MTX acts as a folic acid antagonist and disrupts DNA methylation. As a result, intentional or unintentional use during pregnancy can lead to extensive birth defects.^1,2 These teratogenic effects were once thought to occur only at higher doses, but several studies have demonstrated that spontaneous abortion and birth defects can occur even after exposure to low-dose prenatal therapy during the first trimester of pregnancy.⁴ This finding is consistent with disruption of organogenesis between weeks 6 and 8 of gestation, the most vulnerable period of teratogenicity.⁵

Fetal methotrexate syndrome (FMS) was first described in the 1950s,⁶ and the constellation of symptoms it defines has grown over time as more cases have been reported.^7,8 Some authorities have questioned whether all of the described abnormalities constitute a true association with in utero MTX exposure. Nevertheless, manifestations of MTX embryopathy include craniofacial, cardiac, pulmonary, gastrointestinal (GI), genitourinary, and musculoskeletal anomalies.^1,9 We present a case series of patients with limb and other abnormalities associated with in utero MTX exposure.

Methods

After institutional review board approval, we analyzed the medical records of 7 patients with in utero exposure to MTX and postnatal diagnosis of limb and head abnormalities who presented to our hospital since 2013. Intention to terminate pregnancy was the reason for prenatal exposure to MTX in all patients. Clinical data are summarized in Table 1.

Table 1.

Clinical Data of Patients Exposed Prenatally to Methotrexate.

Case	Time at exposure, wk	Preterm	Birth weight, g	Limb abnormalities	Other abnormalities
1	6–8	+	1252	– Bilateral upper extremity brachydactyly – Bilateral hypoplastic thumbs – Bilateral club foot and bilateral cleft foot with a single great toe on each foot.	– Bicoronal and right lambdoid synostosis – Mild narrowing of the upper cervical canal C1–C3
2	6	–	2523	– Bilateral radiohumeral synostosis with hypoplastic radius and ulna – Bilateral clinodactyly – Bilateral shortened lower extremities and clubfoot	– Right coronal synostosis – Stenosis of the craniocervical junction due to small C1 ring. – Bilateral pyelectasis of the kidneys
3	8	+	1503	– Bilateral absent thumbs – Bilateral small finger clinodactyly – Bilateral feet abnormal with 3 toes on each foot with the medial 2 toes with syndactyly	– Moderate conductive hearing loss – Sagittal and lambdoid synostosis
4	8	+	1503	– Clinodactyly of bilateral index fingers with ulnar deviation – Bilateral feet are narrowed with a single formed ray and digit and 1 rudimentary digit attached to a narrow stalk on the right foot.	– Microcephaly – Chiari I malformation – Hydrocephalus – Sagittal and bilateral lambdoid synostosis – Feeding difficulties—G tube feeding
5	6	+	2335	– Mild bilateral clinodactyly with short fingers – Absent of the third toe with intact metatarsal and rudimentary fourth toe and absent fifth ray	– Microphthalmia
6	6	+	1360	– Bilateral small finger clinodactyly	– Left forehead retrusion, left eyebrow elevation – Left coronal synostosis – Parieto–occipital bone skull defects – Small and low–set ears. – High–arched anterior palate
7	6	–	2665	– Bilateral fifth finger brachial clinodactyly – Widened first toe and a sandal gap of the fourth toe bilaterally with absent toenails	– Microcephaly – Bilateral parietal calvarial defects – Hypospadias and ventral chordee

Note. + symbol indicates the feature was present, –indicates the feature was not present.

Clinical Series

Case 1

A 2-year-old female presented to our clinic with multiple limb abnormalities. She was born via spontaneous vaginal delivery at 33 5/7 weeks of gestation. The patient had in utero exposure to one dose of MTX at approximately 6 to 8 weeks of pregnancy in an attempted termination. Prenatal ultrasonography and magnetic resonance imaging (MRI) revealed a viable fetus with anomalies of the head, limbs, and GI tract.

Physical examination revealed a retruded forehead with orbital proptosis, turricephaly, and inferiorly displaced ears; computed tomographic (CT) scans showed this to be the result of premature fusion of both coronals and the right lambdoid cranial sutures. The patient also had various upper extremity anomalies including bilateral brachydactyly, absent volar creases on all fingers, hypoplastic thumbs with singe volar crease, and limited proximal interphalangeal (PIP) flexion contractures (−10°) (Figure 1). Lower extremity anomalies included bilateral clubfoot and oligodactyly of both feet (single great toe). Radiographs of her hands revealed small right first metacarpal, hypoplastic middle phalanges of the second and fifth left finger with clinodactyly, and absent distal phalanx on the right thumb. No radiographies of the feet were taken.

Figure 1.

Case 1. Bilateral hands with hypoplasia of the index, long, and small finger medial phalanx, and the absence of left thumb distal phalanx.

The upper extremity deformities were managed conservatively. Currently, the patient continues to undergo physical therapy for both hands and feet. At age 5 years, she is able to ambulate and has few functional limitations.

Case 2

An 8-month-old male born at 39 2/7 weeks presented with multiple anomalies. The patient was exposed to MTX at 6 weeks gestation and was born via cesarean section due to fetal bradycardia. Prenatal imaging including ultrasonography and fetal MRI revealed brachycephaly, renal anomalies, and multiple skeletal anomalies. His APGAR scores were 8/9 at 1 and 5 minutes, respectively. He was admitted in the neonatal intensive care unit (NICU) and remained hospitalized for 2 weeks due to feeding problems.

At birth, the patient was noted to have facial asymmetry consistent with right coronal craniosynostosis. All extremities had abnormalities (Figure 2): rhizomelic shortening of both arms with fixed elbow contractures in 90° of flexion, bilateral small finger clinodactyly, bilateral femoral shortening, and a right clubfoot. Radiographs showed short but fully formed humerii, complete radio-ulnar-humeral synostosis, hypoplasia of the radius and ulna, ulnar clinodactyly of the right finger at the PIP, and shortening of both femurs with hip subluxation. The MRI and CT imaging were consistent with right coronal synostosis and C1-C2 subluxation with spinal cord compression.

Figure 2.

Case 2. (a) Clinical and (b) radiograph finding: shortened humerii, radioulnar synostosis with fixed elbow contractures, and small finger clinodactyly.

The patient’s right clubfoot was managed with serial casting and Achilles tenotomy. The bilateral upper extremity anomalies are being managed nonoperatively at this time as he is remarkably functional.

Case 3

A 3-month-old female presented for complex congenital hand and foot anomalies. The patient had a history of MTX exposure at 8 weeks gestation and was born preterm at 35 weeks gestation by cesarean section due to decreased fetal movements. Her mother had poor prenatal care, but the prenatal ultrasonographic studies were normal. The mother also reported alcohol use of 1 to 2 drinks per week during early pregnancy. The infant remained in the NICU for 18 days after birth due to feeding problems, low insulin levels, and low platelets. All of these conditions ultimately resolved.

The patient had bilateral thumb aplasia, small finger radial clinodactyly, and a total of 3 toes on each foot with syndactyly of the medial 2 toes (Figure 3). Imaging studies of the upper extremities demonstrated the absence of both thumbs, and foreshortening of the small finger middle phalanx. Radiographs of the lower extremities showed 3 toes on each foot, and syndactyly of toes 1 and 2. She underwent pollicization of both hands between 12 and 18 months with an uncomplicated postoperative course.

Figure 3.

Case 3. Right hand and foot radiographs. (a) Absence of thumb, small finger clinodactyly and (b) syndactyly of the right foot.

Case 4

A 4-month-old male was evaluated for head and limb abnormalities. The patient has a history of fetal MTX exposure at 8 weeks of gestation. He was born at 35 weeks via cesarean section due to maternal preeclampsia.

Physical examination revealed mild hypertelorism, strabismus, microcephaly, and flattening and narrowing of occipital and parietal bones. The patient showed oligodactyly of both feet, which manifested as a narrow forefoot with a single formed digit, an additional rudimentary digit attached to a narrow stalk on the right foot, and digital syndactyly with a single rudimentary digit on the left foot (Figure 4a).

Figure 4.

Case 4. (a) Clinical and (b) radiograph findings: right foot oligodactyly with a narrow forefoot.

Radiographic findings of the limbs included an abnormal appearance of the left foot with a single ossified ray comprised of a metatarsal bone and proximal and distal phalanges (Figure 4b). The rudimentary toes were removed at 18 months. The patient was fitted for orthotic prostheses to assist with deambulation given his narrow foot.

Case 5

A 4-year-old female presented to our clinic with a history of MTX exposure at 6 weeks gestation secondary to a failed abortion with MTX and misoprostol. The patient was born at 37 weeks via spontaneous vaginal delivery with APGAR scores of 8/9 at 1 and 5 minutes, respectively.

At birth, the infant was found to have hypertelorism, microphthalmia, micrognathia, microcephaly, a wide posterior fontanelle, a flat nasal bridge, and a short neck. The patient presented with a simian crease and mild bilateral clinodactyly with short fingers. Her dysmorphic lower extremities included the absence of the fifth toe on the right foot, a rudimentary fifth toe on the left foot, and missing third and fourth toes on both feet.

The patient’s bilateral upper and lower extremity findings are being managed nonoperatively, and she has minimal, if any, functional deficit.

Case 6

An 8-month-old male presented to our clinic with multiple congenital abnormalities.

The patient was born at 35 weeks via vaginal delivery with intrauterine growth restriction. His prenatal history was significant for MTX exposure at 6 weeks of gestation for attempted pregnancy termination. Soon after birth, he was transferred to our hospital for further evaluation of his anomalies.

The patient presented with left forehead retrusion, a left coronal ridge, and a large extensive defect (5-6 cm) over his parieto-occipital skull extending across the midline. He also had small, low-set ears, and a high-arched palate. His extremities demonstrated bilateral small finger clinodactyly with no other abnormality.

The bilateral clinodactyly was managed nonoperatively as there was no scissoring or overlap of the digits.

Case 7

A 1-year-old male with history of MTX exposure at 6 weeks of gestation was born at full term via spontaneous vaginal delivery.

Physical examination demonstrated a triangularly shaped face and a head circumference below the second percentile for his age. On palpation of his scalp, bilateral parietal calvarial defects were encountered measuring approximately 2 cm on the right side and 1 cm on the left side. He had posteriorly rotated ears and a short flat philtrum with an inverted U-shaped upper lip. Genitourinary examination demonstrated hypospadias and ventral chordee. Examination of the extremities was notable for bilateral fifth finger brachial clinodactyly. His feet demonstrated a widened first toe and a bilateral sandal gap of the fourth toe with absent toenails. The limb abnormalities were managed conservatively without functional limitation.

Discussion

MTX is frequently used as a chemotherapeutic agent in certain tumors, an immunosuppressant in certain autoimmune disorders, and an abortifacient for both early voluntary terminations and ectopic pregnancy treatments.^10-13 Adverse effects on the developing fetus during the first trimester of gestation can occur even in small doses.^3,8 For this reason, its use during early pregnancy is contraindicated for medical treatment and is only indicated for abortive purposes.^1,2 This case series highlights a wide variety of extremity deformities associated with the teratogenic effects of MTX.

Methotrexate competes to occupy the folate binding site of the enzyme dihydrofolate reductase (DHFR). This inhibits RNA and DNA production, which consequently reduces protein synthesis. In the context of a growing embryo or fetus, this has grave effects including demise or, in cases where pregnancy does not terminate, severe developmental anomalies.^3,14 The exact pathway by which MTX adversely affects extremity embryogenesis remains unclear. However, its role in immunosuppression is thought to stem from its ability to inhibit DHFR as well as other folate-dependent enzymes.¹⁰

The FMS or MTX embryopathy extremity findings remain a heterogeneous group of phenotypes previously documented in the literature (Table 2). Aside from the extremity abnormalities, previous groups have described genitourinary, skeletal, and cardiovascular abnormalities, as well as anomalies including cleft lip, craniosynostosis, and other craniofacial malformations.^5,13,15 Studies comparing the incidence of deformities after MTX exposure to those present in the general population have concluded that there is a disproportionately higher incidence of pulmonary atresia, craniosynostosis, and limb deficiencies in patients exposed in utero to MTX.⁸

Table 2.

Reported Extremity Findings in Methotrexate Embryopathy.

Reference	Gestational age at exposure	Methotrexate dose	Gestational age, wk	Limb anomalies	Other anomalies
Shaw et al16	Day 55-58 of pregnancy	Unknown	39	Short forearms	Craniofacial: Globular head shape, poorly develop orbital ridges Moderate facial asymmetry, marked micrognathia High-arched palate Low-set small ear
Buckley, Lenore, et al17	First trimester	100 mg over a period of 8 wk.	35 (wt: 1.79 kg)	Right thumb deformed. Reduction of the radial ray on the right side. Syndactyly of the fourth and fifth toes of the right foot. Absence of the fifth metatarsal bone was absent. Hypoplasic nails.	Craniofacial: Brachycephaly, coronal ridging, shallow orbits with hypertelorism, and retrognathia, bifid uvula. Left bifid lobule, overfolded helix, ear canal closed/stenotic Dorsal kyphosis with L5 and S1 hemivertebrae Heart and lungs: Doubly committed ventricular septal defect with transposed great arteries. Pulmonary stenosis, a restrictive atrial septal defect. Small patent ductus arteriosus. Aberrant right subclavian artery
Bawle et al1	6-9 wk	Case 1: Unknown Case 2: 80 mg of methotrexate weekly + 1200 mg fluorouracil Case 3: 100 mg biweekly	Case 1: Unknown Case 2: 29 Case 3: 29	Case 1: Syndactyly, broad hallux, hypoplasia of the toes Cases 2 and 3: Without limb abnormalities	Craniofacial: Hypertelorism, microcephaly, bitemporal narrowing, ptosis of the eyelids, short palpebral fissures, low-set ears, micrognathia
Granzow et al18	8 wk	Unknown	Unknown	Right toe: Agenesis of the fifth toe with a foreshortened second toe Left toe: Fusion of the third, fourth, and fifth toes with clinodactyly	Craniofacial: Cleft of the soft palate
Goffman et al19	6 wk	10 mg daily for 10 days		Shortened proximal long bones in upper and lower extremities. Bilateral fifth finger clinodactyly and bilateral second toe clinodactyly	Craniofacial: Large flattened anterior fontanelle, hypertelorism, a broad nasal bridge, mild micrognathia Hemivertebra at T10 level resulting in mild scoliosis Genitourinary: Ambiguous genitelia: micropenis
Piggott et al20	Case 1: First trimester of pregnancy	Unknown	35 wk (wt: 1.7 kg)	No limb abnormalities	Craniofacial: Absent of the left auditory canal, micrognathia Cardiovascular: Three aortopulmonary collaterals Gastrointestinal: Intestinal malrotation Genitourinary: Multicystics dysplastic left kidney and a mildly hydronephrotic right kidney
	Case 2: 6-7 wk	Unknown	26 wk	Club feet, accessory digits	Craniofacial: Micrognathia Cardiovascular: Tetralogy of fallot Genitourinary: Abnormal right kidney position with chronic renal parenchymal disease
Hyoun et al8				Short limbs, talipes, hypodactyly, and syndactyly	Craniofacial: Microcephaly, hypoplasia of skull bones, coronal or lambdoid craniosynostosis. Broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears. Maxillary hypoplasia, epicanthal folds
Dawson et al21				Club feet	Craniofacial: Cleft palate, craniosynostosis and microtia Cardiovascular: Congenital heart defects Congenital diaphragmatic hernia Genitourinay: Hypospadias.
Martino et al22				Talipes equinovarus	Craniofacial: Craniosysnostosis Myelomeningocele
Seidahmed et al7	6 wk	A total of 52.5 mg	At term	Mesomelia Hypoplastic first toes and nails	Craniofacial: Hypertelorism, cleft palate, micrognathia, low-set ears. Metopic and coronal synostosis Central nervous system: Agenesis of corpus callosum, a single ventricle, fused thalami, absent cavum septum pellucidum and falx, and a hypoplastic cerebellum with prominent cisterna magna.
Kozma and Ramasethu5	7 wk	75 mg intramuscular + 200 µg misoprostol	35 wk	Fused thumbs and index fingers Bilateral clinodactyly Absent palmar crease Three toes with wide gap between first and second toes Severely hypotonic extremities	Craniofacial: Very wide anterior fontanelle. Shallow orbital ridges, depressed nasal bridge, severe micrognathia, posterior cleft palate Forebrain malformation consistent with arrhinencephaly. No olfactory bulbs Low-set ears Torax: Hypoplastic chest, pulmonary hypoplasia Genitourinary: Undescended testicles

Our series focuses on extremity abnormalities associated with MTX embryopathy. All the deformities encountered were bilateral, with numerous postaxial deformities of the distal limbs including brachydactyly, upper and lower extremity rhizomelia, oligodactyly, syndactyly, and clinodactyly. These deformities varied in functional significance from severely debilitating to completely asymptomatic. Most of the upper extremity anomalies in our group were managed conservatively.

Physical findings similar to the ones described have been previously documented.^16-25 However, not all patients with FMS exhibit limb anomalies. For instance, Corona-Rivera et al²⁴ described a male infant who was exposed to MTX during the fifth and sixth weeks of gestation who had multiple deformities identified at birth. This included genitourinary anomalies and severe central nervous system anomalies, supporting a diagnosis of FMS. Likewise, Poggi and Ghidini¹³ reported a newborn with multiple birth defects including a single umbilical artery, tetralogy of Fallot, and horseshoe lung, despite administration of high doses of folic acid. The reason for the heterogeneity presentation is still unclear. Further research is warranted to understand this phenomenon.

Conclusions

Methotrexate embryopathy is a rare but clinically important entity with phenotypic and functional variability. Our clinical series adds to the growing list of patients who sustained relatively severe teratogenic effects as a consequence of a failed abortion attempt using MTX. This series underscores the need for proper counseling of patients by clinicians using this abortifacient modality. The unusual combination of cranial and extremity anomalies described here and in other case reports should raise concerns for clinicians prescribing this treatment for the purpose of abortion.