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Inadvertent Methotrexate
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My Management
A. Agree with the consulting gynecologist to administer methotrexate
B. Repeat hCG and ultrasound in 2–3 days C. Perform laparoscopy
Diagnosis and Assessment
The patient was indeed at risk to have a second ectopic pregnancy and the index of suspicion was high, as the incidence of recurrence after one tubal ectopic pregnancy is 12–15 % [1]. In general, the discriminatory zone of hCG for a detected intrauterine pregnancy by transvaginal ultrasound is 1500 mIU/mL [2]. However, there is a variation in the level of hCG and the discriminatory levels are not always reliable. Although uncommon, laboratory error can also occur. An adnexal mass could simply represent a corpus luteum.
In addition, the hCG levels in multiple pregnancies are higher at a given gestational age than those in singleton pregnancies. In women with an intrauterine multiple pregnancy, the serum hCG level could be higher than 1500 mIU and yet ultrasound exami- nation will not reveal an intrauterine pregnancy. For example, Usta et al. reported an inadvertent methotrexate administration to a woman who, at 5 gestational weeks, presented with signs and symptoms suspicious of ectopic pregnancy, after being treated with an ovulation induction agent. At 8 weeks of gestation, she was found to be carrying a triplet pregnancy, which eventually sponta- neously reduced to a singleton pregnancy. However, the baby was born with multiple congenital anomalies [3].
Therefore, it is possible that the above clinical findings do not rule out the presence of an intrauterine pregnancy. It has been es- timated that only around 20 % of patients initially diagnosed with pregnancies of unknown location are ultimately diagnosed with ec- topic pregnancies [4].
Management
In a patient who is hemodynamically stable with an uncertain diag- nosis of ectopic pregnancy, one should repeat the serum measure- ment of hCG as well as the ultrasound examination a few days later.
There is no urgency to treat the patient at this stage, and adminis- tering methotrexate could harm an intrauterine pregnancy. Before methotrexate treatment, it is crucial to ask ourselves whether there is a possibility of a viable intrauterine pregnancy. Without doubt, failure to diagnose the possibility of an intrauterine pregnancy and administering methotrexate poses more serious consequences than delaying a diagnosis of an ectopic pregnancy [5].
Methotrexate is a cytotoxic drug that inhibits the action of di- hydrofolate reductase, an enzyme that reduces dihydrofolate to tetrahydrofolate. Tetrahydrofolate is necessary for thymidylate synthesis; therefore, methotrexate acts to prevent DNA synthesis [6]. It is classified as category X (contraindicated in pregnancy), and clearly should not be given to women with a viable intra- uterine pregnancy. Otherwise, there is a risk of severe congenital anomalies, collectively known as methotrexate or aminopterin (a close structural analog of methotrexate) syndrome. This syndrome includes skeletal anomalies, central nervous system and cardiac abnormalities, as well as intrauterine growth restriction and devel- opmental delay [7, 8].
Specific findings in an affected fetus or newborn include micro- cephaly, skull bone hypoplasia, wide fontanels, craniosynostosis, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly [7]. Fetal death has also been reported [7]. Even a single dose of methotrexate can be harmful, especially during the critical window between the sixth and eighth embryonic weeks [4]. Figures 9.1, 9.2, 9.3 show images of a female child who was exposed to methotrexate in utero. Despite the report of a suc- cessful perinatal outcome in a woman with heterotopic pregnancy treated with local injection of methotrexate, the risks of methotrex- ate outweigh its benefit [9]. It appears that fetuses exposed to meth- otrexate intended to treat ectopic pregnancy are at particular risk for tetralogy of Fallot [6].
T. Tulandi and S. Ates 64
Absolute contraindications to methotrexate include breast-feed- ing, evidence of immunodeficiency, blood dyscrasias including significant anemia, sensitivity to methotrexate, active pulmonary or pelvic ulcer disease, hepatic or renal dysfunction, or alcoholism.
Kelly et al. reported a fatal outcome after methotrexate treatment for an ectopic pregnancy in a woman with renal insufficiency [10].
Fig. 9.2 A female child with multiple dysmorphic features related to meth- otrexate exposure in utero (From Seidahmed et al., A Case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype, Birth Defects Research (Part A) 2006;76:138–142. Reproduce with permission.)
Fig. 9.1 Note short forearms (From Seidahmed et al., A Case of methotrexate embry- opathy with holoprosencephaly, expanding the phenotype, Birth Defects Research (Part A) 2006;76:138–142. Reproduce with permission.)
Up to 30 % of patients who receive a single dose of methotrexate and 40 % who receive multiple doses will experience side effects.
The most common side effects are stomatitis and conjunctivitis, which are usually mild and self-limiting. Other rare side effects include pleuritis, dermatitis, alopecia, gastritis, enteritis, elevated liver enzymes, and bone marrow suppression. Therefore, even if there is no viable intrauterine pregnancy developing that is at risk for embryopathy, as in the case of a miscarriage, unnecessary meth- otrexate administration (or surgery) can cause unjustified morbid- ity to the patient.
Outcome
The patient received an intramuscular injection of methotrexate.
The consulting gynecologist performed another ultrasound 3 days later, which, to his dismay, detected an intrauterine pregnancy.
Fig. 9.3 Magnetic resonance imaging of the brain revealed absent corpus cal- losum and cerebellar hypoplasia, and prominence cisterna magna. (From Sei- dahmed et al., A Case of methotrexate embryopathy with holoprosencephaly, expanding the phenotype, Birth Defects Research (Part A) 2006;76:138–142.
Reproduced with permission)
T. Tulandi and S. Ates 66
Termination of the pregnancy was discussed but the patient de- clined, and she subsequently gave birth to a male baby. Unfortu- nately, the baby had a cleft palate and bone deformities. The family took legal action against the gynecologist, the emergency physi- cian, and the hospital.
Clinical Pearls/Pitfalls
• The discriminatory hCG levels are not always reliable.
• In multiple pregnancies, the hCG levels are higher than those in singleton pregnancies at a given gestational age.
• Although uncommon, laboratory error can occur.
• Before methotrexate treatment, one has to be sure that there is no possibility of a viable intrauterine pregnancy.
• Failure to diagnose the possibility of an intrauterine pregnancy and administering methotrexate poses more serious conse- quences than delaying a diagnosis of an ectopic pregnancy.
• Inadvertent methotrexate administration can lead to serious medical litigation against the physician and the institution.
References
1. Tulandi T. Clinical manifestations, diagnosis, and management of ectopic pregnancy. http://www.uptodate.com/ Accessed 2 December 2014.
2. Barnhart KT, Simhan H, Kamelle SA. Diagnostic accuracy of ultrasound above and below the beta-hCG discriminatory zone. Obstet Gynecol.
1999;94:583.
3. Usta IM, Nassar AH, Yunis KA, Abu-Musa AA. Methotrexate embryopathy after therapy for misdiagnosed ectopic pregnancy. Int J Gynaecol Obstet.
2007;99:253–5.
4. van Mello NM, Mol F, Ankum WM, Mol BW, van der Veen F, Hajenius PJ.
Ectopic pregnancy: how the diagnostic and therapeutic management has changed. Fertil Steril. 2012;98:1066–73.
5. Doubilet PM, Benson CB, Bourne T, Blaivas M. Society of radiologists in ultrasound multispecialty panel on early first trimester diagnosis of mis- carriage and exclusion of a viable intrauterine pregnancy. Diagnostic cri- teria for nonviable pregnancy early in the first trimester. N Engl J Med.
2013;369:1443–51.
6. Hyoun SC, Običan SG, Scialli AR. Teratogen update: methotrexate. Birth Defects Res A Clin Mol Teratol. 2012;94:187–207.
7. Poggi SH, Ghidini A. Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiag- nosis of ectopic pregnancy. Fertil Steril. 2011;96:669–71.
8. Feldkamp M, Carey JC. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of preg- nancy. Teratology. 1993;47:533–9.
9. Sijanovic S, Vidosavljevic D, Sijanovic I. Methotrexate in local treatment of cervical heterotopic pregnancy with successful perinatal outcome: case report. J Obstet Gynaecol Res. 2011;37:1241–5.
10. Kelly H, Harvey D, Moll S. A cautionary tale: fatal outcome of metho- trexate therapy given for management of ectopic pregnancy. Obstet Gy- necol. 2006;107:439–41.
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