Methotrexate (MTX), a folate antagonist, is used in various fields, including malignancies and rheumatoid or inflammatory autoimmune diseases. MTX is used for the non-surgical treatment of ectopic pregnancies and the elective termination of pregnancy. The teratogenic effects of MTX have been recognized since the 1960s. Fetal methotrexate syndrome (FMS) was established based on the study of congenital anomalies. Generally, there is a risk of FMS when MTX is used between four and six weeks after conception. Here, we reviewed the literature regarding MTX usage and described a case of FMS that was born with a rare anomaly, such as tibial hemimelia, in a mother who had received MTX 4 months before conception for the management of an ectopic pregnancy.

Ectopic pregnancy occurs when a fertilized ovum attaches outside the uterus. As a complication in approximately 1‑2% of all pregnancies, ectopic pregnancies may cause catastrophic hemorrhage as a result of invading maternal blood vessels. Therefore, early diagnosis and timely treatment are crucial for women with ectopic pregnancy. In this study, we aimed to identify and determine the efficacy of serum biomarkers for the prompt diagnosis of ectopic pregnancy. For this purpose, the serum concentrations of progesterone, β human chorionic gonadotropin (β‑hCG) and cancer antigen‑125 (CA125) were detected by solid‑phase, competitive binding chemiluminescent enzyme immunoassays. Flow cytometry was used to analyze the percentage of CD3+ T cells in women with ectopic pregnancy. Pathological analysis of tubal and villus tissues was performed by hematoxylin and eosin (H&E) staining. After receiving an injection of methotrexate (MTX), patients were examined by transvaginal ultrasound to detect the size of the echogenic mass. The results revealed that the serum levels of progesterone, β‑HCG and CA125 were significantly decreased in women with ectopic pregnancy, whereas the percentage of CD3+ T cells was increased in women with ectopic pregnancy. Histopathological examination revealed blood clots with small tissue fragments of a tubal‑type epithelium and incomplete pile structures. Five days after the MTX injection, an echogenic mass was found with a size of 1.7x1.2x1.6 cm that contained a gestational sac‑like structure and a yolk sac. On the whole, the findings of this study indicate the at the joint detection of progesterone, β‑HCG, CA125 serum levels and the CD3+ T cell percentage could be applied as a reliable indicator for the early diagnosis of ectopic pregnancy. MTX administration was determined to be an efficacious approach for the treatment of ectopic pregnancy.

Methotrexate is a folic acid antagonist known to be teratogenic in humans. Several cases of congenital malformations after fetal exposure to methotrexate have been published, resulting in the establishment of the 'fetal methotrexate syndrome'. However, it is unclear which congenital anomalies can truly be attributed to methotrexate exposure. The objective of this review is to delineate a consistent phenotype of the fetal methotrexate syndrome. We performed a systematic review that yielded 29 cases of (congenital) anomalies after in utero exposure to methotrexate and compared their malformation pattern to that of children and fetuses with congenital anomalies in general. Statistically significant higher proportions of microcephaly, craniosynostosis, tetralogy of Fallot, pulmonary valve atresia, limb reduction defects and syndactyly were found in the methotrexate group, indicating that these congenital anomalies are truly part of the fetal methotrexate syndrome. These results aid clinicians with diagnosing fetal methotrexate syndrome.

To report clinical experience with methotrexate (MTX) treatment for suspected but not definite ectopic pregnancy (EP).

This was a retrospective cohort study. All patients treated with MTX for presumed EP between 2000 and 2016 were included. Demographic, clinical, sonographic, and outcome data were collected and analyzed.

A total of 820 patients were treated with MTX, 692 (84.4%) of which were lacking definitive features of EP; 155 (22.4%) failed to follow up until complete resolution and were excluded. Retrospective sonographic categorization was applied to 537 patients; of those patients, 393 (73.2%) were categorized as probable EPs, 136 (25.3%) pregnancies of unknown location (PULs), and 8 (1.5%) probable intrauterine pregnancies (IUPs). Sixteen were eventually diagnosed with IUP: 6 from the probable EPs, 9 from the PULs, and 1 from the probable IUP group. Patients with final diagnosis of IUP had higher values of β-human chorionic gonadotropin as well as lower prevalence of adnexal mass (38% versus 74%; P = .003), higher prevalence of intracavitary fluid (44% versus 9%; P = .0004) and thicker endometrium (17.1 ± 11.8 versus 9.7 ± 5.6; P = .04). None of the sonographic parameters were able to distinguish patients with IUP. One patient of the 16 with IUP was diagnosed with a viable pregnancy, and 7 additional patients had a possible viable pregnancy. None of them elected to continue the pregnancy.

Most patients with suspected EP who are eligible for medical treatment lack definitive sonographic features of EP. Treatment with MTX in such cases should be delayed, as clinically reasonable, to improve the diagnosis and prevent inadvertent administration of MTX to patients with a viable IUP.

Pregnancy of unknown location is a situation in which a positive pregnancy test occurs, but a transvaginal ultrasound does not show intrauterine or ectopic gestation. One great concern of pregnancy of unknown location is that they are cases of ectopic pregnancy whose diagnosis might be postponed. Transvaginal ultrasound is able to identify an ectopic pregnancy with a sensitivity ranging from 87% to 94% and a specificity ranging from 94% to 99%. A patient with pregnancy of unknown location should be followed up until an outcome is obtained. The only valid biomarkers with clinical application and validation are serum levels of the beta fraction of hCG and progesterone. A single serum dosage of hCG is used only to determine whether the value obtained is above or below the discriminatory zone, that means the value of serum hCG above which an intrauterine gestational sac should be visible on ultrasound. Serum progesterone levels are a satisfactory marker of pregnancy viability, but they are unable to predict the location of a pregnancy of unknown location: levels below 5 ng/mL are associated with nonviable gestations, whereas levels above 20 ng/mL are correlated with viable intrauterine pregnancies. Most cases are low risk and can be monitored by expectant management with transvaginal ultrasound and serial serum hCG levels, in addition to the serum progesterone levels. To minimize diagnostic error and intervene during progressive intrauterine gestation, protocol indicates active treatment only in situations when progressive intrauterine pregnancy is excluded and a high possibility of ectopic pregnancy exists.

Since being introduced more than 30 years ago, endovaginal ultrasonography (US) and quantitative testing of serum levels of the beta subunit of human chorionic gonadotropin have become the standard means of establishing the presence of normal intrauterine pregnancy (IUP), failed IUP, and ectopic pregnancy. Appropriate use of these powerful tools requires clear, standardized interpretations based on conservative criteria to protect both the pregnancy and the mother. Since diagnoses are assigned earlier and available medical treatments for ectopic pregnancy and failed IUP are expanding, emphasis must carefully shift toward watchful waiting when the mother is clinically stable and a definitive location for the pregnancy cannot be established with US. To this end and to prevent inadvertent harm to early normal pregnancies, the Society of Radiologists in Ultrasound convened a consensus panel of radiologists, obstetricians, and emergency medicine physicians in 2012 with the goal of reviewing current literature and clinical practices and formulating modern criteria and terminology for the various first-trimester outcomes.

Ectopic pregnancy (EP) is the leading cause of maternal morbidity and mortality during the first trimester and the incidence increases dramatically with in vitro fertilisation and embryo transfer (IVF-ET). The co-existence of an EP with a viable intrauterine pregnancy (IUP) is known as heterotopic pregnancy (HP) affecting about 1% of patients during assisted conception. EP/HP can cause significant morbidity and occasional mortality and represent diagnostic and therapeutic challenges, particularly during fertility treatment. Many risk factors related to IVF-ET techniques and the cause of infertility have been documented. The combination of transvaginal ultrasound (TVS) and serum human chorionic gonadotrophin (hCG) is the most reliable diagnostic tool, with early diagnosis of EP/HP permitting conservative management. This review describes the risk factors, diagnostic modalities and treatment approaches of EP/HP during IVF-ET and also their impact on subsequent fertility treatment.

The scientific literature was searched for studies investigating EP/HP during IVF-ET. Publications in English and within the past 6 years were mostly selected.

A history of tubal infertility, pelvic inflammatory disease and specific aspects of embryo transfer technique are the most significant risk factors for later EP. Early measurement of serum hCG and performance of TVS by an expert operator as early as gestational week 5 can identify cases of possible EP. These women should be closely monitored with repeated ultrasound and hCG measurement until a diagnosis is reached. Treatment must be customised to the clinical condition and future fertility requirements of the patient. In cases of HP, the viable IUP can be preserved in the majority of cases but requires early detection of HP. No apparent negative impact of the different treatment approaches for EP/HP on subsequent IVF-ET, except for risk of recurrence.

EP/HP are tragic events in a couple's reproductive life, and the earlier the diagnosis the better the prognosis. Due to the increase incidence following IVF-ET, there is a compelling need to develop a diagnostic biomarker/algorithm that can predict pregnancy outcome with high sensitivity and specificity before IVF-ET to prevent and/or properly manage those who are at higher risk of EP/HP.

The evolution of the diagnosis and management of women with an early pregnancy loss has been a success story. The mortality from ectopic pregnancy has objectively been decreased in the past few decades. However, modern management has resulted in a new set of issues. Over-interpretation of a single ultrasound, misunderstanding of the utility of serial hCG values, and inappropriate use of methotrexate can result in iatrogenic complications. Modern management has successfully improved the diagnosis of ectopic pregnancy before rupture; it should now also focus on ensuring that an intrauterine pregnancy is not interrupted as a result of diagnosis and treatment. This article reviews some of the pitfalls of the modern management of early pregnancy failure and introduces a series of articles on the subject.

Medical management has become increasingly popular in the treatment of ectopic pregnancy. Given its convenience, for many it is used as a first-line treatment, however, this is not always the optimal choice for the patient. It is important to understand the options for medical treatment and when it is appropriate to treat a particular patient with medical management, or when one should opt for surgical management. This review outlines the different regimens for methotrexate administration and the associated risks and benefits to medical management.

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.

The objective of this study was to report the outcomes of intrauterine pregnancies misdiagnosed as ectopic and exposed to methotrexate, a major teratogen.

We report the outcomes of all subjects who sought consultation after exposure to high-dose methotrexate to induce abortion in presumed ectopic pregnancies, which were later identified as viable intrauterine pregnancies by 3 North American Teratology Information Services between 2002 and 2010.

Eight women with normal, desired pregnancies were administered high-dose methotrexate in the first trimester because of presumed, misdiagnosed ectopic pregnancies. All pregnancies resulted in catastrophic outcomes. Two pregnancies resulted in severely malformed newborns with methotrexate embryopathy; 3 women miscarried shortly after exposure, and in 3 the erroneous diagnosis led the physicians to advise and perform surgical termination.

Erroneous diagnosis of intrauterine pregnancies as ectopic with subsequent first-trimester exposure to methotrexate may result in the birth of severely malformed babies or fetal demise.

A consideration of teratogenic exposures includes not only an agent (chemical, radiation, biologic) but an exposure level and timing of exposure. There are criteria by which exposures are evaluated for a causal connection with an abnormal outcome. We here review some teratogenic exposures and discuss how they were initially described and confirmed. We have limited our discussion to some of the exposures for which a connection to structural malformations has been accepted in some quarters, and we indicate some exposures for which a causal association awaits confirmation. We recommend that counselors find a reliable and updatable source of information on exposures during pregnancy.

To report a case of embryopathy due to misadministration of methotrexate in the setting of suspected ectopic pregnancy that resulted in a different pattern of malformations than is typically seen with methotrexate.

Case report.

Community hospital.

A 30-year-old primigravida women exposed to methotrexate (50 mg/m(2)) at 5 6/7 weeks' gestation.

The patient underwent amniocentesis because of abnormal results at the first-trimester genetic screening (low levels of pregnancy associated plasma protein A and hCG) and fetal echocardiogram because of single umbilical artery.

Fetal anomalies.

The fetus was found to have a single umbilical artery, tetralogy of Fallot, and a "horseshoe lung," despite administration of high doses of folic acid. The pregnancy ultimately ended with fetal demise at 30 weeks.

As medical management of ectopic pregnancy becomes more common, practitioners should be cautious about the potential teratogenic effects in unrecognized intrauterine pregnancies and be able to diagnose the myriad defects, including cardiac anomalies, that could result from such exposure.

Medication exposure during pregnancy, especially in the first trimester, is a common event that causes considerable concern among patients and healthcare professionals alike. Once the pregnancy is known, the response often consists in stopping or substantially diminishing the use of medications. Some medications are teratogenic and/or fetotoxic, requiring effective birth control and prior information of women of childbearing potential. Nevertheless, limiting the use of medications out of a sense of caution is warranted only if no major adverse impact on the mother is expected throughout the 9 months of the pregnancy. Treatment decisions during pregnancy should rest on a careful reappraisal of treatment practices and on an in-depth evaluation of the risk/benefit ratio of each medication. Here, we will discuss the main rheumatology drug classes whose use during pregnancy is most likely to cause concern.