Abstract and Introduction
Abstract
Non-tubal ectopic pregnancies are a rare subgroup of ectopic pregnancies implanted at sites other than the Fallopian tube. Mortality from non-tubal ectopic pregnancies is higher compared with that for tubal ectopic pregnancies, and they are becoming more common, partly due to the rising incidence of Caesarean sections and use of assisted reproductive technologies. Non-tubal ectopic pregnancies can be especially difficult to treat. Surgical treatment is complex, and follow-up after medical treatment is usually protracted. There is therefore a need for more effective medical therapies to resolve non-tubal ectopic pregnancies and reduce operative intervention. We have recently reported successful use of combination gefitinib (an orally available epidermal growth factor receptor inhibitor) and methotrexate for treatment of tubal pregnancies. To our knowledge, this combination has not been used to treat non-tubal pregnancies. Here we report the use of combination gefitinib and methotrexate to treat eight women with stable, non-tubal ectopic pregnancies at two tertiary academic teaching hospitals (Edinburgh, UK and Melbourne, Australia); five interstitial and three Caesarean section scar ectopic pregnancies. Pretreatment serum hCG levels ranged from 2458 to 48 550 IU/l, and six women had pretreatment hCG levels >5000 IU/l. The women were co-administered 1–2 doses of i.m. methotrexate (50 mg/m on Day 1, ± Day 4 or Day 7) with seven once daily doses of oral gefitinib (250 mg). The women were monitored until complete resolution of the ectopic pregnancy, defined as a serum hCG <15 IU/l. Time to resolution (days from first methotrexate dose until serum hCG <15 IU/l), safety and tolerability, complication rates and subsequent fertility outcomes were also recorded. All eight women were successfully treated with combination gefitinib and methotrexate. The most common side effects were transient acne/rash and diarrhoea, known side effects of gefitinib. All women promptly resumed menstruation and importantly, three women subsequently conceived spontaneously. Two have delivered a healthy infant at term and the third is currently in her second trimester of pregnancy. Hence, our case series supports a future clinical trial to determine the efficacy of combination gefitinib and methotrexate to treat non-tubal ectopic pregnancies.
Introduction
Ectopic pregnancies (EPs) have an incidence of ~1–2% of all pregnancies. They occur when a fertilized ovum implants away from the endometrial cavity, most commonly (>95%) in one of the Fallopian tubes (Jurkovic and Wilkinson, 2011; Fylstra, 2012). EPs can, however, implant in more unusual locations such as within a Caesarean section scar, within the interstitial portion of the Fallopian tubes, in the cervix, on the ovary and potentially anywhere in the abdominal cavity. Mortality from non-tubal ectopic pregnancies is higher than ectopic pregnancies generally, and they are becoming more common due to assisted reproductive technologies, and possibly due to increasing Caesarean section rates (Chetty and Elson, 2009; Verma et al., 2011). Non-tubal ectopic pregnancies are generally difficult to treat and often require a combination of surgical and medical methods.
The literature around management of non-tubal EPs is limited to case reports and series, describing a range of minimally invasive surgical, radiological and medical interventions including laparoscopic and hysteroscopic resection, uterine artery embolization, ultrasound guided injections of the gestational sac with potassium chloride and/or methotrexate, and systemic treatment with drugs such as methotrexate, mifepristone and misoprostil (Verma et al., 2011; Fylstra, 2012). Treatment choice depends on the site, size and pretreatment serum hCG level of the non-tubal EP. In particular, interstitial, Caesarean section scar and cervical EPs often still require surgical resection and/or instrumentation of the uterus, with potential risks to the woman's subsequent reproductive capacity. Because of their rarity as a clinical entity, the best management of non-tubal EPs has been difficult to establish.
In preclinical studies and a phase I single arm, open label study, we demonstrated that co-administering gefitinib (an epidermal growth factor receptor inhibitor) with methotrexate to treat ectopic pregnancies appeared safe. Furthermore, we obtained preliminary data suggesting this combination may have a time to resolution which is 34% faster compared with treatment using methotrexate alone (Nilsson et al., 2013; Skubisz et al., 2013). This suggested adding gefitinib to methotrexate may improve on its efficacy in medically resolving ectopic pregnancies. We therefore wondered whether this combination could be potentially used to treat non-tubal ectopic pregnancies more effectively. Here we report a case series of eight women with non-tubal EPs treated with gefitinib and methotrexate.