A 39 year-old Caucasian G4P1031 was referred for evaluation and management of recurrent pregnancy loss. Medical history was significant for known carrier state for β-thalassemia. Mild hypothyroidism had been diagnosed in 2002 with immediate initiation of replacement therapy. The patient was a non-smoker, in good general health and had no gynecologic complaint. BMI was 21.7 kg/m2. In 1997, she experienced a severe hypotensive anaphylactic reaction following a yellow jacket sting (Vespula spp.) resulting in a full allergy work-up. The patient began subcutaneous injection of 100 mcg mixed vespid hymenoptera venom/venom protein (Pharmalgen®; ALK Abello, Hørsholm, Denmark) every 5–6 weeks, which was well tolerated.
All four conceptions were established without medical assistance, involved the same partner, and were achieved after the hymenoptera hypersensitivity diagnosis. The initial pregnancy occurred three years before presentation and resulted in a first trimester spontaneous abortion. No adjustment was made to the allergy injection regimen during that pregnancy. Fetal cardiac activity was initially present, but was lost at 10 weeks' gestation for unknown reasons. No curettage was performed.
One year later, a second pregnancy was established but for this pregnancy hymenoptera venom therapy was discontinued when pregnancy was first recognized (~6 weeks). A 3170 g female infant was delivered vaginally at 40 1/2 weeks' gestation. In 2001 and 2002, the patient established two additional pregnancies and hymenoptera therapy was maintained at 5–6 week intervals for both; both resulted in first trimester spontaneous abortions. For these miscarriages, dilation and curettage was undertaken but no karyotype was performed and no cause for the losses was identified.
At our institution, euthyroid status was verified, the thalassemia carrier state was confirmed, and we identified a new homozygous A223V mutation at the methyltetrahydrofolate reductase (MTHFR) locus. Folic acid intake was immediately increased to 800 mcg/d, although a baseline serum homocysteine level was not measured. Factor V Leiden, protein S, protein C, and other coagulation tests were normal, as were karyotypes obtained from both partners. Anticardiolipin, antiphospholipid and antiovarian antibody titres were all negative. However, transvaginal saline uterine sonography revealed a uniform 5 mm echodense lesion consistent with an endometrial polyp. Outpatient hysteroscopic polypectomy was performed without complication. After discussing various infertility therapies and associated success rates given her age, the patient elected to undergo IVF.
In March 2003, the patient began programmed ovarian hyperstimulation using a combined recombinant-FSH+hMG protocol (300 IU/d Humegon®, Ferring Pharmaceuticals Inc.; Tarrytown, NY USA and 300 IU/d Gonal-F®, Serono Labs; Norwell, MA USA). Pre-treatment pituitary downregulation was achieved via 5 u/d leuprolide acetate and was continued × 3 d after gonadotropin therapy commenced. No alteration was made in the patient's allergy injection sequence during ovulation induction (i.e., 100 mcg every 5–6 weeks), and serum yellow jacket RAST IgE measurements were obtained via commercial fluoroimmunoassay including positive and negative controls (UniCAP® IgE kit, Pharmacia Diagnostics, Uppsala, Sweden). While absolute IgE levels remained <0.35 kU/l throughout therapy, percentage IgE results were variable and these data are summarized in Figure 1.
On cycle day 10, subcutaneous hCG (10,000 IU) was given [2] with serum estradiol at 1090 pg/ml. Twelve oocytes were retrieved and 7 advanced to the 2pn stage following conventional insemination. A four-day course of methylprednisolone (16 mg/d) was started on the day of oocyte retrieval. On post-fertilization day three, the ultrasound-guided transfer of four embryos was performed. Immediately following embryo transfer, the patient was placed on oral aspirin (81 mg/d) and subcutaneous heparin (5,000 IU b.i.d). Luteal phase support was administered as daily 50 mg IM progsterone in oil injections.
Two weeks after embryo transfer, serum hCG was 72 mIU/ml. On May 5, 2003, transvaginal ultrasound confirmed a single intrauterine pregnancy with fetal cardiac rate at 126/min. Progesterone was discontinued at the 10th gestational week. Immunology and perinatology consultants agreed with reduced dose allergy protocol through the third trimester, and hymenoptera venom protein extract (75 mcg) treatment was maintained to 32 weeks gestation. The patient experienced no untoward reaction or hypersensitivity to gonadotropins, VIT, or supplementary progesterone during therapy.
At 32 weeks, obstetrical sonogram suggested reduced amniotic fluid levels and the patient was given intramuscular betamethasone (12 mg/d × 2 days) and placed on bedrest. At this point allergy injections were discontinued since the patient was not outdoors and risk for insect sting was regarded as low. Intravenous oxytocin was started at 35 weeks due to oligohydramnios and resulted in vaginal delivery of a 2495 g female infant. Mother and baby were discharged home after an uncomplicated two-day postpartum course. Allergy injections resumed (100 mcg every 5–6 weeks) when breastfeeding was completed three months later.