Fertility and Pregnancy Outcomes in Females with Dyskeratosis Congenita

Background:Reduced fertility and increased fetal and maternal complications during pregnancy have been reported in patients with Fanconi anemia, Diamond-Blackfan anemia and Shwachman-Diamond syndrome. Such high-risk pregnancies benefit from coordinated care by hematologists and maternal-fetal medicine specialists with expertise in inherited bone marrow failure syndromes (IBMFS). There are no data on fertility and pregnancy outcomes in women with dyskeratosis congenita (DC).

Objectives: To determine pubertal development, fertility, and pregnancy outcomes in women with DC.

Methods: Prospective evaluation and medical record review was performed of women with DC ≥10 years of age enrolled in the NCI IBMFS cohort study. We examined ages at menarche and menopause, details regarding fertility and pregnancy, hematologic and non-hematologic complications of pregnancy, and maternal and fetal outcomes.

Results: We evaluated 27 women with DC (median age 31 years, range 10-63), who all attained menarche (median age 12 years, range 9-17). The median age at natural menopause was 51 years, range 50-52. Seventeen women had 46 pregnancies (median 2 pregnancies per person, range 1-6); 1 was unable to conceive, 3 were using contraceptives and 6 were not yet sexually active.

Thirty-two of 46 pregnancies (70%) in 17 women who carried to 27-42 weeks gestation (median 39 weeks) resulted in 34 live births (2 sets of twins). Thirty pregnancies (65%) in 11 women were associated with a variety of complications: 13 ended in miscarriages; 1 was an elective abortion. Maternal complications were preeclampsia (n=3), placenta previa with abruption (n=2 pregnancies in the same patient) and cesarean section for failure to progress (n=5; 4 were in 1 patient). Fetal complications were 5 preterm births (3 associated with preeclampsia) and 2 others had fetal distress. Six women had cytopenia during 8 pregnancies: in 2, mild cytopenia worsened during pregnancy but did not need treatment. One progressed to severe aplastic anemia (SAA) and 1 with SAA was transfusion-dependent throughout. Two patients had normal counts at the start of pregnancy, but developed cytopenia with preeclampsia or abruption with placenta previa, respectively. Three others with normal blood counts had macrocytosis. One was post-transplant. Four had only non-hematologic manifestations of DC. And, 3 women, with no DC-associated clinical features, were identified after diagnosis of an affected offspring.

Fourteen of 32 pregnancies were cesarean deliveries performed in 8 patients for maternal complications (n=7), fetal distress (n=2) or failure to progress (n=5). Three of the 18 vaginal deliveries were in 2 mothers with mild cytopenia, and 1 preterm birth in a patient with SAA. Only 14/46 pregnancies (30%) in 6 women were uncomplicated, term vaginal deliveries; of these, 2 occurred in 1 post-hematopoietic stem cell transplant recipient, conceived by in vitro fertilization.

There were 8 patients with TERC mutations, 3 TERT, 2 TINF2, 2 RTEL1and 2 were gene unknown. Fetal loss or maternal complication did not differ significantly in relation to mutated genes in mothers.

Conclusions: This is the first study of fertility and pregnancy outcomes in patients with DC. We show that females with DC attain menarche and menopause at normal ages and have normal fertility. However, women with DC appear to have high rates of maternal and fetal complications resulting in miscarriage, preeclampsia, and worsening cytopenias. These complications may lead to increased likelihood of cesarean section and/or preterm delivery. Thus, similar to Fanconi anemia and Diamond-Blackfan anemia, pregnant women with DC are at high-risk for complications and should be managed by a hematologic and high risk maternal-fetal medicine team.