Study: Most Pregnancies Following alloHCT Were Spontaneous and Had Favorable Outcomes
About 72% of the observed pregnancies after allogeneic hematopoietic cell transplantation occurred spontaneously, whereas remaining pregnancies were a result of assisted reproductive activities.
Clinical findings published in Blood demonstrate that, despite fertility challenges, female patients who undergo allogeneic hematopoietic cell transplantation (alloHCT) can become pregnant and give birth to healthy children following transplant.1 The findings offer some hope for patients who want to have a family in the future and are concerned about the effects treatment may have on their fertility.1,2
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“Fertility is a very important topic for young female patients,” said lead study author Katja Sockel, MD, senior physician, University Hospital Carl Gustav Carus Dresden in Germany, in a news release. “Some patients even opt out of receiving certain treatments because of concerns about fertility. For young adult cancer survivors especially, the return to a normal life includes family planning.”1
The authors noted that previous research—such as Loren et al (2010) published in Biology of Blood and Marrow Transplant—included male HCT recipients in addition to female recipients as well as both alloHCT and autologous transplant recipients, representing 2 distinct and different populations and treatment modalities. Additionally, such studies also had smaller sample sizes compared with the current study, which is the largest systemic study at the time of its publication.2,3
For this study, data collection consisted of 2 parts: a retrospective registry collection and interviews with pregnant women. Data were collected from the German Registry for Stem Cell Transplantation1 and included adult women who are of childbearing age (18 to 40 years) and underwent their first alloHCT in a German transplant center between the 2003 and 2018 were enrolled in the study. The authors noted that this is the largest analysis on birth and pregnancy rates among a homogenous population of adult female alloHCT recipients, which contrasts with prior research.2,3
Baseline data on demographics, their underlying disease, donor characteristics, and the transplant procedure were exported form the registry’s database. Additionally, transplant-specific follow-up data along with information on reported pregnancies and live births post-alloHCT were collected during annual follow-ups. For the interviews, women were asked to detail conception, pregnancy course, and their child’s development.2
The annual pregnancy rate or first live birth rate after alloHCT was calculated by dividing the total number of reported pregnancies or first live births within 10 years after transplantation by the sum of follow-up times in years for all patients during that time. These results were compared with the first live birth rate of women aged 18 to 40 years of “general” women, which was obtained from the German Bureau of Statistics.2
A total of 2654 adults women aged 18 to 40 years who underwent alloHCT were enrolled.1,2 According to the findings, at least 1 pregnancy was reported for 50 women, and some participants reported becoming pregnant several times after alloHCT. This resulted in a total of 74 pregnancies, of which 57 (77%) results in live births. The investigators estimated that the median time between transplantation and the first reported pregnancy was approximately 4.7 years (range: 0.7-14.8 years; IQR: 4.3). There were no women who became pregnant at the timepoint of alloHCT, noted the authors.2
“Per the authors, the previous studies have focused on both allogenic and autologous transplants, or they studied couples where the male had the transplant, not the pregnant patient, so this study provided important findings on pregnancy rates, fetal outcomes, and potential risk factors for female patients undergoing allogenic transplants," said Laly Havern, PharmD, MS, BCACP, director of clinical pharmacy strategy, reproductive health, oncology, and transplant, Walgreens, in an email interview.
According to the investigators, pregnancies were observed most often in younger women who were between the age of 18 and 25 years at the time of alloHCT, and there were no pregnancies reported in women who were older than 35. The median age at which women became pregnant post-alloHCT was about 29.6 years (range: 21.7-39.3 years; IQR: 6.8).2
The following underlying diseases were observed in patients: acute myeloid leukemia (n = 17); acute lymphatic leukemia (n = 4); myelodysplastic neoplasias (n = 2); acquired bone marrow failure syndrome, mainly aplastic anemia (n = 13) and paroxysmal nocturnal hemoglobinuria (n = 3); hemoglobinopathies (n = 17); chronic myeloid leukemia (n = 4); and Hodgkin lymphoma (n = 4). Approximately 20% of women underwent myeloablative conditioning and the remaining 80% underwent non-myeloablative or reduced intensity conditioning (NMA/RIC). Additionally, total body irradiation (TBI) was part of the conditioning regimen in 12 of 20 patients, with 4 receiving a cumulative dose. Further, 11 of 50 women (22%) who became pregnant later had suffered antecedent relevant acute graft-versus-host disease (GVHD), and 15 of these women (30%) reported experiencing chronic GVHD at any timepoint following HCT.2
According to the findings, the annual rate of a first reported pregnancy post-alloHCT was approximately 0.53% (95% CI: 0.31%-0.59%). At 10 years after transplant, the cumulative incidence of a first live birth was about 3.4% (95% CI: 2.3-4.5%) and the annual first live birth was 0.45% (95% CI: 0.31-0.59%) and appeared to remain constant through the observation period.2 These rates were about 6 times lower than that of the general population aged 18 to 40 years, with the live birth rate for this population being about 6.43% in 2019.1,2 Some of the study’s recorded pregnancies were a result of fertility treatments with assisted reproductive technology (ART; n =15); whereas about 72% (n = 39) of the participants had spontaneous pregnancies.1,2
“It’s been widely accepted that undergoing a stem cell transplant negatively impacts fertility, so the fact that the study found 72% of the pregnancies occurred spontaneously is the biggest surprise...and something that pharmacists can play a role in educating patients on. It is also notable to understand that the birth rate was 6 times lower after alloHCT because it underscores the importance to counseling patients about fertility preservation options at time of diagnosis,” said Havern.
Factors that were associated with a higher likelihood of pregnancy were NMA/RIC (RR 2.78 [1.26-6.59], p =.01) and nonmalignant transplant indications, such as hemoglobinopathy or bone marrow failure syndrome (RR 2.65 [1.27-5.51], p = .01). Conversely, higher age at the time of HCT (RR 0.36 [0.25-0.50], p < .001) and the use of TBI (RR 0.29 [0.08-0.83], p = .03) were associated with a lower likelihood of pregnancy post-alloHCT.2
The investigators observed that all 50 patients who became pregnant remained alive at a median follow-up of 8.9 years after alloHCT and 3.7 years since first pregnancy. In addition, maternal complications were observed in 25 of 52 pregnancies, with information unavailable for 2 of the cases. The most common complications were vascular-related (n = 16), with uterovaginal complications (n = 6) and other issues related to medication and typical pregnancy discomfort (n = 6) also being reported.2 Further, fetal outcomes were obtained from only 44 of 54 pregnancies. Preterm deliveries—which was defined as birth at 37 weeks of pregnancy—were reported for 10 pregnancies (23%), of which 2 were born between weeks 28 and 32 of gestation, whereas the remaining 8 were born between weeks 32 and 37. Normal birth weight was documented in most of the babies born (>2500 g, n = 37; 84%).2
Prior to alloHCT, fertility counseling should be provided to every woman who is of childbearing age to discuss fertility preservation techniques and the prevention of any unexpected pregnancies. Collaboration between patients’ transplant clinicians as well as their gynecologists is essential to effectively monitor maternal risk during pregnancy. Further, the authors said that prospective and detailed data collection is crucial to further advance the field, increase awareness of fertility aspects in women with HCT, and offer the support for tailored procedural choices (eg, ART) for conditioning regimens with respect to fertility preservation.2
“Fertility preservation counseling before treatment is the standard of care according to several guidelines, including the American Society of Clinical Oncology and the National Comprehensive Cancer Network, so that patients understand the risks and have a choice in their future reproductive potential,” explained Havern. “[The findings] reinforce the notion that fertility preservation discussions should be provided to all patients due to the lower birth rate; however, a discussion on the potential for natural fertility restoration should also be part of the standard of care to prevent unwanted pregnancies. This also means there may be additional counseling required on contraception methods, especially the first-year post-transplant, due to a higher risk for complications in pregnancy in that timeframe.”
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