Conception and Pregnancy Outcomes after Haematopoietic Stem Cell Transplant: A Retrospective Study from the Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation
Authors: Salooja Nina , Michonneau David , Tichelli André , van der Werf Steffie , Aljurf Mahmoud , Browne Paul V , Dreger Peter , Hill Kate , Nicolaus Kroger , Labopin Myriam , Van Lint Maria Teresa , Lioure Bruno , Ljungman Per , Maertens Johan , Passweg Jakob R. , Schoemans Helene , Sedlacek Petr , Socié Gérard , Apperley Jane , Bader Peter , Duarte Rafael F , Basak Grzegorz W 
Published: October 2019

Abstract
Background.Infertility is common after HCT predominantly as a result of the chemoradiotherapy used in conditioning. Patients are increasingly encouraged to store gametes, tissue or embryos before transplant for use after their potentially sterilising treatment. Furthermore, some patients do retain or recover fertility and conceive naturally.
Methods:We sent questionnaires to 602 EBMT centers requesting retrospective details of number of pregnancies following either allogeneic or autologous HCT, use of artificial reproductive techniques (ART) and pregnancy outcome for all patients treated between 1995-2015.
Results:47 centers responded from 17countries detailing 439 patients (216 female, F), who became pregnant/partners conceived. The most frequent underlying diagnoses were Hodgkin Lymphoma (n=80, 18%), AML (n=77, 17.5%) and acquired bone marrow failure (n= 62, 14.1%). Of 181F conceiving where data was available 60 (33%) involved ART. These included hormone stimulation, IVF, cryopreserved embryos, donor eggs or embryos and cryopreserved ovarian tissue. The most frequent method was use of donor eggs (57/87, 65%). Of 223 men (M) whose partners conceived, mode of conception was detailed for 170, 93 of whom conceived with ART (55%). Techniques usually involved use of sperm cryopreserved prior to HCT. In 25 cases, some chemotherapy was given prior to sperm collection. 30/74 (40%) specified intracytoplasmic sperm injections, 13/74 (18%) intrauterine insemination and 24/74 (32%) IVF either with cryopreserved or fresh sperm.
In female patients return of menstruation was not invariable prior to conception. Data was available for 146F, 31 of whom were amenorrhoeic prior to conception. 20/31 of the latter conceived by ART (64.5%) compared to 18/116 (15%) whose menstruation returned. Of 53F receiving TBI, 30 (57%) had ART compared to 27/111F (24%) specified as not having TBI. Of 31F receiving reduced intensity conditioning (RIC) where mode of conception was specified, 8 (26%) had ART compared to 43/113 (38%) with myeloablative conditioning (MAC).
69M were specified as having TBI and 111M specified as not. 41/58 (71%) receiving TBI had ART compared to 34/92 (37%) who did not. 24 men had RIC vs 133 MAC. Data on mode of conception was not available for all, but 4/19 (21%) with RIC had ART vs 59/113 (52%) with MAC.
656 pregnancies occurred in 439 patients with 162 patients having more than one child. Multiple births occurred for 50 patients and other patients or their partners had more than one pregnancy. 567/650 where data was available culminated in live birth and the prevalence of miscarriage (42/650, 6%) was low. 2 had still births, 5 had therapeutic abortions, 7 were pregnant at time of data collection.
Gestational age (GA) was available for 41% pregnancies following a single HCT; the median GA was 39 weeks (range 22-43 weeks). It was similar in babies born to female patients or partners of male patients (p=0.71). Women who had received TBI had a lower GA at 38 weeks (22-42) compared to non-TBI F at 40 weeks (28-43) (p&lt;0.0001). Female recipients of ART also had a lower median GA compared to non-ART F at 38 weeks (22-42) (p=0.002).
Birthweight was available for 197/593 (33%) pregnancies (95 to female patients) following single HCT. The median birth weight (BW) to F patients was 2999g(300-4700g) with 26 (27%) weighing &lt;2.5kg; in partners of male patients the median BW was 3100g (870-4210) with 20 (20%) &lt;2.5kg. The median BW was lower in women who conceived by ART (2731g, 300-3720) compared to not assisted (3200g, 1330-5700 p=0.032) or else received TBI (2635g, 300-5700) compared to non-TBI regimens (3100 g, 999-4210, p=0.038).
9/300 (3%) pregnancies had congenital abnormalities. The median follow up of offspring was 5 years (range 0-18) but developmental problems and learning difficulties were infrequent at 2/290 and 1/280 respectively.
Conclusion:ART frequently underpinned pregnancy in this group of post-transplant patients particularly in male patients vs female, TBI vs non-TBI, amenorrhoeic vs menstruating women, standard conditioning vs RIC. In women receiving TBI and/or conceiving by ART the median GA and median BW were reduced compared to other groups of transplanted patients. However, our data indicates that in patients who conceive after HCT, either naturally or by use of ART, successful pregnancy leading to healthy offspring is the likely outcome.

Disclosures
Apperley: Incyte: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Bader:Neovii: Research Funding; Riemser: Research Funding; Medac: Patents & Royalties, Research Funding; Novartis: Consultancy, Speakers Bureau; Cellgene: Consultancy.