To the editor:

We read with great interest the recent letter in Blood, by Gansner et al, on the topic of pregnancies in patients with an inherited bone marrow failure syndrome (IBMFS).1  We agree that these rare patients have reduced numbers and complicated pregnancies, and we think that our experience in this area serves to reinforce the points made by those authors. We have been involved in the care of a larger number of patients, with many more pregnancies, with informative complications and outcomes.

The National Cancer Institute (NCI) IBMFS program opened in 2002; enrollment is biased only by volunteerism, based on self-referral and chart review, with 54% of the patients discussed subsequently seen by the authors at the National Institutes of Health Clinical Center. The protocol was approved by the NCI Institutional Review Board, and all participants signed consent forms (registered at www.clinicaltrials.gov as #NCT00027274). This cohort of women includes >100 who were postmenarchal, of whom 67 were sexually active (Table 1). All diagnoses were confirmed with clinical and syndrome-specific laboratory findings, including genotyping in 78% of the 67.2,3  Seven patients had undergone HCT: 1 with FA and 1 with DC; each of these had 2 pregnancies. The FA patient had 1 miscarriage and 1 elective abortion; the DC patient had donor egg and IVF for her first pregnancy, and IVF and preimplantation genetic diagnosis for the second, after the gene had been identified. Two dozen patients did not have any pregnancies and were on androgens or using birth control.

Table 1.

Women with IBMFSs

 FA DC DBA SDS Total 
N attained menarche 36 29 20 10 95 
N ever sexually active 25 23 16 67 
No HCT 21 21 15 60 
N HCT 
N unable or uninterested in pregnancy 24 
Infertility* 15 
 Decreased AMH 12 
IVF 3 
N of women who had pregnancy 17 34 
 No HCT 16 15  32 
 After HCT  
N of pregnancies 13 46 41 102 
Range of pregnancies per woman 1-5 1-6 1-10 1-10 
N of women with miscarriage 13 
N of miscarriages 13 25 
N of women with elective abortions 
N of elective abortions§ 
N of live deliveries (live births)|| 10 (11)|| 32 (34)|| 29 (29) 71 (74) 
N of term (37-42 wk) 25 23 — 55 
N of preterm (27-36 wk) — 16 
N of C-sections 17  26 
N with known gene# 18/25 20/23 13/16 1/3 52/67 
 FA DC DBA SDS Total 
N attained menarche 36 29 20 10 95 
N ever sexually active 25 23 16 67 
No HCT 21 21 15 60 
N HCT 
N unable or uninterested in pregnancy 24 
Infertility* 15 
 Decreased AMH 12 
IVF 3 
N of women who had pregnancy 17 34 
 No HCT 16 15  32 
 After HCT  
N of pregnancies 13 46 41 102 
Range of pregnancies per woman 1-5 1-6 1-10 1-10 
N of women with miscarriage 13 
N of miscarriages 13 25 
N of women with elective abortions 
N of elective abortions§ 
N of live deliveries (live births)|| 10 (11)|| 32 (34)|| 29 (29) 71 (74) 
N of term (37-42 wk) 25 23 — 55 
N of preterm (27-36 wk) — 16 
N of C-sections 17  26 
N with known gene# 18/25 20/23 13/16 1/3 52/67 

AMH, anti-Müllerian hormone; C-section, cesarean section; DBA, Diamond-Blackfan anemia; DC, dyskeratosis congenita; FA, Fanconi anemia; HCT, hematopoietic cell transplantation; IVF, in vitro fertilization; SDS, Shwachman-Diamond syndrome.

*

Infertility: All with FA had primary ovarian insufficiency (POI); 1 with FA used in vitro fertilization (IVF) with donor egg followed by embryo implantation. One DC woman underwent 10 cycles of IVF with 1 successful pregnancy. One with DC required ovarian stimulation with clomiphene for 3 pregnancies. One with severe aplastic anemia followed by myelodysplastic syndrome and then acute myeloid leukemia was unable to get pregnant while aplastic. Two with DBA had POI (1 after HCT, and 1 had ovarian agenesis); and 1 additional with DBA had scarred tubes.

DC: 2 IVF for infertility, 2 in 1 woman for donor egg and preimplantation genetic diagnosis, respectively, 1 DC woman provided her own egg for a surrogate mother because of the DC woman’s prior pregnancy complications; 1 woman with DC had scarred tubes but became pregnant after several attempts; 1 with DBA had scarred tubes and failed to become pregnant.

DC women: 4 had 2, and 1 had 3. DBA women: 2 had 2, and 1 had 4. SDS woman: 1 had 2.

§

DBA women: 1 had 3 elective abortions.

||

Live births exceed deliveries because of twins, 1 set in FA and 2 sets in DC.

One with DBA had C-section associated with uterine fibroids.

#

Known genotypes: FA, FANCA 14, FANCC 4; DC, TERC 11, TERT 4, RTEL1 3, TINF2 2; DBA, RPS29 6, RPS19 3, RPS7 2, RPS26 1, RPL35 1; SBDS 1.

There were a total of 102 pregnancies in the 67 women: 25 miscarriages in 13 women, 71 live deliveries of 74 babies (3 sets of twins), 16 preterm births, and 26 C-sections. Infertility was reported frequently in FA, because of POI. Infertility in DC was less frequent, associated with endometriosis or scarred fallopian tubes. AMH was decreased in all the infertile FA and DC women who were tested.4,5 

Complications were related to hematologic, obstetrical, and fetal circumstances (Table 2). Almost half of the whole group of pregnant women had decreased hematopoiesis in 1 or all lineages, and 20% of the patients received red cell and/or platelet transfusions. The cytopenias may have reflected a combination of the need for expanded hematopoiesis in pregnancy, plus the reduced marrow response because of the IBMFS. Preeclampsia during pregnancy in FA was reported by us earlier6  and was now noted in DC as well. The number of primary C-sections appeared unusually high, perhaps related to maternal hematopoietic problems and preeclampsia.

Table 2.

Number of women with complications during viable pregnancies

 FA DC DBA SDS Total 
N with viable pregnancy 17 32 
N with any complications 20 
Hematology 16 
 AA 
 Anemia without AA 10 
 Thrombocytopenia without AA 
 RBCs and/or platelets transfusion 12 
Obstetric 10 
 Preeclampsia 
 Placenta previa/abruption 
 Failure to progress 
 Gestational diabetes 
Fetal 
 Fetal distress 
 Stillbirth 1 (Hydrops) 
 FA DC DBA SDS Total 
N with viable pregnancy 17 32 
N with any complications 20 
Hematology 16 
 AA 
 Anemia without AA 10 
 Thrombocytopenia without AA 
 RBCs and/or platelets transfusion 12 
Obstetric 10 
 Preeclampsia 
 Placenta previa/abruption 
 Failure to progress 
 Gestational diabetes 
Fetal 
 Fetal distress 
 Stillbirth 1 (Hydrops) 

AA, alastic anemia; RBC, red blood cell.

Overall, patients with FA had decreased fertility, increased POI,4  and increased premature births and C-sections, as well as decreased hematopoiesis during gestation.7-9  Those with DC had normal fertility, increased miscarriages, premature infants, and C-sections, as well as decreased hematopoiesis, although less common than in FA. One woman with DC had scarred fallopian tubes but did become pregnant after several attempts, whereas 1 with DBA and scarred fallopian tubes did not become pregnant. Despite the increased maternal and obstetric complications, most of the live-born babies were clinically well, although half of the babies from mothers with a dominant syndrome would be expected to be affected.

The topic of pregnancy in patients with an IBMFS was addressed by us in the past, and the conclusions from those reports,6,10-13  the Gansner et al letter,1  and our current analyses remain unchanged. Women with any IBMFS who desire pregnancy or are pregnant would benefit from care provided by a multidisciplinary team of fertility specialists, high-risk maternal-fetal specialists, neonatologists, and hematologists, with expertise in bone marrow failure disorders. The women may have hematologic problems that may worsen during pregnancy, the rate of C-sections may be high, and the fetuses may be premature or have neonatal problems (whether affected with the syndrome or not).14  In most cases, the maternal hematologic complications will be transient, and the women will return to their prepregnancy hematologic status. However, all individuals with these syndromes have variably increased risks of cancer, and thus, they must receive appropriate counseling and surveillance during pregnancies and beyond.15 

Authorship

Acknowledgments: Study management and nursing and genetic counseling expertise were provided through contract HHSN261201100018C with Westat Inc. (Rockville, MD), and the authors thank Sara Glashofer, Lisa Leathwood, Maureen Risch, and Ann Carr. The authors thank all the patients for their participation.

This work was supported in part by the Intramural Program of the National Institutes of Health, the National Cancer Institute, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

Contribution: B.P.A. designed and developed the cohort; N.G. and S.A.S. recruited and examined patients; P.S. examined patients and provided obstetric and gynecologic advice; N.G. and B.P.A. wrote the manuscript; and all authors edited and revised the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Blanche P. Alter, Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9606 Medical Center Dr, Room 6E452, MSC 9772, Rockville, MD 20850; e-mail: alterb@mail.nih.gov.

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Author notes

*

N.G. and P.S. contributed equally to this study.