Women with Recurrent Pregnancy Loss More Often Have an Older Brother and a Previous Birth of a Boy: Is Male Microchimerism a Risk Factor?

Overview

Journal J Clin Med

Specialty General Medicine

Date 2021 Jul 2

PMID 34198508

Citations 1

Authors

Caroline Norgaard-Pedersen

Ulrik Schioler Kesmodel

Ole B Christiansen

Affiliations

Soon will be listed here.

Abstract

Known etiologic factors can only be found in about 50% of patients with recurrent pregnancy loss (RPL). We hypothesized that male microchimerism is a risk factor for RPL and aimed to explore whether information on family tree and reproductive history, obtained from 383 patients with unexplained RPL, was supportive of this hypothesis. The male:female sex ratio of older siblings was 1.49 (97:65) in all RPL patients and 1.79 (52:29) in secondary RPL (sRPL) patients, which differed significantly from the expected 1.04 ratio ( = 0.027 and = 0.019, respectively). In contrast, the sex ratio of younger siblings was close to the expected ratio. Sex ratio of the firstborn child before sRPL was 1.51 ( = 0.026). When combined, 79.1% of sRPL patients had at least one older brother, a firstborn boy, or both. This differed significantly from what we expected based on the distribution of younger siblings and a general 1.04 sex ratio of newborns ( = 0.040). We speculate whether (s)RPL patients possibly acquired male microchimerism from older brother(s) and/or previous birth of boy(s) by transplacental cell trafficking. This could potentially have a detrimental impact on their immune system, causing a harmful response against the fetus or trophoblast, resulting in RPL.

Citing Articles

Special Issue Recurrent Pregnancy Loss: Etiology, Diagnosis, and Therapy.

Christiansen O J Clin Med. 2021; 10(21).

PMID: 34768559 PMC: 8584478. DOI: 10.3390/jcm10215040.

References

Lissauer D, Piper K, Goodyear O, Kilby M, Moss P . Fetal-specific CD8+ cytotoxic T cell responses develop during normal human pregnancy and exhibit broad functional capacity. J Immunol. 2012; 189(2):1072-80. DOI: 10.4049/jimmunol.1200544. View

Nielsen H, Nybo Andersen A, Kolte A, Christiansen O . A firstborn boy is suggestive of a strong prognostic factor in secondary recurrent miscarriage: a confirmatory study. Fertil Steril. 2008; 89(4):907-11. DOI: 10.1016/j.fertnstert.2007.04.029. View

Karami N, Boroujerdnia M, Nikbakht R, Khodadadi A . Enhancement of peripheral blood CD56(dim) cell and NK cell cytotoxicity in women with recurrent spontaneous abortion or in vitro fertilization failure. J Reprod Immunol. 2012; 95(1-2):87-92. DOI: 10.1016/j.jri.2012.06.005. View

Bender Atik R, Christiansen O, Elson J, Kolte A, Lewis S, Middeldorp S . ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open. 2019; 2018(2):hoy004. PMC: 6276652. DOI: 10.1093/hropen/hoy004. View

Kwak-Kim J, Chung-Bang H, Ng S, Ntrivalas E, Mangubat C, Beaman K . Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum Reprod. 2003; 18(4):767-73. DOI: 10.1093/humrep/deg156. View

Bianchi D, Zickwolf G, Weil G, Sylvester S, DEMARIA M . Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proc Natl Acad Sci U S A. 1996; 93(2):705-8. PMC: 40117. DOI: 10.1073/pnas.93.2.705. View

Winkelhorst D, Oepkes D, Lopriore E . Fetal and neonatal alloimmune thrombocytopenia: evidence based antenatal and postnatal management strategies. Expert Rev Hematol. 2017; 10(8):729-737. DOI: 10.1080/17474086.2017.1346471. View

Nielsen H, Steffensen R, Varming K, van Halteren A, Spierings E, Ryder L . Association of HY-restricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy. Hum Mol Genet. 2009; 18(9):1684-91. DOI: 10.1093/hmg/ddp077. View

Kolte A, Steffensen R, Christiansen O, Nielsen H . Maternal HY-restricting HLA class II alleles are associated with poor long-term outcome in recurrent pregnancy loss after a boy. Am J Reprod Immunol. 2016; 76(5):400-405. DOI: 10.1111/aji.12561. View

10.

Philipp T, Philipp K, Reiner A, Beer F, Kalousek D . Embryoscopic and cytogenetic analysis of 233 missed abortions: factors involved in the pathogenesis of developmental defects of early failed pregnancies. Hum Reprod. 2003; 18(8):1724-32. DOI: 10.1093/humrep/deg309. View

11.

Gammill H, Nelson J . Naturally acquired microchimerism. Int J Dev Biol. 2009; 54(2-3):531-43. PMC: 2887685. DOI: 10.1387/ijdb.082767hg. View

12.

Christiansen O, Pedersen B, Nielsen H, Nybo Andersen A . Impact of the sex of first child on the prognosis in secondary recurrent miscarriage. Hum Reprod. 2004; 19(12):2946-51. DOI: 10.1093/humrep/deh516. View

13.

Gammill H, Stephenson M, Aydelotte T, Nelson J . Microchimerism in recurrent miscarriage. Cell Mol Immunol. 2014; 11(6):589-94. PMC: 4220842. DOI: 10.1038/cmi.2014.82. View

14.

Egerup P, Lindschou J, Gluud C, Christiansen O . The Effects of Intravenous Immunoglobulins in Women with Recurrent Miscarriages: A Systematic Review of Randomised Trials with Meta-Analyses and Trial Sequential Analyses Including Individual Patient Data. PLoS One. 2015; 10(10):e0141588. PMC: 4627734. DOI: 10.1371/journal.pone.0141588. View

15.

Christiansen O . A fresh look at the causes and treatments of recurrent miscarriage, especially its immunological aspects. Hum Reprod Update. 1996; 2(4):271-93. DOI: 10.1093/humupd/2.4.271. View

16.

Klonisch T, Drouin R . Fetal-maternal exchange of multipotent stem/progenitor cells: microchimerism in diagnosis and disease. Trends Mol Med. 2009; 15(11):510-8. DOI: 10.1016/j.molmed.2009.09.002. View

17.

Kruse C, Steffensen R, Varming K, Christiansen O . A study of HLA-DR and -DQ alleles in 588 patients and 562 controls confirms that HLA-DRB1*03 is associated with recurrent miscarriage. Hum Reprod. 2004; 19(5):1215-21. DOI: 10.1093/humrep/deh200. View

18.

Jorgensen K, Pedersen B, Nielsen N, Jacobsen S, Frisch M . Childbirths and risk of female predominant and other autoimmune diseases in a population-based Danish cohort. J Autoimmun. 2011; 38(2-3):J81-7. DOI: 10.1016/j.jaut.2011.06.004. View

19.

Khosrotehrani K, Johnson K, Lau J, Dupuy A, Cha D, Bianchi D . The influence of fetal loss on the presence of fetal cell microchimerism: a systematic review. Arthritis Rheum. 2003; 48(11):3237-41. DOI: 10.1002/art.11324. View

20.

Christiansen O, Kolte A, Krog M, Nielsen H, Egerup P . Treatment with intravenous immunoglobulin in patients with recurrent pregnancy loss: An update. J Reprod Immunol. 2019; 133:37-42. DOI: 10.1016/j.jri.2019.06.001. View