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Female parental consanguinity is associated with a reduced ovarian reserve

Published:December 03, 2021DOI:https://doi.org/10.1016/j.rbmo.2021.11.023

      Abstract

      Research question

      Is parental consanguinity associated with a reduced ovarian reserve in women from the Arabian Peninsula, comparing anti-Müllerian hormone (AMH) and antral follicle count (AFC)?

      Design

      Retrospective large-scale observational study including 2482 women from the Arabian Peninsula, aged 19–49 years, who had their serum AMH and AFC measured as part of their fertility assessment, from May 2015 to November 2019. Consanguinity was defined as women whose parents were first-degree or second-degree cousins. Serum AMH was measured for all participants.

      Results

      A total of 2198 women were included: 605 in the consanguine group (27.53%), 1593 (72.47%) in the non-consanguine group. There were no significant differences between groups in terms of body mass index, years of infertility or smoking status. Women from the consanguine group were significantly younger (mean age 33.74 ± 6.64 years) compared with the non-consanguine group (mean age 34.78 ± 6.64 years, P < 0.0001). Median AMH and AFC for the consanguine group were 1.90 ng/ml (min–max: 0.01–23.8) and 11 (0–80), respectively, and for the non-consanguine group 1.84 ng/ml (min–max: 0.01–23.0) and 11 (0–60), respectively. AMH and AFC exhibit an age-dependent decline. As both parameters are age-dependent, the multivariate analysis showed that women from the consanguine group presented significantly lower AMH (coefficient of variation [CV] –0.07 ± 0.03, P = 0.036) and AFC (CV –0.16 ± 0.06, P = 0.003) compared with non-consanguine women, and the highest differences were found for women below 35 years of age (AMH median [min–max]: 2.82 ng/ml (0.01–23.80) versus 2.92 ng/ml (0.01–23.00); P = 0.035; AFC median [min–max]: 15 (0–80) versus 14 (0–80); P = 0.001).

      Conclusion

      The adjusted analysis by age indicates that female parental consanguinity is associated with reduced ovarian reserve in the studied population. Clinical evaluation should include extensive family history and subsequent counselling of the affected couples.

      Keywords

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      References

        • Al-Agha A.E.
        • Ahmed I.A.
        • Nuebel E.
        • Moriwaki M.
        • Moore B.
        • Peacock K.A.
        • Mosbruger T.
        • Neklason D.W.
        • Jorde L.B.
        • Yandell M.
        • Welt C.K.
        Primary ovarian insufficiency and azoospermia in carriers of a homozygous PSMC3IP stop gain mutation.
        J. Clin. Endocrinol. Metab. 2018; 103: 555-563https://doi.org/10.1210/jc.2017-01966
        • Alkuraya F.
        Impact of new genomic tools on the practice of clinical genetics in consanguineous populations: the Saudi experience: new genomic tools on the practice of clinical genetics in consanguineous populations.
        Clin. Genet. 2013; 84: 203-208https://doi.org/10.1111/cge.12131
        • Bittles A.H.
        The role and significance of consanguinity as a demographic variable.
        Popul. Dev. Rev. 1994; 20: 561https://doi.org/10.2307/2137601
        • Bittles A.
        Consanguinity and its relevance to clinical genetics.
        Clin. Genet. 2001; 60: 89-98https://doi.org/10.1034/j.1399-0004.2001.600201.x
        • Bittles A.H.
        A community genetics perspective on consanguineous marriage.
        Community Genet. 2008; 11: 324-330https://doi.org/10.1159/000133304
      1. Bittles, A.H., Black, M.L., 2010. Consanguinity, human evolution, and complex diseases. Proc. Natl. Acad. Sci. 107, 1779–1786. https://doi.org/10.1073/pnas.0906079106

        • Bittles A.H.
        • Grant J.C.
        • Sullivan S.G.
        • Hussain R.
        Does inbreeding lead to decreased human fertility?.
        Ann. Hum. Biol. 2002; 29: 111-130https://doi.org/10.1080/03014460110075657
        • Blanco Villegas M.J.
        • Fuster V.
        Reproductive pattern in consanguineous and non-consanguineous marriages in La Cabrera.
        Spain. Ann. Hum. Biol. 2006; 33: 330-341https://doi.org/10.1080/03014460600627529
        • Broekmans F.J.M.
        • de Ziegler D.
        • Howles C.M.
        • Gougeon A.
        • Trew G.
        • Olivennes F.
        The antral follicle count: practical recommendations for better standardization.
        Fertil. Steril. 2010; 94: 1044-1051https://doi.org/10.1016/j.fertnstert.2009.04.040
        • Caburet S.
        • Zavadakova P.
        • Ben-Neriah Z.
        • Bouhali K.
        • Dipietromaria A.
        • Charon C.
        • Besse C.
        • Laissue P.
        • Chalifa-Caspi V.
        • Christin-Maitre S.
        • Vaiman D.
        • Levi G.
        • Veitia R.A.
        • Fellous M.
        Genome-wide linkage in a highly consanguineous pedigree reveals two novel loci on chromosome 7 for non-syndromic familial premature ovarian failure.
        PLoS One. 2012; 7: e33412https://doi.org/10.1371/journal.pone.0033412
        • Chen B.
        • Li L.
        • Wang J.
        • Li T.
        • Pan H.
        • Liu B.
        • Zhou Y.
        • Cao Y.
        • Wang B.
        Consanguineous familial study revealed biallelic FIGLA mutation associated with premature ovarian insufficiency.
        J. Ovarian Res. 2018; 11: 48https://doi.org/10.1186/s13048-018-0413-0
        • Cohen S.B.
        Geopolitics of the World System.
        Rowman & Littlefield Publishers, Lanham2003: 337
        • Deb S.
        • Campbell B.K.
        • Clewes J.S.
        • Pincott-Allen C.
        • Raine-Fenning N.J.
        Intracycle variation in number of antral follicles stratified by size and in endocrine markers of ovarian reserve in women with normal ovulatory menstrual cycles: intracycle variation in markers of ovarian reserve.
        Ultrasound Obstet. Gynecol. 2013; 41: 216-222https://doi.org/10.1002/uog.11226
        • Feichtinger M.
        • Göbl C.
        • Weghofer A.
        • Feichtinger W.
        Reproductive outcome in European and Middle Eastern/North African patients.
        Reprod. Biomed. Online. 2016; 33: 684-689https://doi.org/10.1016/j.rbmo.2016.09.003
        • Ferraretti A.P.
        • La Marca A.
        • Fauser B.C.J.M.
        • Tarlatzis B.
        • Nargund G.
        • Gianaroli L.
        • ESHRE Working Group on Poor Ovarian Response Definition
        ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria.
        Hum. Reprod. Oxf. Engl. 2011; 26: 1616-1624https://doi.org/10.1093/humrep/der092
        • Ferraretti A.P.
        • Gianaroli L.
        The Bologna criteria for the definition of poor ovarian responders: is there a need for revision?.
        Hum. Reprod. 2014; 29: 1842-1845https://doi.org/10.1093/humrep/deu139
        • Hamamy H.
        • Antonarakis S.E.
        • Cavalli-Sforza L.L.
        • Temtamy S.
        • Romeo G.
        • Kate L.P.T.
        • Bennett R.L.
        • Shaw A.
        • Megarbane A.
        • van Duijn C.
        • Bathija H.
        • Fokstuen S.
        • Engel E.
        • Zlotogora J.
        • Dermitzakis E.
        • Bottani A.
        • Dahoun S.
        • Morris M.A.
        • Arsenault S.
        • Aglan M.S.
        • Ajaz M.
        • Alkalamchi A.
        • Alnaqeb D.
        • Alwasiyah M.K.
        • Anwer N.
        • Awwad R.
        • Bonnefin M.
        • Corry P.
        • Gwanmesia L.
        • Karbani G.A.
        • Mostafavi M.
        • Pippucci T.
        • Ranza-Boscardin E.
        • Reversade B.
        • Sharif S.M.
        • Teeuw M.E.
        • Bittles A.H.
        Consanguineous marriages, pearls and perils: Geneva International Consanguinity Workshop Report.
        Genet. Med. 2011; 13: 841-847https://doi.org/10.1097/GIM.0b013e318217477f
        • Jolly A.
        • Bayram Y.
        • Turan S.
        • Aycan Z.
        • Tos T.
        • Abali Z.Y.
        • Hacihamdioglu B.
        • Coban Akdemir Z.H.
        • Hijazi H.
        • Bas S.
        • Atay Z.
        • Guran T.
        • Abali S.
        • Bas F.
        • Darendeliler F.
        • Colombo R.
        • Barakat T.S.
        • Rinne T.
        • White J.J.
        • Yesil G.
        • Gezdirici A.
        • Gulec E.Y.
        • Karaca E.
        • Pehlivan D.
        • Jhangiani S.N.
        • Muzny D.M.
        • Poyrazoglu S.
        • Bereket A.
        • Gibbs R.A.
        • Posey J.E.
        • Lupski J.R.
        Exome sequencing of a primary ovarian insufficiency cohort reveals common molecular etiologies for a spectrum of disease.
        J. Clin. Endocrinol. Metab. 2019; 104: 3049-3067https://doi.org/10.1210/jc.2019-00248
        • Laissue P.
        The molecular complexity of primary ovarian insufficiency aetiology and the use of massively parallel sequencing.
        Mol. Cell. Endocrinol. 2018; 460: 170-180https://doi.org/10.1016/j.mce.2017.07.021
        • Li H.W.R.
        • Wong B.P.C.
        • Ip W.K.
        • Yeung W.S.B.
        • Ho P.C.
        • Ng E.H.Y.
        Comparative evaluation of three new commercial immunoassays for anti-Müllerian hormone measurement.
        Hum. Reprod. Oxf. Engl. 2016; 31: 2796-2802https://doi.org/10.1093/humrep/dew248
        • Ober C.
        • Hyslop T.
        • Hauck W.W.
        Inbreeding effects on fertility in humans: evidence for reproductive compensation.
        Am. J. Hum. Genet. 1999; 64: 225-231https://doi.org/10.1086/302198
        • Oniya O.
        • Neves K.
        • Ahmed B.
        • Konje J.C.
        A review of the reproductive consequences of consanguinity.
        Eur. J. Obstet. Gynecol. Reprod. Biol. 2019; 232: 87-96https://doi.org/10.1016/j.ejogrb.2018.10.042
        • Peng T.
        • Lv C.
        • Tan H.
        • Huang J.
        • He H.
        • Wang Y.
        • Zeng M.
        • Yi D.
        • Li J.
        • Deng H.
        • Shi X.
        • Xiao H.
        Novel PMM2 missense mutation in a Chinese family with non-syndromic premature ovarian insufficiency.
        J. Assist. Reprod. Genet. 2020; 37: 443-450https://doi.org/10.1007/s10815-019-01675-8
        • Postma E.
        • Martini L.
        • Martini P.
        Inbred women in a small and isolated Swiss village have fewer children.
        J. Evol. Biol. 2010; 23: 1468-1474https://doi.org/10.1111/j.1420-9101.2010.02013.x
        • Qin Y.
        • Jiao X.
        • Simpson J.L.
        • Chen Z.-J.
        Genetics of primary ovarian insufficiency: new developments and opportunities.
        Hum. Reprod. Update. 2015; 21: 787-808https://doi.org/10.1093/humupd/dmv036
        • R Core Team
        R: A Language and Environment for Statistical Computing.
        R Foundation for Statistical Computing, Vienna, Austria2013
        • Romeo G.
        • Bittles A.H.
        Consanguinity in the contemporary world.
        Hum. Hered. 2014; 77: 6-9https://doi.org/10.1159/000363352
        • RStudio Team
        RStudio: Integrated Development for R.
        RStudio, PBC, Boston, MA2020
        • Ruth K.
        • Murray A.
        Lessons from genome-wide association studies in reproductive medicine: menopause.
        Semin. Reprod. Med. 2016; 34: 215-223https://doi.org/10.1055/s-0036-1585404
        • Seher T.
        • Thiering E.
        • al Azemi M.
        • Heinrich J.
        • Schmidt-Weber C.B.
        • Kivlahan C.
        • Gutermuth J.
        • Fatemi H.M.
        Is parental consanguinity associated with reduced ovarian reserve?.
        Reprod. Biomed. Online. 2015; 31: 427-433https://doi.org/10.1016/j.rbmo.2015.06.003
        • Tabbalat A.M.
        • Pereira N.
        • Klauck D.
        • Melhem C.
        • Elias R.T.
        • Rosenwaks Z.
        Arabian Peninsula ethnicity is associated with lower ovarian reserve and ovarian response in women undergoing fresh ICSI cycles.
        J. Assist. Reprod. Genet. 2018; 35: 331-337https://doi.org/10.1007/s10815-017-1071-7
        • Tadmouri G.O.
        • Nair P.
        • Obeid T.
        • Al Ali M.T.
        • Al Khaja N.
        • Hamamy H.A.
        Consanguinity and reproductive health among Arabs.
        Reprod. Health. 2009; 6: 17https://doi.org/10.1186/1742-4755-6-17
        • Torgerson D.J.
        • Thomas R.E.
        • Reid D.M.
        Mothers and daughters menopausal ages: is there a link?.
        Eur. J. Obstet. Gynecol. Reprod. Biol. 1997; 74: 63-66https://doi.org/10.1016/s0301-2115(97)00085-7
        • Usta T.
        • Oral E.
        Is the measurement of anti-Müllerian hormone essential?.
        Curr. Opin. Obstet. Gynecol. 2012; 24: 151-157https://doi.org/10.1097/GCO.0b013e3283527dcf
        • Wang Y.
        • Xiang M.
        • Yu Z.
        • Hao Y.
        • Xu Q.
        • Kong S.
        • Wang F.
        • Shi X.
        • Song G.
        • Cao Y.
        • Huang L.
        • Zhu F.
        A homozygous missense mutation inTBPL2 is associated with oocyte maturation arrest and degeneration.
        Clin. Genet. 2021; 100: 324-328https://doi.org/10.1111/cge.13993
        • Zhe J.
        • Ye D.
        • Chen X.
        • Liu Y.
        • Zhou X.
        • Li Y.
        • Zhang J.
        • Chen S.
        Consanguineous Chinese familial study reveals that a gross deletion that includes the SYCE1 gene region is associated with premature ovarian insufficiency.
        Reprod. Sci. 2020; 27: 461-467https://doi.org/10.1007/s43032-019-00037-0

      Biography

      Dr Laura Melado graduated as MD in 2002 (Universidad Autónoma in Madrid), where she completed her doctoral dissertation on ‘AMH during controlled ovarian stimulation’ in 2015. She worked as an ob/gyn/IVF specialist in Spain and today is the Medical Director at ART Fertility Clinics, Abu Dhabi, United Arab Emirates.
      Key message
      Female parental consanguinity is associated with reduced ovarian reserve in women from the Arabian Peninsula. Genetic counselling, risk prediction and earlier intervention should be considered for these women.