Reproduction, Fertility and Development Reproduction, Fertility and Development Society
Vertebrate reproductive science and technology
RESEARCH ARTICLE

Potential risks to offspring of intrauterine exposure to maternal age-related obstetric complications

Juan J. Tarín A F , Miguel A. García-Pérez B C and Antonio Cano D E
+ Author Affiliations
- Author Affiliations

A Department of Cellular Biology, Functional Biology and Physical Anthropology, Faculty of Biological Sciences, University of Valencia, Dr. Moliner 50, Burjassot, Valencia 46100, Spain.

B Department of Genetics, Faculty of Biological Sciences, University of Valencia, Dr. Moliner 50, Burjassot, Valencia 46100, Spain.

C Research Unit-INCLIVA, University Clinic Hospital, Avda. Menéndez Pelayo, 4 accesorio, 46010 Valencia, Spain.

D Department of Pediatrics, Obstetrics and Gynecology, Faculty of Medicine, University of Valencia, Avda. Blasco Ibañez 15, Valencia 46010, Spain.

E Service of Obstetrics and Gynecology, University Clinic Hospital, Avda. Blasco Ibañez 17, Valencia 46010, Spain.

F Corresponding author. Email: tarinjj@uv.es

Reproduction, Fertility and Development - https://doi.org/10.1071/RD16163
Submitted: 19 April 2016  Accepted: 10 July 2016   Published online: 10 August 2016

Abstract

Several hypotheses have been proposed to explain the negative effects of delayed motherhood on an offspring’s morbidity later in life. However, these hypotheses are not supported by clinical and epidemiological evidence. Because advanced maternal age is associated with increased risk of obstetric complications, the aim of the present study was to ascertain whether the negative effects on offspring of intrauterine exposure to maternal age-related obstetric complications may explain the reported negative effects of delayed motherhood on offspring. To this end, a literature search was performed to identify relevant publications up to March 2016 on PubMed; references cited in relevant articles were also searched. There was a direct correlation between the risks to offspring conferred by intrauterine exposure to at least one of the obstetric complications present at the time of delivery in women aged ≥35 years and the risks to offspring of delayed motherhood. This correlation was not observed when comparing the risks to offspring of delayed motherhood and the risks associated with maternal transmission of defective mitochondria, chromosomal anomalies or DNA double-strand breaks. Most of the effects on offspring of intrauterine exposure to maternal age-related obstetric complications may be induced by epigenetic DNA reprogramming during critical periods of embryo or fetal development. Women wanting to enrol in a fertility preservation program to offset age-related declines in fertility should be informed not only about their chances of pregnancy and the percentage of live births, but also about the risks to themselves and their prospective offspring of delaying motherhood.

Additional keywords: advanced maternal age, chromosome anomalies, defective mitochondria, DNA double-strand breaks, epigenetics, long-term effects.


References

Boyd, P. A., Loane, M., Garne, E., Khoshnood, B., Dolk, H., EUROCAT Working Group (2011). Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy. Eur. J. Hum. Genet. 19, 231–234.
Sex chromosome trisomies in Europe: prevalence, prenatal detection and outcome of pregnancy.CrossRef | 20736977PubMed | open url image1

Brooks-Wilson, A. R. (2013). Genetics of healthy aging and longevity. Hum. Genet. 132, 1323–1338.
Genetics of healthy aging and longevity.CrossRef | 1:CAS:528:DC%2BC3sXht1OqurfP&md5=e612846194dbb9903eeb3881084b7da3CAS | 23925498PubMed | open url image1

Cassina, A., Silveira, P., Cantu, L., Montes, J. M., Radi, R., and Sapiro, R. (2015). Defective human sperm cells are associated with mitochondrial dysfunction and oxidant production. Biol. Reprod. 93, 119.
Defective human sperm cells are associated with mitochondrial dysfunction and oxidant production.CrossRef | 26447142PubMed | open url image1

Cedars, M. I. (2015). Introduction: childhood implications of parental aging. Fertil. Steril. 103, 1379–1380.
Introduction: childhood implications of parental aging.CrossRef | 25936233PubMed | open url image1

Chinnery, P. F. (2000). Mitochondrial disorders overview. In ‘GeneReviews®’. (Eds Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya,A., Bean, L.J.H., Bird, T.D., Fong, C.T., Mefford, H.C., Smith, R.J.H., and Stephens, K. (University of Washington: Seattle, WA). Available at http://www.ncbi.nlm.nih.gov/books/NBK1224/ [verified 18 July 2016].

Chinnery, P. F., DiMauro, S., Shanske, S., Schon, E. A., Zeviani, M., Mariotti, C., Carrara, F., Lombes, A., Laforet, P., Ogier, H., Jaksch, M., Lochmüller, H., Horvath, R., Deschauer, M., Thorburn, D. R., Bindoff, L. A., Poulton, J., Taylor, R. W., Matthews, J. N., and Turnbull, D. M. (2004). Risk of developing a mitochondrial DNA deletion disorder. Lancet 364, 592–596.
Risk of developing a mitochondrial DNA deletion disorder.CrossRef | 1:CAS:528:DC%2BD2cXmslaltrk%3D&md5=53e9a8b74b2362b5b26c99ccbafa532aCAS | 15313359PubMed | open url image1

Cummins, J. M., Jequier, A. M., and Kan, R. (1994). Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress? Mol. Reprod. Dev. 37, 345–362.
Molecular biology of human male infertility: links with aging, mitochondrial genetics, and oxidative stress?CrossRef | 1:CAS:528:DyaK2cXktVKitrY%3D&md5=8ea3afaaef697416bdcb3dcd7abcb917CAS | 8185940PubMed | open url image1

Denduluri, N., and Ershler, W. B. (2004). Aging biology and cancer. Semin. Oncol. 31, 137–148.
Aging biology and cancer.CrossRef | 15112145PubMed | open url image1

Fall, C. H., Sachdev, H. S., Osmond, C., Restrepo-Mendez, M. C., Victora, C., Martorell, R., Stein, A. D., Sinha, S., Tandon, N., Adair, L., Bas, I., Norris, S., Richter, L. M., COHORTS Investigators (2015). Association between maternal age at childbirth and child and adult outcomes in the offspring: a prospective study in five low-income and middle-income countries (COHORTS collaboration). Lancet Glob. Health 3, e366–e377.
Association between maternal age at childbirth and child and adult outcomes in the offspring: a prospective study in five low-income and middle-income countries (COHORTS collaboration).CrossRef | 25999096PubMed | open url image1

Giráldez-García, C., Sangrós, F. J., Díaz-Redondo, A., Franch-Nadal, J., Serrano, R., Díez, J., Buil-Cosiales, P., García-Soidán, F. J., Artola, S., Ezkurra, P., Carrillo, L., Millaruelo, J. M., Seguí, M., Martínez-Candela, J., Muñoz, P., Goday, A., Regidor, E., PREDAPS Study Group (2015). Cardiometabolic risk profiles in patients with impaired fasting glucose and/or hemoglobin A1c 5.7% to 6.4%: evidence for a gradient according to diagnostic criteria: the PREDAPS Study. Medicine (Baltimore) 94, e1935.
Cardiometabolic risk profiles in patients with impaired fasting glucose and/or hemoglobin A1c 5.7% to 6.4%: evidence for a gradient according to diagnostic criteria: the PREDAPS Study.CrossRef | 26554799PubMed | open url image1

Gorman, G. S., Schaefer, A. M., Ng, Y., Gomez, N., Blakely, E. L., Alston, C. L., Feeney, C., Horvath, R., Yu-Wai-Man, P., Chinnery, P. F., Taylor, R. W., Turnbull, D. M., and McFarland, R. (2015). Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann. Neurol. 77, 753–759.
Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease.CrossRef | 1:CAS:528:DC%2BC2MXms1Giurw%3D&md5=29b8c6bc4abf32c9951651f90fa16742CAS | 25652200PubMed | open url image1

Grotegut, C. A., Chisholm, C. A., Johnson, L. N., Brown, H. L., Heine, R. P., and James, A. H. (2014). Medical and obstetric complications among pregnant women aged 45 and older. PLoS One 9, e96237.
Medical and obstetric complications among pregnant women aged 45 and older.CrossRef | 24769856PubMed | open url image1

Hassold, T. J., and Jacobs, P. A. (1984). Trisomy in man. Annu. Rev. Genet. 18, 69–97.
Trisomy in man.CrossRef | 1:STN:280:DyaL2M7kslKhtQ%3D%3D&md5=12017e01b93e787893d24c7ffc30c885CAS | 6241455PubMed | open url image1

Jalali-Farahani, S., Amiri, P., Karimi, M., Gharibzadeh, S., Mirmiran, P., and Azizi, F. (2016). Socio-behavioral factors associated with overweight and central obesity in Tehranian adults: a structural equation model. Int. J. Behav. Med. , .
Socio-behavioral factors associated with overweight and central obesity in Tehranian adults: a structural equation model.CrossRef | 27272681PubMed | open url image1

Kim, M. A., Yee, N. H., Choi, J. S., Choi, J. Y., and Seo, K. (2012). Prevalence of birth defects in Korean livebirths, 2005–2006. J. Korean Med. Sci. 27, 1233–1240.
Prevalence of birth defects in Korean livebirths, 2005–2006.CrossRef | 23091323PubMed | open url image1

Kujjo, L. L., and Perez, G. I. (2012). Ceramide and mitochondrial function in aging oocytes: joggling a new hypothesis and old players. Reproduction 143, 1–10.
Ceramide and mitochondrial function in aging oocytes: joggling a new hypothesis and old players.CrossRef | 1:CAS:528:DC%2BC38Xhs1yht7g%3D&md5=da22a802c1799a1aedc9f812f0c888ddCAS | 22046054PubMed | open url image1

Mosconi, L., Tsui, W., Murray, J., McHugh, P., Li, Y., Williams, S., Pirraglia, E., Glodzik, L., De Santi, S., Vallabhajosula, S., and de Leon, M. J. (2012). Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer’s disease. Neurobiol. Aging 33, 624.e1–624.e9.
Maternal age affects brain metabolism in adult children of mothers affected by Alzheimer’s disease.CrossRef | open url image1

Myrskylä, M., Elo, I. T., Kohler, I. V., and Martikainen, P. (2014). The association between advanced maternal and paternal ages and increased adult mortality is explained by early parental loss. Soc. Sci. Med. 119, 215–223.
The association between advanced maternal and paternal ages and increased adult mortality is explained by early parental loss.CrossRef | 24997641PubMed | open url image1

Oktay, K., Turan, V., Titus, S., Stobezki, R., and Liu, L. (2015). BRCA mutations, DNA repair deficiency, and ovarian aging. Biol. Reprod. 93, 67.
BRCA mutations, DNA repair deficiency, and ovarian aging.CrossRef | 26224004PubMed | open url image1

Payne, B. A., Wilson, I. J., Yu-Wai-Man, P., Coxhead, J., Deehan, D., Horvath, R., Taylor, R. W., Samuels, D. C., Santibanez-Koref, M., and Chinnery, P. F. (2013). Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390.
Universal heteroplasmy of human mitochondrial DNA.CrossRef | 1:CAS:528:DC%2BC38XhvV2gtr%2FN&md5=6ae88960eb11e3e4c28848e7c4f31b79CAS | 23077218PubMed | open url image1

Ramalho-Santos, J., Varum, S., Amaral, S., Mota, P. C., Sousa, A. P., and Amaral, A. (2009). Mitochondrial functionality in reproduction: from gonads and gametes to embryos and embryonic stem cells. Hum. Reprod. Update 15, 553–572.
Mitochondrial functionality in reproduction: from gonads and gametes to embryos and embryonic stem cells.CrossRef | 1:CAS:528:DC%2BD1MXhtVals7nI&md5=a32bcdc43d29aaaa1489a12c294efb54CAS | 19414527PubMed | open url image1

Rebolledo-Jaramillo, B., Su, M. S., Stoler, N., McElhoe, J. A., Dickins, B., Blankenberg, D., Korneliussen, T. S., Chiaromonte, F., Nielsen, R., Holland, M. M., Paul, I. M., Nekrutenko, A., and Makova, K. D. (2014). Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA 111, 15 474–15 479.
Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA.CrossRef | 1:CAS:528:DC%2BC2cXhslKmtbzJ&md5=717c57236428631ff78b627d7630ab67CAS | open url image1

Rueness, J., Vatten, L., and Eskild, A. (2012). The human sex ratio: effects of maternal age. Hum. Reprod. 27, 283–287.
The human sex ratio: effects of maternal age.CrossRef | 22025225PubMed | open url image1

Sauer, M. V. (2015). Reproduction at an advanced maternal age and maternal health. Fertil. Steril. 103, 1136–1143.
Reproduction at an advanced maternal age and maternal health.CrossRef | 25934599PubMed | open url image1

Savva, G. M., Walker, K., and Morris, J. K. (2010). The maternal age-specific live birth prevalence of trisomies 13 and 18 compared to trisomy 21 (Down syndrome). Prenat. Diagn. 30, 57–64.
| 19911411PubMed | open url image1

Schaefer, G. B. (2016). Clinical genetic aspects of ASD spectrum disorders. Int. J. Mol. Sci. 17, E180.
Clinical genetic aspects of ASD spectrum disorders.CrossRef | 26840296PubMed | open url image1

Schulkey, C. E., Regmi, S. D., Magnan, R. A., Danzo, M. T., Luther, H., Hutchinson, A. K., Panzer, A. A., Grady, M. M., Wilson, D. B., and Jay, P. Y. (2015). The maternal-age-associated risk of congenital heart disease is modifiable. Nature 520, 230–233.
The maternal-age-associated risk of congenital heart disease is modifiable.CrossRef | 1:CAS:528:DC%2BC2MXlslensLc%3D&md5=81f1f6d68748dbb312e9d4f6ed9a7eaaCAS | 25830876PubMed | open url image1

Stoop, D., Silber, S., and Cobo, A. (2015). Fertility preservation for age-related fertility decline – authors’ reply. Lancet 385, 507–508.
Fertility preservation for age-related fertility decline – authors’ reply.CrossRef | 25705841PubMed | open url image1

Stranc, L. C., Evans, J. A., and Hamerton, J. L. (1997). Chorionic villus sampling and amniocentesis for prenatal diagnosis. Lancet 349, 711–714.
Chorionic villus sampling and amniocentesis for prenatal diagnosis.CrossRef | 1:STN:280:DyaK2s3jt12ktw%3D%3D&md5=395c222f494f4bf7caa0cbddd5b071acCAS | 9078211PubMed | open url image1

Tarín, J. J., Brines, J., and Cano, A. (1998). Long-term effects of delayed parenthood. Hum. Reprod. 13, 2371–2376.
Long-term effects of delayed parenthood.CrossRef | 9806250PubMed | open url image1

Tarín, J. J., Gómez-Piquer, V., Rausell, F., Navarro, S., Hermenegildo, C., and Cano, A. (2005). Delayed motherhood decreases life expectancy of mouse offspring. Biol. Reprod. 72, 1336–1343.
Delayed motherhood decreases life expectancy of mouse offspring.CrossRef | 15689534PubMed | open url image1

Tarín, J. J., García-Pérez, M. A., and Cano, A. (2014). Assisted reproductive technology results: why are live-birth percentages so low? Mol. Reprod. Dev. 81, 568–583.
Assisted reproductive technology results: why are live-birth percentages so low?CrossRef | 24810886PubMed | open url image1

Tatone, C. (2008). Oocyte senescence: a firm link to age-related female subfertility. Gynecol. Endocrinol. 24, 59–63.
Oocyte senescence: a firm link to age-related female subfertility.CrossRef | 18210326PubMed | open url image1

Tearne, J. E. (2015). Older maternal age and child behavioral and cognitive outcomes: a review of the literature. Fertil. Steril. 103, 1381–1391.
Older maternal age and child behavioral and cognitive outcomes: a review of the literature.CrossRef | 26041693PubMed | open url image1

Wapner, R. J. (1997). Chorionic villus sampling. Obstet. Gynecol. Clin. North Am. 24, 83–110.
Chorionic villus sampling.CrossRef | 1:STN:280:DyaK2s3ktFWhsw%3D%3D&md5=16b6009907ced9ce10546fc2268c6fe6CAS | 9086520PubMed | open url image1

Wilding, M. (2015). Potential long-term risks associated with maternal aging (the role of the mitochondria). Fertil. Steril. 103, 1397–1401.
Potential long-term risks associated with maternal aging (the role of the mitochondria).CrossRef | 25936236PubMed | open url image1

Xiong, X., Dickey, R. P., Pridjian, G., and Buekens, P. (2015). Maternal age and preterm births in singleton and twin pregnancies conceived by in vitro fertilisation in the United States. Paediatr. Perinat. Epidemiol. 29, 22–30.
Maternal age and preterm births in singleton and twin pregnancies conceived by in vitro fertilisation in the United States.CrossRef | 25483622PubMed | open url image1



Supplementary MaterialSupplementary Material (217 KB) Export Citation

View Altmetrics