|Year : 2020 | Volume
| Issue : 2 | Page : 71-77
Effect of advancing maternal age on some histomorphological characteristics and other parameters of the offspring of wistar rats
Taiwo O Kusemiju1, Oshiozokhai Eboetse Yama2, OO Olabiyi1, AA Aladejare1, Timothy Danboyi3, Anthony Donatus Teru Goj3, Ohunene Makoju Avidime3
1 Department of Anatomy, College of Medicine, University of Lagos, Idi-Araba, Lagos, Nigeria
2 Department of Human Anatomy, College of Medicine, Kaduna State University, Kaduna, Nigeria
3 Department of Human Physiology, College of Medicine, Kaduna State University, Kaduna, Nigeria
|Date of Submission||08-May-2020|
|Date of Decision||21-Jun-2020|
|Date of Acceptance||29-Jun-2020|
|Date of Web Publication||11-Feb-2021|
Dr. Timothy Danboyi
Department of Human Physiology, College of Medicine, Kaduna State University, Kaduna
Source of Support: None, Conflict of Interest: None
Background: The average age of mothers at the time of first childbirth has been increasing over the past decades. Delayed motherhood comes with several adverse outcomes. Objective: We investigated the effect of advancing maternal age on some histomorphological parameters in the litters of female Wistar rats. Materials and Methods: Twenty-seven female rats (11–40 weeks old) were divided into three groups (young-, mid-, and old aged) of 9 rats each and mated with 12 male rats. The morphological parameters of the litters were obtained and a classic maze task was performed. Data were analyzed using the Statistical Package for the Social Sciences version 23 and values at P < 0.05 were considered significant. Results: The litters of young-age mothers were significantly fewer (5.0 ± 0.4) compared to litters of mid- (8.0 ± 0.3) and old-aged (11.6 ± 0.8) mothers. Sex ratio significantly increased as the maternal age increases. Litters of young-aged mothers committed more errors (3.4 ± 0.5) and took longer to complete the maze task (147.0 ± 24.9s) compared to litters of the other groups. However, the biomarkers of oxidative stress (OS) in the brain homogenate were worse with advancing maternal age. Histologically, there was a significant decrease in the external pyramidal layer width with advancing maternal age (8.18 ± 0.23 mm in young aged; 4.16 ± 0.09 mm in the old aged). Conclusion: Advancing maternal age has an enhancing effect on the litters' size, sex ratio, and cognitive abilities but a negative effect on OS and cortical width.
Keywords: AJdvancing, age, litter, maternal, ratio, sex
|How to cite this article:|
Kusemiju TO, Yama OE, Olabiyi O O, Aladejare A A, Danboyi T, Teru Goj AD, Avidime OM. Effect of advancing maternal age on some histomorphological characteristics and other parameters of the offspring of wistar rats. Niger J Exp Clin Biosci 2020;8:71-7
|How to cite this URL:|
Kusemiju TO, Yama OE, Olabiyi O O, Aladejare A A, Danboyi T, Teru Goj AD, Avidime OM. Effect of advancing maternal age on some histomorphological characteristics and other parameters of the offspring of wistar rats. Niger J Exp Clin Biosci [serial online] 2020 [cited 2021 Feb 25];8:71-7. Available from: https://www.njecbonline.org/text.asp?2020/8/2/71/309163
| Introduction|| |
Gender selection refers to the use of reproductive techniques/technologies such as in vitro fertilization for the deliberate and unnatural selection of one's offspring, either pre- or postconception., The main reasons for sex selection include medical, such as preventing the birth of children affected or at risk of X-linked disorders, family balancing, and gender preference, stemming from the sociocultural and economic bias often in favor of male children. The natural sex ratio, which is often distorted by sex-selection practices, has been explained by several theories such as the Trivers and Willard's theory, a sex ratio biased toward sons, and the local resource competition theory, biased toward daughters. Sex ratio which had been biased toward sons has been declining over the past three decades now due to harsh industrial chemicals against the male androgens, particularly testosterone, stress, harsh socioeconomic condition, and natural and man-made horrors.
With an increase in age, there is a decline in physiological functions, called senescence, in which cellular processes are halted or even arrested. The concept of female “biological clock” and advancing maternal age constitutes a source of concern for many women. The average age of mothers at the time of first childbirth has been increasing over the past decades., This may be due to the societal trend in which couples delay child bearing for career or socioeconomic reasons. However, this increase had been associated with several adverse outcomes such as infertility, miscarriages, trisomy 21, low birth weights, cancers, and hypertension.,,,,,,,,,, Could there also be positive effects of advancing maternal age on the offspring? This study aimed to find out the effect of advancing maternal age on sex ratio, litters' intelligence, and other histomorphological parameters in the offspring of Wistar rats.
| Materials and Methods|| |
Experimental animals and laboratory conditions
Thirty-nine apparently healthy adult rats (Rattus norvegicus) of both sexes (27 females and 12 males) were housed in plastic cages (three rats per cage), measuring 30 cm × 20 cm × 13 cm, with soft wooden shavings as beddings. They were fed with rat chow and water ad libitum. They were kept under standardized animal house conditions (temperature: 28°C–-31°C; light: approximately 12 h natural light per day; and humidity: 50%–55%) and allowed 2 weeks of acclimatization to these conditions before the commencement of the study.
All procedures conformed to the National Academy of Sciences' Guide for the Care and Use of Laboratory Animals.
Twenty-seven female rats were divided into three groups of nine rats each, based on their ages: those within 11–20 weeks old were placed in the young-aged group, those within 21–30 weeks old, mid-aged group, and those 31–40 weeks old, old-aged group. The 12 mid-aged male rats (within 21–30 weeks old) were used to mate the females. After grouping, blood samples were collected for analysis of biomarkers for oxidative stress (OS).
Determining stage of estrous cycle and mating
Representative photographs and micrographs for each stage of the estrous cycle were obtained following the steps described by Byers et al., via assessment of the vaginal opening and vaginal cytology. The male Wistar rats were introduced overnight to the female Wistar rats during the estrus phase. A vaginal smear was carried out the following morning to confirm mating. If sperm plugs were seen under the microscope, that day was termed “day 1” of pregnancy.
After parturition, the gross morphology of the litters was carried out, then subdivided into subgroups A and B before humanely sacrificing them. The brains of subgroup A were harvested for homogenate preparation but those from subgroup B for histology.
The cerebral tissues were cut to 5 mm size by a sharp sterilized blade. The tissue processing was carried out according to the method described by Akpantah et al.
After harvesting the cerebral tissues from the litters, the tissues were preserved immediately in a freezing chamber. Five gram was cut from the frontal cerebral lobe and homogenized with 0.4 M phosphate buffer and later centrifuged for 10 min at 3000 rpm. Biomarkers for OS analyzed include superoxide (SOD) according to the method described by Kakkar et al.; reduced glutathione (GSH), according to the method described by Ellman; catalase (CAT), based on the method of Sinha, and malondialdehyde (MDA) according to the method described by Okhawa et al.
The classic maze task
The classic maze task was performed according to the method described by Hanson. It consists of a branching pathway with six closed (false) routes, a “Start” point (to place the rat) and an “End” point (where it's feed is placed). To train the rats, oil from a fried meat was used to trace the open (true) route from the “Start” to the “End” of the maze. The rat is expected to trace the aroma of the meat through to the “End.” This was done three times daily (9 am, 12 pm, and 3 pm) for the first 7 days. On the 8th day, the classic maze was cleaned and dried in the sun to clear away the aroma of the fried meat. The rat was introduced and expected to go through the only true route from the “Start” to the “End” of the maze with minimal errors. The time taken for each rat in each group to complete the tour round the maze was recorded. The number of entries into the false routes was counted as an error and recorded.
Data were expressed as mean ± standard deviation and were analyzed using the Statistical Package for the Social Sciences (SPSS) software version 23 (Armonk, NY:IBM Corp, 2017). One-way analysis of variance was employed for multiple comparisons between groups, followed by the Student–Newman–Keuls test. The difference between the groups was considered statistically significant at P < 0.05.
| Results|| |
There was a significant increase in the number of litter size (5.0 ± 0.4 in the young-aged; 8.0 ± 0.3 in the mid-aged, and 11.6 ± 0.8 in the old-aged mothers) and in the sex ratio (0.42 in the young-aged; 0.90 in the mid-aged and 2.41, in the old-aged mothers), with advancing maternal age [Table 1].
The litters' weight and other morphological parameters (umbilical cord, crown-rump, and tail lengths) significantly decrease with increasing maternal age [Table 2].
|Table 2: Morphological characteristics of the litters across the maternal age groups|
Click here to view
Acclimatization of the maze was fastest among the litters born to young-aged mothers (31.6 ± 6.5s), but with advancing maternal age, the number of errors as well as the total time to complete the task decreases (87.0 ± 8.1s in mid-aged and 82.0 ± 9.8s in the old-aged mothers) [Table 3].
|Table 3: Litters intelligence in the classic maze across the maternal age groups|
Click here to view
The cell count in the external pyramidal layer remains relatively the same across the age group, but the width of the same layer decreases as the maternal age increases (from 8.18 ± 0.23 cm in young-aged mothers to 4.16 ± 0.09 cm in the old-aged mothers) [Table 4].
|Table 4: Average cell count (per grid) of the external pyramidal layer and width of the litters' cerebral frontal lobe|
Click here to view
The MDA concentration, GSH, and CAT levels were significantly higher (12.61 ± 0.04 umol/g, 38.85 ± 0.54 μmol/mgpr and 4.01 ± 0.05 μmol/mg respectively), while the SOD level was lower (2.17 ± 0.01 μmol/mg) in litters born to old-aged mothers than those seen in the other age groups [Table 5] and this corresponds with the parameters of the maternal sera [Table 6].
|Table 5: Stress markers activities in the frontal cerebral tissue of the litter across the groups|
Click here to view
| Discussion|| |
The effects of maternal age on sex ratio can be variable. While a decline in the male-to-female ratio with advancing maternal age was reported in some studies,, no association was found in another study, but we found a significant increase in the male-to-female sex ratio of the litters as the maternal age increased [Table 1]. Our finding is in line with that of some studies, which showed an increase in the sex ratio among older dams compared to the younger ones, and they predicted the ratio to be increased when young dams give birth to big litters and old dams give birth to small litters and vice versa. This is absolutely a true reflection of our findings. This may be due to a combination of both maternal and paternal factors, but it, however, deviates from the Trivers-Willard hypothesis discussed above.
It had been established that litter size is often affected by maternal age. Although the young-aged mothers in the present study gave birth to much fewer litters compared to the mid- and old-aged mothers, the morphologic characteristics of their litters were surprisingly significantly higher [Table 2]. Hence, the litters' size (in terms of their number) is inversely related to their weights as the pups of young-age mothers were significantly weightier than the pups of the old-aged mothers but fewer in number. This is contrary to the findings of Sampino et al., who found that young-age mice mothers gave birth to significantly more pups compared to old-aged mice mothers.
Litters of young-age mothers are expected to have smaller weights and other morphologic characteristics since the mothers are also growing and competition for available nutrient during gestation will most likely exist between their (the mothers) bodies and their fetuses. This was demonstrated in some human studies., The increase in fetal characteristics in such studies was notably significant only in the first trimester, and the birth weights and other parameters were higher among babies born to the optimum (or mid) age and advanced (or old) mothers compared to the young-aged mothers.
The increase in number of litters born to the mid- and old-aged mothers may be probably due to an increase in the number of ova shed during estrus, increase in sizes of their pregnancies, parity as well as body surface areas or mass. Since the mid- and old-aged mothers had more fetuses, fetal competition for nutrient in utero might have accounted for the smaller litter's weights and other parameters compared to the young-aged mothers. This was explained by some studies, who found that advanced maternal age is associated with fetal growth restriction caused by aberrant or dysregulated methylation and gene expression in oocytes and reproductive tissues of maternally aged mice, but younger maternal age was also associated with low birth weight study. However, the prevalence of small for gestational age outcome was highest among babies those to advanced age mothers owing to placental aging.
Furthermore, older mothers are more likely to have longer body length and heavier weight than the younger-age mothers. A study by Polzlberger et al. revealed a significantly positive association between maternal height and crown-rump length in the first trimester and other fetal characteristics in the second and third trimesters. Their study also demonstrated that prepregnancy maternal weight status is significantly and positively associated with all fetal parameters in the third trimester. It is, therefore, not surprising Polzlberger et al. found the maternal height and prepregnancy weight to be significantly and positively associated with newborn size. Hence, irrespective of the maternal age, the pregestation height and weight determine the fetal morphological characteristics as well as litters' weights and this also explains the increase in litters' weights and fetal morphological parameters observed among the young aged mothers in the present study.
Litters' intelligence appeared to increase with increasing maternal age [Table 3]. The litters from the old-aged mothers ran through the maze in the shortest time and made the least number of errors, even though their adaptation to the experimental procedure was delayed. This shows that they have a superior spatial learning ability and better working memory compare to litters of both young- and mid-aged mothers. The delay in adapting to the procedure may be due to persistent olfactory cues from litters of the other groups, who were first to perform the procedure each day despite the pretest wiping with alcohol wet cotton wool. However, litters from the young-aged mothers had the quickest adaptation to the experimental procedure.
Saha et al. and Myrskyla et al. demonstrated that increasing maternal age was associated with better performance in some cognitive tasks. This may be due to age-related alterations in fetal neurodevelopment in utero,, including alterations in hippocampal gene expression which play a role in anxiety-related behaviors and synaptic plasticity, but it is still controversial as recent studies showed poorer performances in some cognitive tasks.,, While “early” advanced maternal age (35–40 years) was significantly and positively associated with cognitive and behavioral outcomes, such association ceases to exist after the age of 40 years according to a study. Moreover, no association was found between advanced maternal age and neurodevelopmental impairment among very low birth weight preterm babies born to advanced-aged mothers. In fact, it is believed that advanced maternal age is protective on offspring's behavioral and cognitive outcomes.
It is possible that as the maternal age increases, the cerebral cortical layers shrink, resulting in compaction of the neural cells in each layer [Figure 1]a,[Figure 1]b,[Figure 1]c. Stereologically, neural cell count was relatively the same across the age groups [Table 4]. Hence, the neural cells are most dense in the most shrunk cerebral frontal lobe of litters of old-aged mothers. This in line with the finding of Cabeza et al., who demonstrated that brain shrinkage is differential, i.e., the rate of shrinkage varies spatially (across regions, structures, and compartment) and temporarily, along the age continuum.
|Figure 1: Histology of cerebral frontal lobe tissue: Photomicrograph sections of litters of young.aged (a), mid.aged (b), and old aged (c) Wistar rats showing the cytoarchitecture of the cerebral frontal lobes (M: Molecular, EG: External granular, EP: External pyramidal, IG: Internal granular, IP: Internal pyramidal, F layers: Fusiform) using hematoxylin and eosin stain, ×100|
Click here to view
The observed increase in biomarkers for OS in the cerebral frontal lobe of the litters with advancing maternal age [Table 5] corresponded with that in the maternal sera [Table 6], showing the effect of aging on OS, which, in turn, contributes to the aging process through the uncontrolled production of reactive oxygen species by aging mitochondria and decreases ability of the body to produce antioxidants. In some human studies and reviews, OS had been associated with an increase in ovulation.,, This may explain our earlier assertion that there might have been increase in the number of ova shed by the older-aged mothers in this study. Hence, the more the OS, the more ova are shed (ovulation), and the more the litters' size.
| Conclusion|| |
The findings of this study show enhancing effects of advancing maternal age on the litter's intelligence, male-to-female sex ratio and litter size, and deleterious effects on the cerebral frontal lobe histo-architecture, OS, and other morphological parameters such as litters' weight, and umbilical, crown-rump and tail lengths.
There have been concerns about the negative outcomes of delayed motherhood, but these might have been exaggerated as it has been established to have so many advantages,, some of which had been demonstrated in this study. As rightly pointed out by Cardin, a complete or balanced information outlining both the “risks” and benefits (which outweighs the risks) of delayed motherhood should be provided for all intending mothers so that no woman should be under pressure to conceive too early or too late.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Webb DC. The sex selection debate: A comparative study of sex selection laws in the United States and the United Kingdom. South Carol J Intl Law Bus 2013;109:163-202.
World Health Organization. Gender and Genetics: Sex Selection and Discrimination. Genomic Resource Centre; 2014. Available from: https://www.who.int/gender-and-genetics
. [Last accessed on 2015 May 19].
Trivers RL, Willard DE. Natural selection of parental ability to vary the sex ratio of offspring. Science 1973;179:90-2.
Clark AB. Sex ratio and local resource competition in a prosimian primate. Sci 1978;201:163-5.
Perret M. Revisiting the trivers-willard theory on birth sex ratio bias: Role of paternal condition in a Malagasy primate. PLoS One 2018;13:e0209640.
Jeyapalan JC, Sedivy JM. Cellular senescence and organismal aging. Mech Ageing Dev 2008;129:467-74.
Locke A, Budds K. Age, infertility risk and the timing of pregnancy in older first-time mothers. Health Risk Soc 2013;15:525-42.
Bray I, Gunnell D, Smith GD. Advancing paternal age: How old is too old? J Epidemiol and Commun Health 2006;60:851-3.
Tarin JJ, Brines J, Cano A. Long-term effect of delayed parenthood. Hum Reprod 1998;13:2371-6.
Jacobsson B, Ladfors L, Milson I. Advanced maternal age and adverse perinatal outcome. Obst Gyneacol 2004;104:727-33.
Brion MJ, Leary SD, Lawlor DA, Smith GD, Ness AR. Modifiable maternal exposures and offspring blood pressure: A review of epidemiological studies of maternal age, diet and smoking. Pediatr Res 2008;63:593-8.
Durkin MS, Maenner MJ, Newschaffer CJ, Lee LC, Cunniff CM, Daniels JL, et al
. Advanced parental age and the risk of autism spectrum disorder. Am J Epidemiol 2008;168:1268-76.
Johnson KJ, Carozza SE, Chow EJ, Fox EE, Horel S, Mclaughlin CC, et al
. Parental age and risk of childhood cancer: A pooled analysis. Epidemiology 2009;20:475-83.
Nassar AH, Usta IM. Advanced maternal age part II: Long-term consequences. Am J Perinatol 2009;26:107-12.
Gale EA. Maternal age and diabetes in childhood. Br Med J 2010;340:c623.
Menemez PR, Lewis G, Rasmussen F, Zammit S, Sipos A, Harrison GL, et al
. Paternal and maternal ages at conception and risk of bipolar affective disorder in their offspring. Psychol Med 2010;40:477-85.
Myrskyla M, Fenelon A. Maternal age and offspring adult health: Evidence from the health and retirement study. Demography 2012;49:1231-57.
Daly I, Bewley S. Reproductive ageing and conflicting clocks: King Midas' touch. Reprod BioMed Online 2013;27:722-32.
National Academy of Sciences. Guide for the Care and Use of Laboratory Animals. 8th
ed. Washington, DC: The National Academies Press; 2011. p. 246.
Byers SL, Wiles MV, Dunn SL, Taft RA. Mouse estrus cycle identification tool and images. PLoS One 2012;7:e35538.
Akpantah AO, Oremosu AA, Nouronha CC, Okanlawon AO. The effects of crude extracts of Garcina Kola on the histology and hormonal milieu of male Sprague-Dawley rats' reproductive organs. Nig J Health Biomed Sci 2003;2:40-6.
Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric assay of superoxide dismutase (SOD). Indian J Biochem Biophysics 1984;21:130-2.
Ellman GL. Tissue sulphydryl groups. Arch Biochem Biophys 1959;82:70-7.
Sinha KA. Colorimetric assay of catalase. Annals Biochem 1972;47:389-94.
Okhawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351-8.
Hanson A. Rats and Mazes. Rat Behavior and Biology; 2003. Available from: http://www.ratbehavior.org
. [Last accessed on 2019 Apr 14].
Clutton-Brock TH, Iason GR. Sex ratio variation in mammals. Quart Rev Biol 1986;61:339-74.
James WH, Rostron J. Parental age, parity, and sex ratio in births in England and Wales 1968-1977. J Biosoc Sci 1985;17:47-56.
Santos MM, Maia LL, Nobre DM, Neto JF, Garcia TR, Lage MC, et al
. Sex ratio of equine offspring is affected by the ages of the mare and stallion. Theriogenology 2015;84:1238-45.
Rueness J, Vatten L, Eskild A. The human sex ratio: Effects of maternal age. Hum Reprod 2012;27:283-7.
Martins AC, Vaz MA, Macedo MM, Santos RL, Galdino CA, Wenceslau RR, et al
. Maternal age, paternal age, and litter size interact to affect the offspring sex ratio of German Shepherd dogs. Theriogenology 2019;135:169-73.
Torres JI, Neves IA, Yariwake VY, Miglino MA, Veras MM. Advanced maternal age and placental morphofunctional changes: An experimental study in mice. Placenta 2017;2017:51.
Sampino S, Stankiewicz AM, Zacchini F, Goscik J, Szostak A, Swiergiel AH, et al
. Pregnancy at advanced maternal age affects behavior and hippocampal gene expression in mouse offspring. J Gerontol Biol Sci 2017;72:1465-73.
Restrepo-Mendez MC, Lawlor DA, Horta BL, Matijasevich A, Santos IS, Menezes AM, et al
. The association of maternal age with birthweight and gestation age: A cross-cohort comparison. Paed Perin Epidemiol 2015;29:31-40.
Kirchweger F, Kirchengast S, Hafner E, Stumpflein I, Hartmann B. The impact of maternal age on fetal growth patterns and newborn size. Anthropol Rev 2018;81:111-29.
Folio DM, Aars J, Gimenez O, Derocher AE, Wiig O, Cubaynes S. How many cubs can a mum nurse? Maternal age and size influence litter size in polar bears. Biol Lett 2019;15:20190070.
Paczkowski M, Schoolcraft WB, Krisher, RL. Dysregulation of methylation and expression of imprinted genes in oocytes and reproductive tissues in mice of advanced maternal age. J Assist Reprod Gen 2015;32:713-23.
Demirci O, Yilmaz E, Tosun Ö, Kumru P, Arinkan A, Mahmutoglu M, et al
. Effect of young maternal age on obstetric and perinatal outcomes: Results from the tertiary center in Turkey. Balkan Med J 2016;33:344-9.
Polzlberger E, Hartmann B, Hafner E, Stumpflein I, Kirchengast S. Maternal height and pre-pregnancy weight status are associated with fetal growth patterns and newborn size. J Biosoc Sci 2017;49:392-407.
Saha S, Barnett AG, Buka SL, Mcgarth JJ. Maternal age and paternal age are associated with distinct childhood behavioural outcomes in a general population birth cohort. Schiz Res 2009;115:130-5.
Myrskyla M, Barclay K, Goisis A. Advantages of later motherhood. Der Gynäkologe 2017;50:767-72.
Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, et al
. Paternal age and intelligence: Implications for age-related genomic changes in male germ cells. Psychiatr Genet 2005;15:117-25.
Falster K, Hanly M, Banks E, Lynch J, Chambers G, Brownell M, et al
. Maternal age and offspring developmental vulnerability at age five: A population-based cohort study of Australian children. PLoS Med 2018;15:e1002558.
Goisis A, Schneider DC, Myrskyla M. The reversing association between advanced maternal age and child cognitive ability: Evidence from three UK birth cohorts. Int J Epidemiol 2017;46:850-9.
Mao W, Wu Z, Yang Z, Xu Y, Wang S. Advanced maternal age impairs spatial learning capacity in young adult mouse offspring. Am J Transl Res 2018;10:975-88.
Goisis A. How are children of older mothers doing? Evidence from the United Kingdom. Biodemography Soc Biol 2015;61:231-51.
Tseng K, Peng C, Chang J, Hsu C, Lin C, Jim W, et al
. The impact of advanced maternal age on the outcomes of very low birth weight preterm infants. Medicine (Baltimore) 2019;98:e14336.
Tearne JE. Older maternal age and child behavioral and cognitive outcomes: A review of the literature. Fertil Steril 2015;103:1381-91.
Cabeza R, Nyberg L, Park D, editors. Cognitive Neuroscience of Aging: Linking Cognitive and Cerebral Aging. 2nd
ed. New York: Oxford University Press-Medical; 2004. p. 47-8.
Koppula S, Kumar H, More SV, Kim BW, Kim IS, Choi DK. Recent advances of the neuroprotective potentials of antioxidants in experimental models of Parkinson's disease. Int J Mol Sci 2012;13:10608-29.
Junqueira VB, Barros SB, Chan S, Rodrigues L, Giavarotti L, Abud R, et al
. Aging and oxidative stress. Mol Aspects Med 2004;25:5-16.
Ruder EH, Hartman TJ, Goldman MB. Impact of oxidative stress on female fertility. Curr Opin Obst Gynecol 2009;21:219-22.
Shkolnik K, Tadmor A, Ben-Dor S, Nevo N, Galiani D, Dekel N. Reactive oxygen species are indispensable in ovulation. Proc Natl Acad Sci USA 2011;108:1462-7.
Agarwal A, Aponte-Mellado A, Premkumar PJ, Shaman A, Gupta S. The effect of oxidative stress on female reproduction: A review. Reprod Biol Endocrinol 2012;10:49-80.
Barclay K, Myrskyla M. Advanced maternal age and offspring outcomes: reproductive aging and counterbalancing period trends. Pop Dev Rev 2016;42:69-94.
Myrskylä M, Sylventoinen K, Tylelius P, Rasmussen F. Is later better or worse? Association of advanced parental age with offspring cognitive ability among half a million young Swedish men. Am J Epidemiol 2013;177:649-55.
Cardin M. Reconsidering “advanced maternal age”: Communicating about pregnancy, disability risk and ageing. Femin Med Stud 2019;2019:1-15.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]