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The paradox of declining fertility but increasing twinning rates with advance maternal Age
Abstract and Figures
Advancing female age is associated with declining fertility potential due to decreasing numbers and quality of oocytes but also with a distinct increase in dizygotic twinning rates, a phenomenon that has never been explained.
An analysis of follicle development was made in 959 spontaneous ovulatory cycles of 507 women.
Multiple ovarian follicular development (>1 follicle >14 mm) and, by implication, multiple rather than single ovulations occurred in 105 women whose mean age (36.1 versus 34.6 years) and mean basal FSH concentrations (10.3 versus 7.7 IU/l) were significantly greater than those with monofollicular development (P < 0.01). The prevalence of multifollicular development increased with age.
Dizygotic twinning must be associated with the development of >1 large follicle, which we found to be a significantly more frequent occurrence in older women. It is hypothesized that the response of pituitary release of FSH to the decreased negative feedback induced by impending ovarian failure often 'overshoots', causing multiple follicular development. In the presence of two good-quality oocytes, a twin pregnancy may result.
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... Ergin RN, Yayla M 164 covered so far. [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] In family studies, the possibility of babies to be dizygotic in dizygotic mothers (1/58) was found to be 2 times higher than in dizygotic fathers (1/116). [16] Therefore, in genetic researches carried on dizygotic twin pregnancies in which it was believed that genetic factors are mainly responsible, genetic mutations such as PPRAG (peroxisome proliferator-activated receptor gamma) at chromosome 3p25 and GDF6 which are significant in fertility and ovary function were considered as responsible. ...
... [17,18] The possibility to be dizygotic twin increases by maternal age and parity. [19][20][21] The possibility which is 1.3% during first pregnancy increases to 2.7% in 4th pregnancy. [19] It has been asserted that oral contraceptive and folic acid use affects dizygotic twin formation. ...
... Some observations cannot be reconciled with the grandmother hypothesis. Older women have an increased chance of giving birth to twins and triples [46]. Furthermore, the outcome of such pregnancies in older mothers are better than in younger mothers [47,48]. ...
... It is in agreement with hyperfunction theory. Hyperstimulation with FSH leads to multiple ovulation and a higher incidence of twins and triplets with age [46]. ...
There is no doubt that prostate cancer is a disease. Then, according to hyperfunction theory, menopause is also a disease. Like all age-related diseases, it is a natural process, but is also purely harmful, aimless and unintended by nature. But exactly because these diseases (menopause, prostate enlargement, obesity, atherosclerosis, hypertension, diabetes, presbyopia and thousands of others) are partially quasi-programmed, they can be delayed by slowing aging. Is aging a disease? Aging is a quasi-programmed disease that is partially treatable by rapamycin. On the other hand, aging is an abstraction, a sum of all quasi-programmed diseases and processes. In analogy, the zoo consists of animals and does not exist without animals, but the zoo is not an animal.
... In the literature, a positive association between natural DZ twinning and advancing maternal age was found (Abel & Kruger, 2012;Beemsterboer et al., 2006;Bonnelykke, 1990;Bortolus et al., 1999;Derom et al., 2011;Hoekstra, Zhao et al., 2008;Tandberg et al., 2007). A hormonal reason underlying this relation was established: under equal ovarian feedback conditions, older mothers experience hyperstimulation by endogenous follicle-stimulating hormones due to neuroendocrine, hypothalamic or pituitary mechanisms (Lambalk et al., 1998). ...
... However, Derom et al. (2011) observed that when adjusted for the nonspontaneous conceiving and the maternal age at birth, the observed increase in the natural DZ twinning rate disappeared and a constant time trend remained, indicating a stable population fecundity regardless of the advancing maternal age. Moreover, according to Beemsterboer et al. (2006), there is a greater probability of poliovulation in fertile women of advanced age. Our results were consistent with previous evidence: the higher DZ twinning rates were observed among older mothers (aged more than 35 years), and the MZ twinning rate was almost stable across classes of maternal age and dramatically declined in women aged 40 years or more. ...
In this study, we analyzed the estimated frequency of monozygotic (MZ) and dizygotic (DZ) spontaneous twins in Lombardy during the period 2007−2017. This is a population-based study using the regional healthcare utilization databases of the Lombardy Region. The total number of spontaneous twin deliveries, in separate strata of like and unlike sex, was obtained. Moreover, estimates of DZ and MZ twin births were calculated using Weinberg’s method. The standardized rates (SRs), adjusted for maternal age, of DZ and MZ twin births were computed according to calendar period. The twinning rates were calculated among strata of parity and maternal age. Finally, DZ:MZ ratio was calculated. Among the 734,278 spontaneous deliveries, 9176 (12.5 out of 1000 births) couples of twins were identified. In the three periods considered (i.e. 2007−2010, 2011−2014 and 2015−2017), no trend in the SRs of MZ twins was observed, respectively 0.41 (95% CI [0.40, 0.43]), 0.43 (95% CI [0.42, 0.45]) and 0.43 (95% CI[0.42, 0.45]). Differently, a slightly decreasing trend was observed in DZ twins SRs, respectively 0.87 (95% CI [0.84, 0.89]), 0.81 (95% CI [0.79, 0.83]), and 0.78 (95% CI [0.76, 0.80]). As concerns parity and maternal age, the rate of DZ twin births was consistently higher in nulliparae women aged 35 years or more. In our cohort, despite the increase of maternal age, a decline of spontaneous twin births emerged, especially due to the downward trend of DZ twins.
... Multiple births were excluded from the analyses (Denmark: 32 505 or 3.4 %; Finland: 23 585 or 2.9%; Norway: 28 380 or 3.5%; Sweden: 32 370 or 2.7%), because multiple births have higher risks of LBW and PTB, and are more common at later maternal ages. 19 Since sibling fixed-effects models are estimated using the variation between siblings, it was necessary to exclude children without siblings. ...
Background
Advanced maternal age at birth is considered a risk factor for adverse birth outcomes. A recent study applying a sibling design has shown, however, that the association might be confounded by unobserved maternal characteristics.
Methods
Using total population register data on all live singleton births during the period 1999–2012 in Denmark (N = 580 133; 90% population coverage), Norway (N = 540 890) and Sweden (N = 941 403) and from 2001–2014 in Finland (N = 568 026), we test whether advanced maternal age at birth independently increases the risk of low birthweight (LBW) (<2500 g) and pre-term birth (<37 weeks gestation). We estimated within-family models to reduce confounding by unobserved maternal characteristics shared by siblings using three model specifications: Model 0 examines the bivariate association; Model 1 adjusts for parity and sex; Model 2 for parity, sex and birth year.
Results
The main results (Model 1) show an increased risk in LBW and pre-term delivery with increasing maternal ages. For example, compared with maternal ages of 26–27 years, maternal ages of 38–39 years display a 2.2, 0.9, 2.1 and 2.4 percentage point increase in the risk of LBW in Denmark, Finland, Norway and Sweden, respectively. The same patterns hold for pre-term delivery.
Conclusions
Advanced maternal age is independently associated with higher risk of poor perinatal health outcomes even after adjusting for all observed and unobserved factors shared between siblings.
... The most important perhaps is the mother's age (the greater the age, the higher the twinning rate) and parity (how many children came before the twins). Other factors affect the DZ twinning rate, including diet, seasonality, geographic location (Hoekstra et al., 2007), and financial well-being and the mother's education (Beemsterboer, 2006). All five of the Amish groups in this study came from the same European ethnic stock. ...
The Amish are known for their high fertility and large families, but the Amish twinning rate has been of less interest. In an article published in 1970 (over 50 years ago), Cross and McKusick determined the Holmes County, Ohio, Amish twinning rate to be 15.3 twin pairs per 1,000 live births, which ranked among the highest known twinning rates at that time, while the U.S. national twinning rate hovered at around 9 per 1,000 per year. Within a few decades following the Cross and McKusick study, the twinning rates of the American population increased dramatically, and surpassed the Amish twinning rates. This surge in the twinning rate among the general American population was generally accredited to the widespread use of medically assisted reproduction (MAR), which favors multiple births, and the increased birth rates for older women, who have a significantly higher rate of multiple births. Holmes County has eight different Amish sects, ranging from fairly progressive to ultraconservative, and the five largest ones were the subjects of this study. The twinning rates of the different groups vary, parallel with degree of conservatism. The New Order Amish (most progressive) have a twinning rate of 20.1 twins per 1,000 births, whereas the Swartzentruber Amish have a rate of 34.5. Since all the groups are of identical ethnic stock and share virtually identical historical experiences, these twinning variances are difficult to explain, but may be due to diverging dietary practices that paralleled the conservative fragmentation.
... In developed countries, introduction of assisted reproductive technologies may have contributed to increased number of multiple pregnancies [1]. Additionally, high proportion of mothers with advanced age naturally conceived dizygotic twins [2], which can attribute to increases in follicle-stimulating hormone concentration with women's aging [3]. Moreover, older women are also more likely to utilize fertility medications for superovulation to increase the odds of pregnancy which are also associated with multiple gestation [4]. ...
Twins involve a higher risk of perinatal complications compared to singletons. We compared the risk of under five mortality between twins and singletons among late preterm and term births. The national birth data of South Korea pertaining to the years 2010–2014 linked with the mortality record of children aged under 5 years in 2010–2019 was analyzed. The final study population was 2,199,632 singletons and 62,351 twins. We conducted a survival analysis of under-five mortality with adjustment for neonatal and familial factors. Overall under-five mortality rates during the study period were 3.6 and 2.0 for twins and singletons, respectively. Although the unadjusted overall under-five mortality was higher in twins (hazard ratio [HR] = 1.80, 95% confidence interval [CI]: 1.57, 2.06, overall risk), twin birth was associated with comparable or lower risk (HR = 0.70, 95% CI: 0.58, 0.85, overall; 0.70, 95% CI: 0.56, 0.87, excluding neonatal mortality; 0.59, 95% CI: 0.40, 0.86, excluding infant mortality) after controlling for both neonatal and familial factors. Twins born at a gestational age of 34–35 weeks showed a generally lower risk of under-five mortality than their singleton counterparts, regardless of model specification.
Conclusion: Among late preterm and term birth, under-5-year mortalities for twins were lower than singleton births when adjusted for neonatal and familial risk factors. This highlights the differential implication of gestational age at birth between twin and singleton in the child mortality.
What is Known:
• Twin births involve a higher risk of perinatal complications compared to singletons.
What is New:
• Among late preterm and term birth, twins showed lower under-5-year mortalities than singleton births when adjusted for neonatal and familial risk factors.
• Birth at 34–35 weeks of gestation implicates different prognosis between twin and singleton in the child mortality.
Objective
Adverse pregnancy outcomes (APOs) and early menopause are each associated with increased risk of cardiovascular disease (CVD); whether APOs are associated with age at menopause is unclear. We examined the association of gestational diabetes (GDM), hypertensive disorders of pregnancy (HDP), preterm birth, and multiple gestation with age at natural menopause.
Study design
Observational, prospective study within the Nurses' Health Study II cohort (1989–2019).
Main outcomes measures
Risk of early natural menopause, defined as occurring before the age of 45 years, and age at onset of natural menopause (hazard ratio (HR) >1 indicates younger age at menopause).
Results
The mean [SD] baseline age of 69,880 parous participants was 34.5 [4.7] years. Compared with participants who had a term singleton first birth, those with a term multiple-gestation first birth had higher risk of early menopause (HR: 1.65, 95 % CI: 1.05, 2.60) and younger age at natural menopause (HR: 1.46, 95 % CI: 1.31, 1.63). Estimates for preterm multiple gestation were of similar magnitude. Menopause occurred at a younger age for those with a preterm birth with spontaneous labor (HR: 1.08, 95 % CI: 1.03, 1.14) compared to those with a term birth with spontaneous labor. Conversely, estimates for GDM (HR: 0.95, 95 % CI: 0.89, 1.02) and HDP (preeclampsia, HR: 0.93, 95 % CI: 0.89, 0.97) suggested an association with older age at menopause.
Conclusions
In this large cohort study, several statistically significant associations between APOs and age at natural menopause were observed. A deeper understanding of the relationships among APOs, menopause, and CVD is needed to help identify people at higher risk for early menopause and later CVD.
Although the majority of pregnancies are uneventful, sometimes complications do happen. Pregnancy complications are the conditions or pathological processes associated with pregnancy. They can occur during or after pregnancy and range from minor discomforts to serious diseases that require medical interventions. They can involve the mother's health, the baby's health, or both. Complication of pregnancy can cause maternal morbidity and mortality. The most common causes of maternal mortality are maternal bleeding, maternal sepsis, hypertensive disease, obstructed labour, and pregnancy with the consequence of abortion, which includes miscarriage, ectopic pregnancy, and medical abortion. The primary means of preventing maternal deaths is to provide rapid access to emergency obstetric care, including treatment of haemorrhage, infection, hypertension, and obstructed labour. Proper antenatal care can reduce the maternal mortality rate by reducing the number of pregnancies among women of reproductive age. Thus, adequate monitoring and appropriate intervention strategies should be provided for better maternal and fetal outcome.
We analysed the relationship between coffee and alcohol intake, smoking and risk of multiple pregnancies using data from a case-control study on risk factors for multiple births conducted in Italy. Cases were 133 women who delivered multiple births not related to treatment for infertility (33 monozygotic and 100 dizygotic twins). Controls were 395 women admitted for normal delivery at the same clinic where cases had been identified. The odds ratios (OR) of multiple pregnancy were 1.5[95% confidence interval (CI) 0.8-2.8] and 2.0 (95% CI 1.0-3.7) for women drinking respectively one to two or three or more cups of coffee per day in comparison with non-coffee drinkers. Considering separately dizygotic and monozygotic pregnancies, the estimated OR were respectively for women drinking three or more cups of coffee, 1.7 and 3.1 for dizygotic and monozygotic pregnancies. The risk of multiple pregnancy tended to be higher in women drinking >or= 15 alcohol drinks per week: in comparison with tea-totallers the estimated OR for drink > or = 15 glasses per week were 2.3 and 2.6 respectively for dizygotic and monozygotic pregnancies. Heavy smokers (> or = 10 cigarettes per day) were at increased risk of multiple pregnancy: in comparison with never smokers, the estimated OR for multiple pregnancy was 1.6 (95% CI 0.9-2.7). Considering separately the two groups of multiple pregnancy, the OR of dizygotic and monozygotic pregnancy were 1.4 (95% CI 0.8-2.5) and 2.4 (95% CI 0.9-6.1) for women smoking > or = 10 cigarettes/day, but the trend in risk with number of cigarettes smoked per day and duration of the habit was not significant.
To study trends in multiple pregnancies not explained by changes in maternal age and parity patterns.
Trends in population based figures for multiple pregnancies in Denmark studied from complete national records on parity history and vital status.
497,979 Danish women and 803,019 pregnancies, 1980-94.
National rates of multiple pregnancies, infant mortality, and stillbirths controlled for maternal age and parity. Special emphasis on primiparous women > or = 30 years of age, who are most likely to undergo fertility treatment.
The national incidence of multiple pregnancies increased 1.7-fold during 1980-94, the increase primarily in 1989-94 and almost exclusively in primiparous women aged > or = 30 years, for whom the adjusted population based twinning rate increased 2.7-fold and the triplet rate 9.1-fold. During 1989-94, the adjusted yearly increase in multiple pregnancies for these women was 19% (95% confidence interval 16% to 21%) and in dizygotic twin pregnancies 25% (21% to 28%). The proportion of multiple births among infant deaths in primiparous women > or = 30 years increased from 11.5% to 26.9% during the study period. The total infant mortality, however, did not increase for these women because of a simultaneous significant decrease in infant mortality among singletons.
A relatively small group of women has drastically changed the overall national rates of multiple pregnancies. The introduction of new treatments to enhance fertility has probably caused these changes and has also affected the otherwise decreasing trend in infant mortality. Consequently, the resources, both economical and otherwise, associated with these treatments go well beyond those invested in specific fertility enhancing treatments.
On the basis of MEDLINE and manual searches, we examined the main papers in the English literature regarding risk factors for spontaneous (i.e. not related to fertility drug use) multiple births. The constant frequency of monozygotic (MZ) pregnancies over time and in different geographical areas suggests that the determination of MZ twins is largely unchanged over time, and that a genetic mechanism may have a role. In contrast, temporal and geographical trends observed in dizygotic (DZ) pregnancies suggest that environmental factors play a role in determining this condition. At present, maternal age and hereditary components are the best-defined determinants for spontaneous multiple births.
Hemon D [U170 Statistique, INSERM, 16 bis. Avenue Paul Vaillant Couturier, 94800 Villejuif, France], Berger C and Lazar P. Twinning following oral contraceptive discontinuation. International Journal of Epidemiology 1981, 10: 319–328.
The characteristics of 673 mothers of twins were compared to those of a matched sample of mothers of singletons. Both groups of mothers were interviewed just after delivery, and births in each group were matched for time and place. Of the characteristics studied, the use of oral contraceptives (OC) displayed a significant negative association with dizygotic twinning, with an estimated relative risk of 0.55 (95% confidence limits: 0.39/0.78). Among other maternal traits significantly associated with dizygotic twinning, only age, parity and weight were possible con-founders as far as the relationship between OC use and dizygotic twinning was concerned. Adjustment for these 3 characteristics left this relationship unaltered. These findings are compatible with the existence of a direct relationship between OC use and a reduction in dizygotic twinning. Review of the available evidence concerning reproductive capacities following OC discontinuation suggests that the higher incidence of chromosomic abnormalities among spontaneous abortuses of OC users or their lower fertility could explain a reduction of dizygotic twinning rate after OC discontinuation. It is concluded that examination of the time and place variations in OC use and dizygotic twinning would help to clarify the nature of their relationship.
To evaluate the specific contribution of artificial induction of ovulation to the increasing number of multiple gestations in East Flanders and the effects of this treatment on the frequencies of monozygotic and dizygotic twinning.
Since 1976 the East Flanders Prospective Twin Study has collected data on artificial induction of ovulation for all the multiple births listed in its registry.
East Flanders Prospective Twin Survey.
Between 1976 and 1992, 458 twin and 78 triplet pregnancies resulting from artificial induction of ovulation were analyzed.
Zygosity and frequency of iatrogenic multiple births.
Since 1985 there is an explosive increase in twin and triplet births in East Flanders. This increase has been caused mainly by the sole use of fertility-enhancing drugs and in the last few years by resorting to other technologies of assisted reproduction, such as IVF-ET, GIFT, or zygote intrafallopian transfer.
In view of the elevated risk inherent to multiple pregnancies in terms of perinatal mortality and morbidity, the over enthusiastic or improper use of fertility drugs should be curtailed.
Women experience a decline in fertility that precedes the menopause by several years. Previous studies have demonstrated a monotropic rise in FSH associated with reproductive aging: however, the mechanism of this rise and its role in the aging process are poorly understood. The purpose of this study was to characterize ovarian follicular development and ovarian hormone secretion in older reproductive age women. Sixteen women, aged 40-45 yr, with regular ovulatory cycles were studied. The control group consisted of 12 ovulatory women, aged 20-25 yr. Serum obtained by daily blood sampling was analyzed for FSH, LH, estradiol (E), progesterone, and inhibin (Monash polyclonal assay). Follicle growth and ovulation were documented by transvaginal ultrasound. Older women had significantly higher levels of FSH throughout the menstrual cycle. E, progesterone, LH, and inhibin levels did not differ between the two age groups when compared relative to the day of the LH surge. Ultrasound revealed normal growth, size, and collapse of a dominant follicle in all subjects. Older women had significantly shorter follicular phase length associated with an early acute rise in follicular phase E, reflecting accelerated development of a dominant follicle. We conclude that older reproductive age women have accelerated development of a dominant follicle in the presence of the monotropic FSH rise. This is manifested as a shortened follicular phase and elevated follicular phase E. The fact that ovarian steroid and inhibin secretion were similar to those in the younger women suggests that elevated FSH in women of advanced reproductive age may represent a primary neuroendocrine change associated with reproductive aging.
Imminent ovarian failure (IOF) in women is characterized by regular menstrual cycles and elevated early follicular phase FSH.
This study explored underlying neuroendocrine causes of elevated FSH concentrations on day 3 of the menstrual cycle. The characteristics
of episodic secretion of FSH and LH, the pituitary response to gonadotrophin-releasing hormone (GnRH), plasma oestradiol,
and dimeric inhibin A and inhibin B on day 3 were compared in 13 women with elevated FSH concentrations (>10 IU/l) and 16
controls. FSH amplitudes were higher in the IOF group than in the controls (P < 0.0001). The FSH pulse frequency did not differ between groups. The FSH response to GnRH was higher in the IOF patients
than in the controls (P < 0.0001). Mean LH, LH amplitude and LH response to GnRH were higher in the IOF group, but LH pulse frequency did not differ
between the groups. Concentrations of inhibin A and inhibin B were lower in the IOF group, while oestradiol showed no differences.
We concluded that in women with IOF, the pituitary is more sensitive to GnRH. This leads to higher FSH and LH pulse amplitudes
which underlie the elevated FSH concentrations in the early follicular phase.