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OUR LATEST RESEARCH Published in December 2017 Issue of Reproductive Biomedicine Online

2017. Yavas Y. Curvilinear relationship between age and assisted reproduction technique success: retrospective analyses of US National ART Surveillance System data from 2010‑2014.  Reprod. Biomed. Online 35(6): 657-668 (Dec 2017) (Epub online Aug 15, 2017) (ScienceDirect LINK) (PubMed LINK).

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SUMMARY OF OUR RESEARCH          (Click here, or see below, for Figures)

As the sole researcher and author of his most recent study published in December 2017 issue of Reproductive Biomedicine Online journal, Dr. Yavas disproved previously-held assumption that Assisted Reproductive Technology / In Vitro Fertilization (ART / IVF) success rates in women using their own fresh eggs / embryos initially remain stable with age and decline steadily only after 30s or mid‑30s, by showing that the age‑driven decline in ART / IVF success rates not only begins as early as before age 30 but also occurs at increasing rates, suggesting that women who are older than 30 years of age with infertility should not delay ART / IVF treatment, if ART / IVF is their only option.

In his study with almost half a million (488,351) ART / IVF cycles between 2010-2014 in the U.S. population, using NASS (National ART Surveillance System) data from CDC, Dr. Yavas showed for the first time and in the U.S. population that, in women using their own fresh eggs / embryos:

  1. ART / IVF success rates change with age following well‑fitted, highly significant, Ç‑shaped mathematical models of curvilinear (quadratic, cubic and quartic) regressions.

  2. Therefore, ART / IVF success rates initially and steadily increase to age 28, and decline steadily thereafter (disproving the previously-held assumption that ART / IVF success rates initially remain stable with age and decline steadily only after 30s or mid‑30s).

  3. Therefore, the effect of increasing age on ART / IVF success rates can be either positive or negative, depending on woman's age - positive effect until age 28, and negative effect after age 28.

  4. Therefore, ART / IVF success rates are lower not only in older women but also in very young women, albeit to a lesser, but still significant, extent.

  5. Therefore, the age-driven steady decline in ART / IVF success rates begins after age 28 - earlier than at previously-assumed 30s or mid-30s.

  6. Due to the curvilinear nature of the quadratic regressions between age and ART / IVF success rates, the initial age‑driven increase in ART / IVF success rates (to age 28) occurs at decreasing rates, and the subsequent age‑driven decline in ART / IVF success rates (after age 28) occurs at increasing rates (as shown by "derivative" function of the quadratic regression models). This may suggest that the major underlying causes of declining ART / IVF success rates after age 28 (such as declining egg quality/quantity, or degenerative or aging eggs) may also occur at increasing rates at every age.

More specifically, Dr. Yavas obtained from CDC, as part of the U.S. National ART Surveillance System (NASS) data, the raw data consisting of the numbers of ART / IVF cycles that started as well as the numbers of ART / IVF cycles that resulted in clinical pregnancy and in live-birth delivery for every age and for every year between 2010-2014, with a total number of 488,351 started ART / IVF cycles resulting in 173,369 pregnancies, and 141,752 live-birth deliveries. Using these numbers (the raw data), Dr. Yavas created a dataset from scratch for 488,351 ART / IVF cycles to statistically analyze outcomes per started cycle (clinical pregnancy and live birth) and per clinical pregnancy (live birth and miscarriage), as well as to develop mathematical models to predict those outcomes. By further analyzing the curvilinear mathematical models themselves and determining the "derivative" functions of the curvilinear model functions, he determined not only how a success rate changes with age but also how the "rate of change" in a success rate also changes with age (which indicates whether the age-driven change in a success rate occurs at a constant rate or more slowly / rapidly at every additional age).

The three fitted curvilinear regression model equations predicting the percent probability for occurrence of (as an example) live birth per started cycle (LB/C) are as follows:

 

Quadratic Model Equation:

LB/C = (-53.21944291) + (7.27532642 x age) + (-0.13718085 x age2)

 

Cubic Model Equation:

LB/C = (-190.521704) + (19.5054647 x age) + (-0.4946022 x age2) + (0.00343 x age3)

 

Quartic Model Equation:

LB/C = (550.3961082) + (-69.8458045 x age) + (3.4899734 x age2) + (-0.0744934 x age3) + (0.0005642 x age4)

 

Conversely, with regard to miscarriage:

  1. Miscarriage rate in ART / IVF changes with age following well‑fitted, highly significant, È‑shaped mathematical models of curvilinear (quadratic, cubic and quartic) regressions.

  2. Therefore, miscarriage rate in ART / IVF initially and steadily declines to age 28, and increases steadily thereafter.

  3. Therefore, the effect of increasing age on ART / IVF miscarriage rate can be either negative or positive, depending on women's age - negative effect to age 28, and positive effect after age 28.

  4. Therefore, miscarriage rate in ART / IVF is higher not only in older women but also in very young women, albeit to a lesser, but still significant, extent.

  5. Therefore, the age-driven steady increase in ART / IVF miscarriage rate begins after age 28 - earlier than at 30s or mid-30s.

  6. Due to the curvilinear nature of the quadratic regression between age and ART / IVF miscarriage rate, the initial age‑driven decline in ART / IVF miscarriage rate (to age 28) occurs at decreasing rates, and the subsequent age‑driven increase in miscarriage rate (after age 28) occurs at increasing rates (as shown by "derivative" function of the quadratic regression model). This may suggest that the major underlying causes of increasing ART / IVF miscarriage rate after age 28 (such as embryo aneuploidy) may also occur at increasing rates at every age.

 

FIGURES (Click on images below)

Figure 1

Figure 2

Figure 3

Figures 1-3

 

SAME FIGURES WITH GRIDS (Click on images below)

Figure 4

Figure 5

Figure 6

Figure 4-6

 

PRESS RELEASE - April 13, 2018 (View our Press Release on PR.com)

Assisted Reproductive Technology / In Vitro Fertilization (ART / IVF) Success is Lower in Very Young Women; Its Decline Begins Earlier Than Thought, Occurs at Increasing Rates

Previously, it was assumed that ART/IVF success in women using their fresh embryos remains stable until mid-30s before it begins to decline. But a new study of CDC data with almost half a million cycles disproves this and shows success is lower also in very young women, up to age 28, and declining thereafter. Age-driven decline begins earlier than at previously thought mid-30s and occurs at increasing rates. Infertile women older than 30 should not delay ART/IVF treatment, if it is their option.

Pregnancy and live birth rates in women undergoing ART treatment using their own fresh embryos (with IVF being >99% of ART) decline with advancing age. It had been assumed that ART / IVF success in those women remains stable with age until mid-30s and declines only thereafter. However, a recent study analyzing CDC data in U.S. population, published in December 2017 issue of Reproductive Biomedicine Online journal, just disproved this assumption. The study showed that ART / IVF success is lower not only in older but also in very young women, albeit to a lesser extent, with success increasing steadily to age 28 and declining steadily thereafter in n-shaped curvilinear regressions. As a result, while women aged 28 years achieve the highest success, women aged <25 years have lower success than do women aged 25-28 years.

The study further showed, for the first time and in the population, that the age-driven steady decline in ART / IVF success not only begins earlier than at previously assumed mid-30s (before age 30) but also occurs at increasing rates. This means that the decline in success at every year of age is greater than the decline at the preceding year of age, meaning that the adverse effect of advancing age on success becomes more pronounced with every additional year of age. This suggests that infertile women who are older than 30 years of age should not delay ART / IVF treatment, if it is their only option.

Yalcin Yavas, Ph.D., the sole researcher and author of the study at STATS of the ART and Palm Beach Fertility Center, both in South Florida, analyzed almost half a million ART / IVF cycles performed in the U.S. from 2010-2014. The data, made available to Dr. Yavas by Centers for Disease Control and Prevention (CDC), had been annually collected by CDC from hundreds of fertility clinics across the U.S. The study showed, for the first time and in the population, that ART / IVF success rates (pregnancy and live birth per started cycle, and live birth per pregnancy) change with age following n-shaped mathematical models of curvilinear regressions, increasing steadily to age 28 at decreasing rates, and declining steadily thereafter at increasing rates. These curvilinear regressions are quadratic, cubic and quartic regressions (that is, with polynomial equations of the second, third and fourth degree, respectively).

Although it is known that ART / IVF miscarriage rate increases with advancing age, the recent study showed that miscarriage rate is higher not only in older but also in very young women, albeit to a lesser extent, with miscarriage rate declining steadily to age 28 and increasing steadily thereafter in a u-shaped curvilinear regressions. “What that means is that,” Dr. Yavas said, “very young women not only have lower pregnancy rate but also, if they get pregnant, have higher miscarriage rate, both of which, in turn, result in lower live birth per ART / IVF cycle.” The study further showed, for the first time and in the population, that the age-driven steady increase in miscarriage rate not only begins before age 30 but also occurs at increasing rates. Dr. Yavas said this again reinforces the recommendation that infertile women who are older than 30 years of age should not delay ART / IVF treatment, if it is their only option.

While the adverse effect of advancing age on natural fertility and ART / IVF success is due to declining egg quality and/or quantity, very young women may have other problems, such as unexplained infertility or premature ovarian failure, contributing to lower success, Dr. Yavas said. He said, “a few recent studies have shown that embryo aneuploidy (chromosome abnormality preventing embryo implantation or causing miscarriage) changes with age in a u-shaped curvilinear regressions, declining steadily before age 30 and increasing steadily thereafter. Being higher in very young women, embryo aneuploidy may also lower ART / IVF success in those women.” Since both the age-driven steady decline in success and increase in miscarriage after age 28 occur at increasing rates, the recent study suggests that the major underlying causes of declining success with advancing age (such as declining egg quality/quantity) and the major underlying causes of increasing miscarriage with advancing age (such as embryo aneuploidy) may also occur at increasing rates with advancing age.

Dr. Yavas’ goal was to develop mathematical models to determine the pattern of change in ART / IVF success with age in the population. “Mean ART / IVF success rates for age groups are already published annually by CDC but the actual data had never been subjected to statistical analyses to develop such mathematical models, hence assumptions were based on mean success rates for age groups published in CDC reports or on small-scale studies,” Dr. Yavas said. For this purpose, he obtained from CDC, as part of the U.S. National ART Surveillance System (NASS) data, the numbers of started ART / IVF cycles and the numbers of those resulting in pregnancy and live birth for every age and year between 2010-2014, with 488,351 cycles resulting in 173,369 pregnancies and 141,752 live-birth deliveries. Dr. Yavas then created a dataset to statistically analyze outcomes per started cycle (pregnancy and live birth) and per pregnancy (live birth and miscarriage) as well as to develop mathematical models to predict those outcomes. By further analyzing the curvilinear mathematical models themselves, he determined not only how a success rate changes with age but also how the “rate of change” in a success rate changes with age.

As reported by the 2011-2013 National Survey of Family Growth, about 6% of married American women had infertility problems, and 11% (almost 7 million) of 61 million American women between 15-44 years of age had received an infertility service. Since 1981, ART / IVF is one of the most common treatments to help those women conceive. Fertility clinics in the U.S. are mandated by the Fertility Clinic Success Rate and Certification Act of 1992 to annually submit their ART / IVF data to CDC, which publishes the outcomes annually, with the first report published in 1997 for 1995.

Journal Reference:

Yalcin Yavas. Curvilinear relationship between age and assisted reproduction technique success: retrospective analyses of US National ART Surveillance System data from 2010–2014. Reproductive BioMedicine Online, 35(6):657-668 (Dec 2017) (Epub online Aug 15, 2017) DOI: 10.1016/j.rbmo.2017.07.018

 

 


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