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Age and IVF Success

 

AGE and SUCCESS OF IVF / ART (IN VITRO FERTILIZATION / ASSISTED REPRODUCTIVE TECHNOLOGY)

 

HOW WOMAN'S AGE DETERMINES SUCCESS (LIVE BIRTH and PREGNANCY) in IN VITRO FERTILIZATION (IVF) / ASSISTED REPRODUCTIVE TECHNOLOGY (ART)

 

HIGHLIGHTS from our latest published study analyzing CDC data of almost half a million IVF / ART cycles in women using their own fresh eggs:

  1. Woman's age is the most important factor that determines success of IVF (pregnancy and live birth per started cycle).

  2. The age-driven steady decline in IVF success begins after age 28 -- much earlier than at previously-assumed 30s or mid-30s.

  3. This age-driven decline (after age 28) in IVF success occurs not at a steady rate but at increasing rates (the decline at every age occurs more rapidly than that at the preceding age).

  4. IVF success is most likely to occur at age 28.

  5. Until age 28, the effect of increasing age on IVF success is positive, as success increases with age until age 28 (the older the woman the higher chance of success; or the younger the woman the lower chance of success).

  6. After age 28, the effect of advancing age on IVF success is negative, as success declines with age after age 28 (the older the woman the lower chance of success; or the younger the woman the higher chance of success).

  7. Women older than 30 with infertility should not delay IVF / ART treatment, if IVF / ART is their only option.

Summary: It was previously assumed that success (live birth and pregnancy) in IVF / ART cycles in women using their own fresh eggs initially remains stable with age and begins to decline steadily ONLY AFTER 30s or mid‑30s. However, our latest study published in December 2017 in Reproductive Biomedicine Online journal analyzing CDC data with almost half a million IVF / ART cycles disproved this assumption and showed that: [1] The age‑driven decline in IVF success not only begins much earlier (at age 28) but also occurs at increasing rates, and [2] IVF success is also lower in younger women prior to age 28, as IVF success increases with age until age 28. This study suggests that women who are older than 30 years of age with infertility should not delay IVF / ART treatment, if IVF / ART is their only option.

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).

FULL PDF

 

Assisted Reproductive Technology (ART) is one of the most common infertility treatments, with In Vitro Fertilization (IVF) being the most common type of ART treatment. In 2016 in the U.S., ART / IVF cycles using a woman's own fresh eggs comprised almost half (44%) of all cycles with the prospective intent to transfer at least one embryo (i.e., of all cycles excluding banking; 86,237 / 197,737) (CDC, 2018).

However, just as natural fertility in women declines with advancing age (1-7), so too assisted fertility (success / pregnancy / live birth) in women undergoing IVF / ART treatment with their own fresh eggs also declines with advancing age (8-18).

Hence, age is the most important factor that determines both natural and assisted fertility of a woman.

For this reason, and to take into account the adverse effect of advancing age, national IVF / ART registries break down, in their annual reports, IVF / ART outcomes into age categories (e.g., <35, 35‑37, 38‑40, 41‑42, 43‑44 and >44 in the U.S. by CDC; and <35, 35‑37, 38‑39, 40‑42, 43‑44 and >44 in the U.K. by HFEA).

Based on annual reports by those national registries and on small-scale studies, it was previously assumed that success of IVF / ART cycles in women using their own fresh eggs initially remains stable with age, and begins to decline steadily ONLY AFTER 30s or mid‑30s (i.e., that advancing age begins to exert its adverse effect ONLY AFTER 30s or mid‑30s).

However, although it is well known that success of IVF / ART treatment in women using their own fresh eggs declines with advancing age, it had not been known:

a) Whether the assumption that the age-driven decline begins ONLY AFTER 30s or mid‑30s holds true both statistically and in the population; and

b) Hence, the precise pattern by which age (from the youngest to the oldest) affects success of those IVF / ART cycles.

Our latest study published in December 2017 issue of Reproductive Biomedicine Online journal investigated this question by statistically analyzing, for the first time in U.S. population, the CDC data with almost half a million (488,351) IVF / ART cycles in women using their own fresh eggs between 2010-2014.

Our study disproved the previously-held assumption, and showed that in women undergoing IVF / ART treatment with their own fresh eggs:

  1. The age‑driven decline in success BEGINS NOT after 30s or mid‑30s but AS EARLY AS BEFORE AGE 30 (at age 28) (i.e., that advancing age begins to exert its adverse effect NOT after 30s or mid‑30s but as early as before age 30);

  2. In contrast to negative effect of increasing age after age 30, the effect of increasing age until age 28 is positive (i.e., success increases with age until age 28, and declines thereafter with age); and

  3. The age‑driven decline (beginning at age 28) in success occurs not at a steady rate but at increasing rates,

which suggests that women who are older than 30 years of age with infertility should not delay IVF / ART treatment, if IVF / ART is their only option.

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

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

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

  3. Therefore, the effect of increasing age on IVF / ART 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, IVF / ART 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 IVF / ART success rates begins at age 28 - earlier than at previously-assumed 30s or mid-30s.

  6. Due to the curvilinear nature of the quadratic regressions between age and IVF / ART success rates, the initial age‑driven increase in IVF / ART success rates (to age 28) occurs at decreasing rates, and the subsequent age‑driven decline in IVF / ART 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 IVF / ART 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.

We obtained from CDC, as part of the U.S. National ART Surveillance System (NASS) data, the raw data consisting of the numbers of IVF / ART cycles that started as well as the numbers of IVF / ART 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 IVF / ART cycles resulting in 173,369 pregnancies, and 141,752 live-birth deliveries. Using these numbers (the raw data), we created a dataset from scratch for 488,351 IVF / ART 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, we 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 = (-0.13718085 x age2) + (7.27532642 x age) + (-53.21944291)

 

Cubic Model Equation:

 

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

 

Quartic Model Equation:

 

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

 

Conversely, with regard to miscarriage:

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

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

  3. Therefore, the effect of increasing age on IVF / ART 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 IVF / ART 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 IVF / ART 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 IVF / ART miscarriage rate, the initial age‑driven decline in IVF / ART 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 IVF / ART 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

 

(1) Jansen, R.P. 1984. Fertility in older women. IPPF Med. Bull. 18, 4-6.

(2) Gindoff, P.R., Jewelewicz, R. 1986. Reproductive potential in the older woman. Fertil. Steril. 46, 989‑1001.

(3) Navot, D., Bergh, P.A., Williams, M.A., Garrisi, G.J., Guzman, I., Sandler, B., Grunfeld, L. 1991. Poor oocyte quality rather than implantation failure as a cause of age-related decline in female fertility. Lancet. 337, 1375-1377.

(4) Frank, O., Bianchi, P.G., Campana, A. 1994. The end of fertility: age, fecundity and fecundability in women. J. Biosoc. Sci. 26, 349-368.

(5) Speroff, L. 1994. The effect of aging on fertility. Curr. Opin. Obstet. Gynecol. 6, 115-120.

(6) Lim, A.S.T., Tsakok, M.F.H. 1997. Age-related decline in fertility: a link to degenerative oocytes? Fertil. Steril. 68, 265-271.

(7) O'Connor, K.A., Holman, D.J., Wood, J.W. 1998. Declining fecundity and ovarian ageing in natural fertility populations. Maturitas. 30, 127-136.

(8) Roseboom, T.J., Wermeiden, J.P.W., Schoute, E., Lens, J.W., Schats, R. 1995. The probability of pregnancy after embryo transfer is affected by the age of the patient, cause of infertility, number of embryos transferred and the average morphology score, as revealed by multiple logistic regression analysis. Hum. Reprod. 10, 3035-3041.

(9) Templeton, A., Morris, J.K., Parslow, W. 1996. Factors that affect outcome of in-vitro fertilisation treatment. Lancet. 348, 1402-1406.

(10) Hunault, C.C., Eijkemans, M.J.C., Pieters, M.H.E.C., te Velde, E.R., Habbema, J.D.F., Fauser, B.C.J.M., Macklon, N.S. 2002. A prediction model for selecting patients undergoing in vitro fertilization for elective single embryo transfer. Fertil. Steril. 77, 725-732.

(11) Lintsen, A.M.E., Eijkemans, M.J.C., Hunault, C.C., Bouwmans, C.A.M., Hakkaart, L., Habbema, J.D.F., Braat, D.D.M. 2007. Predicting ongoing pregnancy chances after IVF and ICSI: a national prospective study. Hum. Reprod. 22, 2455-2462.

(12) Ottosen, L.D.M., Kesmodel, U., Hindkjaer, J., Ingerslev, H.J. 2007. Pregnancy prediction models and eSET criteria for IVF patients � do we need more information? J. Assist. Reprod. Genet. 24, 29‑36.

(13) van Loendersloot, L.L., van Wely, M., Limpens, J., Bossuyt, P.M.M., Repping, S., van der Veen, F. 2010. Predictive factors in in vitro fertilization (IVF): a systematic review and meta-analysis. Hum. Reprod. Update. 16, 577-589.

(14) Cai, Q.F., Wan, F., Huang, R., Zhang, H.W. 2011. Factors predicting the cumulative outcome of IVF/ICSI treatment: a multivariable analysis of 2450 patients. Hum. Reprod. 26, 2532-2540.

(15) Nelson, S.M., Lawlor, D.A. 2011. Predicting live birth, preterm delivery, and low birth weight in infants born from in vitro fertilisation: a prospective study of 144,018 treatment cycles. PLoS Med. 8(1):e1000386.

(16) van Loendersloot, L.L., van Wely, M., Repping, S., Bossuyt, P.M.M., van der Veen, F. 2013. Individualized decision-making in IVF: calculating the chances of pregnancy. Hum. Reprod. 28, 2972-2980.

(17) Vaegter, K.K., Lakic, T.G., Olovsson, M., Berglund, L., Brodin, T., Holte, J. 2017. Which factors are most predictive for live birth after in vitro fertilization and intracytoplasmic sperm injection (IVF/ICSI) treatments? Analysis of 100 prospectively recorded variables in 8,400 IVF/ICSI single-embryo transfers. Fertil. Steril. 107, 641-648.

(18) CDC. 2018. Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology. 2016 Assisted Reproductive Technology Fertility Clinic Success Rates Report. Atlanta (GA): US Dept of Health and Human Services.

 

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) (FULL PDF).

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