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Impact of female age and nulligravidity on fecundity in an older reproductive age cohort

      Objective

      To provide female age-related estimates of fecundity and incidence of infertility by history of prior pregnancy among women 30–44 years of age.

      Design

      Prospective, time-to-pregnancy cohort study.

      Setting

      Not applicable.

      Patient(s)

      Women, between 30 and 44 years of age, attempting to conceive for ≤3 months, and no known history of infertility, polycystic ovarian syndrome (PCOS), or endometriosis.

      Intervention(s)

      Not applicable.

      Main Outcome Measure(s)

      Fecundability and incidence of infertility.

      Result(s)

      Compared to women aged 30–31 years, fecundability was reduced by 14% in women 34–35 years of age (fecundability ratio [FR] 0.86, 95% confidence interval [CI] 0.68–1.08), 19% in women 36–37 years of age (FR 0.81, 95% CI 0.60–1.08, 30% in women 38–39 years of age (FR 0.70, 95% CI 0.48–1.01), 53% in women 40–41 years of age (FR 0.47, 95% CI 0.28–0.78), and 59% in women 42–44 years of age (FR 0.39, 95% CI 0.16–0.93). Fecundability did not differ between women aged 30–31 years and 32–33 years. In general, fecundability and cumulative probability of pregnancy was lower for women who had never had a prior pregnancy.

      Conclusion(s)

      Women experience a significant reduction in fecundity and increase in the probability of infertility in their late thirties. At any age >30 years, women who have never conceived have a lower probability of achieving a pregnancy.

      Clinical Trial Registration Number

      Key Words

      Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/steinera-female-age-fecundity/
      During the 20th and the 21st centuries women had increasing access to graduate and professional schools, careers, and contraceptive methods (
      ESHRE Capri Workshop Group
      Social determinants of human reproduction.
      ). This has led to a delay in age at marriage and in age at first birth. In fact, the average age at first birth increased from 22.7 years in 1980 to 27.2 in 2000 and 28.2 years in 2013 (

      Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Mathews TJ. Births: final data for 2013. National Vital Statistics Reports 2015;64.

      ). Many women are choosing to delay attempts to conceive to their thirties and forties. Women wish to know their probability of conceiving or having infertility at “older” ages. In addition, women choosing to delay now have the option and are choosing to freeze oocytes for fertility preservation for reproductive aging.
      Data on success rates after assisted reproductive technology (ART) by female age are readily available. There is a suggestion that pregnancy rates (PRs) start to decline in the early thirties; however, PRs for women 30–34 years of age are similar to women <30 years of age. This may be because PRs appear to “peak” in the late twenties to early thirties. An almost linear downward trend is observed after age 35 years (
      Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology
      2013 Assisted Reproductive Technology National Summary Report.
      ). Data from therapeutic donation cycles also show an age- related decline in female fertility independent of male factor (
      • Schwartz D.
      • Mayaux M.J.
      Female fecundity as a function of age: results of artificial insemination in 2193 nulliparous women with azoospermic husbands. Federation CECOS.
      ).
      Cross-sectional data on natural marital fertility rates in noncontracepting populations such as the Hutterites are available (
      • O'Connor K.A.
      • Holman D.J.
      • Wood J.W.
      Declining fecundity and ovarian ageing in natural fertility populations.
      ). Prospective data in contemporary populations are available; however, the number of cohorts are relatively limited (
      • Gnoth C.
      • Godehardt D.
      • Godehardt E.
      • Frank-Herrmann P.
      • Freundl G.
      Time to pregnancy: results of the German prospective study and impact on the management of infertility.
      ,
      • Rothman K.J.
      Volitional determinants and age-related decline in fecundability: a general population prospective cohort study in Denmark.
      ). Cohorts having adequate representation of women more than age 35 years are even more limited. A recent study by Rothman (
      • Rothman K.J.
      Volitional determinants and age-related decline in fecundability: a general population prospective cohort study in Denmark.
      ) sampled 2,820 women in Denmark, who were attempting to conceive, of which 208 were between the ages of 35 and 40 years. They found that 72% of women between the ages of 35 and 40 years compared with 87% of women between the ages of 30 and 34 years conceived within 12 cycles of pregnancy attempt. Women >40 years were not included and more refined estimates for women between ages 35 and 40 years were not provided.
      To study female age-related declines in fertility, one must be assured that male factor or other causes of infertility do not contribute to the estimate. Women, who have previously conceived naturally, can be assumed to have patent fallopian tubes and partners with sufficient sperm. Thus, this population would be the purest to study age-related declines in fertility. However, women who have never conceived, are an inherently different population. Meaningful estimates of their fecundity at any given age are needed for counseling. Therefore, we sought to provide female age-related estimates of fecundity by history of prior pregnancy using a prospective, time-to-pregnancy cohort.

      Materials and methods

      Time to Conceive is a prospective, time-to-pregnancy cohort study that enrolls women who are trying to conceive naturally, between the ages of 30 and 44 years. Women were recruited through informational mass e-mails, introductory letters, web and radio advertising and instructed to contact study personnel by e-mail or telephone if interested. Women were screened for eligibility by telephone. Eligible women had been attempting to conceive, defined as having regular intercourse without doing anything to prevent pregnancy, for ≤3 months. Women were excluded if they reported a history of infertility, polycystic ovarian syndrome (PCOS), endometriosis, a partner with infertility, or were currently breastfeeding. Institutional Review Board approval was obtained for this research.
      After enrollment and consent, women completed a questionnaire including demographics, reproductive history, contraceptive history, and habits. They were subsequently followed without intervention for up to 12 months or until pregnancy was detected. Women were provided with home pregnancy tests and standardized instructions on their use. Women completed daily diaries for the first 4 months of enrollment and then monthly diaries thereafter. Women withdrew if they initiate fertility treatment, stop trying to conceive, or self-withdraw. Enrollment for Time to Conceive began in April 2008 and concluded in August 2015. Women enrolled between April 2008 and April 2015 are included in this analysis.

       Statistical Analysis

      Pregnancy was defined as a positive pregnancy test. Cycle of attempt at enrollment was determined using data from the baseline questionnaire. Number of cycles-at-risk was determined using menses data from daily and monthly diaries; women who had not conceived were censored at 12 cycles. Female age, when the subject began trying to conceive, was collapsed into 2-year intervals and modeled using indicator variables. Kaplan Meier curves were constructed. Subsequently discrete-time Cox-proportional hazard models (
      • Baird D.D.
      • Wilcox A.J.
      • Weinberg C.R.
      Use of time to pregnancy to study environmental exposures.
      ) were constructed to predict fecundability in the first cycle of attempt, average fecundability during the cycles of attempt, probability of pregnancy by 6 cycles of attempt, probability of pregnancy by 12 cycles of attempt, and fecundability ratios. The analysis was then repeated within the subgroups: no prior pregnancy and prior pregnancy. Prior pregnancy was based on a subject's report to the question “Have you ever been pregnant before” in the enrollment questionnaire. The proportional hazards assumption was tested before analysis using Schoenfeld residuals, and no significant violation was noted (P=−.30). All analyses were completed using Stata 14.0 (STATA).

      Results

      A total of 960 women provided 3,593 cycles for analysis. Of these 960 subjects 17% either withdrew, were censored for fertility medication use, or were lost to follow-up. The likelihood of such an event increased with age (P=.01) and cycle of attempt (P=.001). The cohort is described in Supplemental Table 1, available online. In summary, 79% of subjects were between the ages of 30 and 35 years, 16% were between 36 and 39 years, and 5% were ≥40 years. Most women were non-Hispanic white, well-educated, and of normal weight. Half of the cohort had conceived previously and 36% had a prior live birth. Most women enrolled in their first cycle of attempt (median cycle 1, interquartile range 1–2). Average fecundability in the cohort was 17.5%. Sixty-five percent of the cohort conceived in the first 6 cycles of attempt and 78% by 12 cycles of attempt. In the cohort, as female age increased, the probability of being white decreased, body mass index (BMI) increased, male partner age increased, and probability of having previously been pregnant increased (Table 1).
      Table 1Description and comparison of female age groups based on baseline characteristics.
      CharacteristicFemale age (y)P value
      χ2 or -test, where appropriate.
      30–3435–3940–44
      Race.07
       African American58 (9)32 (14)8 (16)
       American Indian/Alaskan1 (<1)1 (<1)0
       Asian/Pacific Islander37 (5)20 (9)4 (8)
       White543 (80)163 (70)33 (64)
       Hispanic14 (2)8 (3)3 (6)
       Other (mixed/unknown)23 (3)9 (4)3 (6)
      Current alcohol use456 (67)144 (62)33 (65).29
      Attempt cycle at enrollment1.8 (±1.1)1.8 (±1.3)2.2 (1.4).05
      Nulligravid369 (55)81 (35)10 (20)<.001
      Parous210 (31)112 (48)27 (53)<.001
      History of one or more therapeutic abortions66 (10)34 (15)18 (35)<.001
      History of ectopic pregnancy7 (1)4 (2)2 (4).32
      History of miscarriage114 (17)66 (28)16 (31)<.001
      Education level.03
       High school or less7 (1)02 (4)
       Some college41 (6)22 (9)4 (8)
       College degree130 (19)46 (20)15 (29)
       Some graduate or professional school63 (9)23 (10)4 (8)
       Masters degree276 (41)76 (33)14 (27)
       Advanced postgraduate degree159 (24)66 (28)12 (24)
      Current marijuana use29 (4)7 (3)0.24
      Partner age (y), mean (±SD)33 (4.2)37 (5.6)42 (5.2)<.001
      Regular menstrual cycles (yes)571 (84)206 (88)46 (90).50
      Smoking history.15
       Never524 (77)173 (74)34 (27)
       Current12 (2)1 (<1)1 (2)
       Past140 (21)59 (25)16 (31)
      Body mass index.006
       Underweight16 (2)8 (3)0
       Normal weight444 (66)125 (54)32 (63)
       Overweight134 (20)51 (22)8 (16)
       Obese82 (12)49 (21)11 (21)
      Note: Values presented as n (%) unless stated otherwise.
      a χ2 or -test, where appropriate.
      Time-to-pregnancy was longer for older women (Fig. 1). The median time-to-pregnancy was 3 months for women <38 years, 4 months for women 38–39 years of age, 8 months for women 40–41 years of age, and >12 months for women ≥42 years. Fecundability and cumulative probability of pregnancy by female age for the entire cohort is presented in Table 2. Women 34–35 years of age had a 14% reduction in fecundability (fecundability ratio [FR] 0.86, 95% confidence interval [CI] 0.68–1.08), women 36–37 years had a 19% reduction in fecundability (FR 0.81,95% CI 0.60–1.08), women 38–39 years had a 30% reduction in fecundability (FR 0.70, 95% CI 0.48–1.01), women 40–41 years had a 53% reduction in fecundability (FR 0.47, 95% CI 0.28–0.78), and women 42–44 years had a 59% reduction in fecundability (FR 0.39, 95% CI 0.16–0.93) fecundability compared with women aged 30–31 years. Fecundability was similar for women aged 32–33 years compared with 30–31 years (FR 1.06, 95% CI 0.87–1.29). There was no interaction between age and BMI, and adjustment for BMI did not substantially change these estimates.
      Figure thumbnail gr1
      Figure 1Kaplan Meier curves for cumulative probability of pregnancy across cycles of pregnancy attempt by age group.
      Table 2Fecundability and cumulative pregnancy rates for the cohort as calculated from survival analysis.
      Age (y)Subjects, nCycles at risk, n
      Number of cycles of attempt observed for all subjects in the given age group.
      FecundabilityCumulative pregnancy rate
      First cycleAverage6 cycles12 cycles
      30–313531,26119.7 (15.9–25.9)19.5 (17.3–22.2)77 (72–81)87 (82–91)
      32–3324782626.0 (19.2–34.7)20.9 (18.0–24.3)76 (70–81)88 (83–92)
      34–3515362922.0 (14.4–32.6)16.2 (13.4–19.7)71 (63–78)82 (74–88)
      36–379538023.9 (14.0–39.0)14.5 (11.1–18.9)69 (59–79)76 (66–85)
      38–396123416.1 (7.1–34.5)13.2 (9.3–18.8)62 (49–76)71 (56–84)
      40–41371876.2 (0.9–36.8)8.6 (5.2–14.0)47 (31–66)54 (37–72)
      42–44147606.6 (2.7–15.8)29 (10–65)48 (24–80)
      Note: Data presented as percentage with 95% confidence interval.
      a Number of cycles of attempt observed for all subjects in the given age group.
      In general, fecundability and cumulative probability of pregnancy was lower for women who had never conceived (Table 3). The pattern of the decline, however, differed by whether they had previously been pregnant. Women who had previously been pregnant, had a less steep decline in fecundability across age groups compared with women who had not previously been pregnant. Differences in PRs between groups were small at younger ages (30–31 years) and greatest at older ages. Women >40 years of age, who had never conceived, were half as likely to conceive in 12 cycles compared with their counterparts with proven prior fertility.
      Table 3Fecundability and cumulative pregnancy rates by history of prior pregnancy as calculated from survival analysis.
      Nulligravid
      Age (y)Subject, nCycles at risk, n
      Number of cycles of attempt observed for all subjects in the given age group.
      FecundabilityCumulative pregnancy rate
      First cycleAverage6 cycles12 cycles
      30–3121279617.2 (11.5–25.4)17.3 (14.7–20.5)74 (67–80)83 (77–89)
      32–3311942029.3 (19.4–42.8)18.8 (15.1–23.5)73 (64–81)85 (77–92)
      34–357134513.2 (5.7–28.8)11.3 (8.3–15.5)56 (44–69)66 (54–77)
      36–373414216.7 (4.5–51.8)12 (7.4–19.3)58 (39–78)73 (53–89)
      38–39147605.2 (2.0–14.0)35 (15–68)35 (16–68)
      40–4163402.9 (0.4–20.9)025 (4–87)
      42–4443103.2 (0.5–22.9)033 (5–95)
      History of prior pregnancy
      30–3114146523.0 (15.5–33.3)23.4 (19.4–28.2)81 (74–87)92 (85–96)
      32–3312840623.1 (14.6–35.3)23.2 (18.9–28.3)79 (71–86)90 (83–95)
      34–358228429.6 (18.4–45.4)22.2 (17.4–28.4)83 (74–90)93 (84–98)
      36–376123826.5 (14.8–44.7)16 (11.6–21.9)75 (62–85)78 (66–88)
      38–394715821.7 (9.7–44.6)17.1 (11.7–24.9)71 (57–85)81 (65–93)
      40–41311537.7 (1.1–43.4)9.8 (5.9–16.3)52 (35–72)56 (39–75)
      42–44104508.9 (3.3–23.7)43 (16–83)54 (25–88)
      Note: Data presented as percentage with 95% confidence interval.
      a Number of cycles of attempt observed for all subjects in the given age group.

      Discussion

      In our cohort, fecundity declined for women in their late thirties and early forties. Among women with proven prior fertility, the probability of infertility increased from 10%–20% after age 35 years and to 45% in the early forties. Women, who had never conceived, were at a greater risk of infertility at all ages. Among these women, the decline in fertility began at a younger age.
      It should be noted that we present the incidence of infertility and not the prevalence. Prevalence, as measured in cross-sectional studies, will always be higher, as once a woman is diagnosed with infertility she will always be considered infertile. Infertile women can be treated to help them conceive, but in general, the infertility is not reversed. We believe that the incidence of infertility is more meaningful to an individual woman.
      There are few prospective time-to-pregnancy studies that have data on women in their thirties and forties. In a cohort of German women, Gnoth et al. (
      • Gnoth C.
      • Godehardt D.
      • Godehardt E.
      • Frank-Herrmann P.
      • Freundl G.
      Time to pregnancy: results of the German prospective study and impact on the management of infertility.
      ) found that 88% of women between the ages of 31–34 years (N = 82) and 73% of women aged 35–44 years (N = 10) conceived in 12 cycles of attempt. Rothman (
      • Rothman K.J.
      Volitional determinants and age-related decline in fecundability: a general population prospective cohort study in Denmark.
      ), using a cohort from Denmark, also found an 87% PR among women 30–34 years of age (N = 791) and a 72% PR in women 35–40 years of age (N = 208). Thus there is relative consistency across cohorts.
      The lower fecundity among women who have never conceived is not surprising. The fact that the difference between gravid and nulligravid women is not stable, but diverges across age categories is interesting. It is likely because even among women who use contraception regularly, unplanned pregnancies occur. Thus, as women age, if they do not experience an unplanned pregnancy, it may suggest lower underlying fecundity. Women may also intermittently attempt to conceive in their lifetime. Women, who may have attempted to conceive for a month or two in the past and never became pregnant, are inherently less fertile than women who conceived.
      This study has some weaknesses. First, although the cohort was designed to only include women of “older reproductive age,” few women enrolled in the cohort who were in their forties. Second, for those women, who previously conceived, we could not differentiate those trying to conceive with a new partner from those trying to conceive with their partner from their prior pregnancy. In general, the cohort is white and highly educated; however, this likely reflects the population planning pregnancies at older ages. According to national statistics, 69% of pregnancies in black women are unplanned (
      • Finer L.B.
      • Henshaw S.K.
      Disparities in rates of unintended pregnancy in the United States, 1994 and 2001.
      ), and the average age at first delivery for black women is 3.6 years younger than for white women (
      • Mathews T.J.
      • Hamilton B.E.
      Mean age of mother, 1970–2000.
      ). However, this cohort has a number of strengths in that it enrolled women early in their attempts to conceive. Women were queried multiple ways to determine when they started attempting to conceive, and women were followed using standardized and free pregnancy testing.
      The topic of female age-related declines in fertility is commonly discussed in the media. There has been debate as to “when” fertility starts to decline and “when” there is a steep drop off. These data may serve as a resource for women, researchers, physicians, and the media. Current guidelines encourage women >35 years of age to seek reproductive evaluation and necessary treatment after 6 months of attempting to conceive (
      Practice Committee of the American Society for Reproductive Medicine
      Diagnostic evaluation of the infertile female: a committee opinion.
      ). These data suggest that perhaps the age at which women seek fertility evaluation after 6 months of attempt should differ by prior pregnancy history. Women, who are in their thirties and have previously conceived, may be able to wait longer before seeking infertility evaluation and treatment, assuming they have no risk factors for infertility.
      When using these data to advise women, it will be important for clinicians to clarify that these data do not necessarily reflect live birth rates. Miscarriage rates increase with age. Therefore, age-associated decrease in live birth rates may be due to the decline in PRs and the increase in miscarriage rates with aging. In conclusion, women experience a significant reduction in fecundity and an increase in the probability of infertility in their late thirties. At any age >30 years, women who have never conceived, have a lower probability of achieving a pregnancy compared with women with prior fertility.

      Appendix

      Supplemental Table 1Description of the cohort (N = 960).
      CharacteristicData
      Age (y)
       30–31353 (37)
       32–33247 (26)
       34–35153 (16)
       36–3795 (10)
       38–3961 (6)
       40–4137 (4)
       42–4414 (1)
      Race
       African American98 (10)
       American Indian/Alaskan2 (<1)
       Asian/Pacific Islander61 (6)
       White739 (77)
       Hispanic25 (3)
       Other (mixed/unknown)35 (4)
      Current alcohol use633 (66)
      Attempt cycle at enrollment, mean ± SD1.8 ± 1.2
      Nulligravid460 (48)
      Parous349 (36)
      History of one or more therapeutic abortions118 (12)
      History of ectopic pregnancy13 (1)
      History of miscarriage196 (20)
      Education level
       High school or less9 (1)
       Some college67 (7)
       College degree191 (20)
       Some graduate or professional school90 (9)
       Masters degree366 (38)
       Advanced postgraduate degree237 (25)
      Current marijuana use36 (4)
      Partner age (y), mean ± SD34.7 ± 5.2
      Regular menstrual cycles (yes)823 (86)
      Smoking history
       Never731 (76)
       Current14 (2)
       Past215 (22)
      Body mass index
       Underweight24 (2)
       Normal weight601 (63)
       Overweight193 (20)
       Obese142 (15)
      Note: Values presented as n (%), unless stated otherwise. All characteristics were self-reported at enrollment.

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