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Anti-Müllerian hormone has limited ability to predict fecundability in Chinese women: a preconception cohort study

  • Author Footnotes
    # Contributed equally to this work.
    Wei Qiu
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    # Contributed equally to this work.
    Affiliations
    Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • Author Footnotes
    # Contributed equally to this work.
    Kai Luo
    Footnotes
    # Contributed equally to this work.
    Affiliations
    Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • Yao Lu
    Affiliations
    Center for Reproductive Medicine, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • Jian Zhao
    Affiliations
    Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • Yuqing Wang
    Affiliations
    Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • Hua Yang
    Correspondence
    Corresponding authors.
    Affiliations
    Hainan Women and Children's Medical Center, Haikou Hainan, China
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  • Yun Sun
    Correspondence
    Corresponding authors.
    Affiliations
    Center for Reproductive Medicine, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • Jun Zhang
    Correspondence
    Corresponding authors.
    Affiliations
    Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, School of Public Health, Shanghai Jiao Tong University School of Medicine Shanghai, China

    Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China
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  • for theShanghai Birth Cohort
  • Author Footnotes
    # Contributed equally to this work.
Open AccessPublished:February 27, 2022DOI:https://doi.org/10.1016/j.rbmo.2022.02.014

      Abstract

      Research question

      Can anti-Müllerian hormone (AMH) level predict female fecundity in healthy reproductive-aged Chinese women?

      Design

      Preconceptional couples (n = 993) attempting pregnancy without contraception provided information on serum AMH concentrations and essential covariates. They were followed up for 12 months or until a clinically recognized pregnancy occurred between August 2013 and April 2015. Fecundability was indirectly assessed by time-to-pregnancy, defined as the number of menstrual cycles taken to conceive by a sexually active couple without using birth control. Discrete-time Cox proportional hazards model was used to estimate fecundability ratios in relation to AMH levels. Potential effect modifications by woman's age, BMI and menstrual cycle irregularity were examined through stratified analyses. Restricted cubic splines were applied to model the potential non-linear relationship between AMH and fecundability.

      Results

      After adjusting for woman's age, BMI, education status, smoking status, alcohol consumption and parity, AMH level (either as a continuous or categorical variable) was not significantly associated with fecundability. Stratified analyses revealed that, compared with intermediate AMH level (2.78–6.94 ng/ml), low AMH level (<2.78 ng/ml) was associated with reduced fecundability among women with menstrual cycle irregularity; the estimate did not reach statistical significance (adjusted fecundability ratio 0.43, 95% CI 0.16 to 1.15, P for interaction <0.1).

      Conclusions

      Serum AMH levels were not associated with fecundability in Chinese women of childbearing age. A suggestive association, however, was observed among women with cycle irregularity. Regular monitoring of AMH in fecundity prediction may be of limited value among healthy reproductive-aged Chinese women.

      KEYWORDS

      Introduction

      Delaying childbearing has led to lower female fertility overall in past decades (
      GBD 2017 Population and Fertility Collaborators
      Population and fertility by age and sex for 195 countries and territories, 1950-2017: A systematic analysis for the global burden of disease study 2017.
      ). Diminished ovarian reserve in older women is thought to be one of the main reasons (
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      Human ovarian reserve from conception to the menopause.
      ;
      • Franasiak J.M.
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      • Hong K.H.
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      • Upham K.M.
      • Treff N.R.
      • Scott Jr., R.T.
      The nature of aneuploidy with increasing age of the female partner: A review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening.
      ). Although indicators of ovarian reserve, such as FSH, oestradiol and inhibin B are available, they have low sensitivity and high variation in early stages of reduced ovarian reserve (
      • van Rooij I.A.
      • Broekmans F.J.
      • Hunault C.C.
      • Scheffer G.J.
      • Eijkemans M.J.
      • de Jong F.H.
      • Themmen A.P.
      • te Velde E.R.
      Use of ovarian reserve tests for the prediction of ongoing pregnancy in couples with unexplained or mild male infertility.
      ). Conversely, anti-Müllerian hormone (AMH), as a dimeric glycoprotein of the transforming growth factor-β superfamily produced by growing preantral and early antral follicles (
      • Weenen C.
      • Laven J.S.
      • Von Bergh A.R.
      • Cranfield M.
      • Groome N.P.
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      • Fauser B.C.
      • Themmen A.P.
      Anti-mullerian hormone expression pattern in the human ovary: Potential implications for initial and cyclic follicle recruitment.
      ), has a relatively stable level throughout the ovarian cycle among adult women and reflects the continuous non-cyclic growth of small follicles (
      • Korsholm A.S.
      • Petersen K.B.
      • Bentzen J.G.
      • Hilsted L.M.
      • Andersen A.N.
      • Hvidman H.W.
      Investigation of anti-mullerian hormone concentrations in relation to natural conception rate and time to pregnancy.
      ). It was, therefore, regarded as a promising marker for ovarian reserve (
      • Grynnerup A.G.
      • Lindhard A.
      • Sorensen S.
      The role of anti-mullerian hormone in female fertility and infertility - an overview.
      ), and has been commonly measured in women seeking pregnancy (
      • Dewailly D.
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      • Wallace W.H.
      • Anderson R.A.
      The physiology and clinical utility of anti-mullerian hormone in women.
      ).
      Whether AMH levels can predict female fecundability well, however, is still under debate.
      • Steiner A.Z.
      • Herring A.H.
      • Kesner J.S.
      • Meadows J.W.
      • Stanczyk F.Z.
      • Hoberman S.
      • Baird D.D.
      Antimullerian hormone as a predictor of natural fecundability in women aged 30-42 years.
      found that low AMH levels (≤0.7 ng/ml) was associated with reduced fecundability (fecundability ratio 0.38, 95% CI 0.08 to 0.91) in women aged between 30 and 42 years, and high AMH levels (>33 pmol/l, approximately >4.6 ng/ml) were associated with increased fecundity (hazard ratio 1.58, 95% CI 1.12 to 2.24) (
      • Korsholm A.S.
      • Petersen K.B.
      • Bentzen J.G.
      • Hilsted L.M.
      • Andersen A.N.
      • Hvidman H.W.
      Investigation of anti-mullerian hormone concentrations in relation to natural conception rate and time to pregnancy.
      ). In contrast, other studies have reported conflicting results (
      • Hagen C.P.
      • Vestergaard S.
      • Juul A.
      • Skakkebaek N.E.
      • Andersson A.M.
      • Main K.M.
      • Hjollund N.H.
      • Ernst E.
      • Bonde J.P.
      • Anderson R.A.
      • Jensen T.K.
      Low concentration of circulating antimullerian hormone is not predictive of reduced fecundability in young healthy women: A prospective cohort study.
      ;
      • Hvidman H.W.
      • Bang A.K.
      • Priskorn L.
      • Scheike T.
      • Birch Petersen K.
      • Nordkap L.
      • Loft A.
      • Pinborg A.
      • Tabor A.
      • Jorgensen N.
      • Nyboe Andersen A.
      Anti-mullerian hormone levels and fecundability in women with a natural conception.
      ). In the study by
      • Hagen C.P.
      • Vestergaard S.
      • Juul A.
      • Skakkebaek N.E.
      • Andersson A.M.
      • Main K.M.
      • Hjollund N.H.
      • Ernst E.
      • Bonde J.P.
      • Anderson R.A.
      • Jensen T.K.
      Low concentration of circulating antimullerian hormone is not predictive of reduced fecundability in young healthy women: A prospective cohort study.
      , a high AMH level (>5.5ng/ml) was associated with a reduced probability of conception, whereas a low AMH level (≤28.8 pmol/l, approximately ≤4.0 ng/ml) was linked to a shorter time to pregnancy (TTP) in the study by
      • Hvidman H.W.
      • Bang A.K.
      • Priskorn L.
      • Scheike T.
      • Birch Petersen K.
      • Nordkap L.
      • Loft A.
      • Pinborg A.
      • Tabor A.
      • Jorgensen N.
      • Nyboe Andersen A.
      Anti-mullerian hormone levels and fecundability in women with a natural conception.
      . Moreover, several other studies failed to find any significant association between AMH level and fecundability in reproductive-aged women mostly from western countries (
      • Streuli I.
      • de Mouzon J.
      • Paccolat C.
      • Chapron C.
      • Petignat P.
      • Irion O.P.
      • de Ziegler D.
      Amh concentration is not related to effective time to pregnancy in women who conceive naturally.
      ;
      • Zarek S.M.
      • Mitchell E.M.
      • Sjaarda L.A.
      • Mumford S.L.
      • Silver R.M.
      • Stanford J.B.
      • Galai N.
      • White M.V.
      • Schliep K.C.
      • DeCherney A.H.
      • Schisterman E.F.
      Is anti-mullerian hormone associated with fecundability? Findings from the eager trial.
      ;
      • Depmann M.
      • Broer S.L.
      • Eijkemans M.J.C.
      • van Rooij I.A.J.
      • Scheffer G.J.
      • Heimensem J.
      • Mol B.W.
      • Broekmans F.J.M.
      Anti-mullerian hormone does not predict time to pregnancy: Results of a prospective cohort study.
      ;
      • Steiner A.Z.
      • Pritchard D.
      • Stanczyk F.Z.
      • Kesner J.S.
      • Meadows J.W.
      • Herring A.H.
      • Baird D.D.
      Association between biomarkers of ovarian reserve and infertility among older women of reproductive age.
      ). The inconsistency in published research highlights the need for additional research on this issue.
      In addition, it has been acknowledged that racial differences exist in AMH levels owing to varied genetic and environmental factors (
      • Seifer D.B.
      • Golub E.T.
      • Lambert-Messerlian G.
      • Benning L.
      • Anastos K.
      • Watts D.H.
      • Cohen M.H.
      • Karim R.
      • Young M.A.
      • Minkoff H.
      • Greenblatt R.M.
      Variations in serum müllerian inhibiting substance between white, black, and hispanic women.
      ;
      • Gleicher N.
      • Weghofer A.
      • Barad D.H.
      Effects of race/ethnicity on triple CGG counts in the FMR1 gene in infertile women and egg donors.
      ;
      • Gleicher N.
      • Kim A.
      • Weghofer A.
      • Barad D.H.
      Differences in ovarian aging patterns between races are associated with ovarian genotypes and sub-genotypes of the fmr1 gene.
      ;
      • Tal R.
      • Seifer D.B.
      Potential mechanisms for racial and ethnic differences in antimüllerian hormone and ovarian reserve.
      ), whereas previous studies are predominantly from western countries. Studies on AMH levels in generally healthy Asian women are still limited. Therefore, findings from recent published research may not be applicable to other settings.
      The aim of the present study was to explore the associations bewteen AMH and fecundability among reproductive-aged women in a Chinese preconception cohort.

      Materials and methods

      Study design and population

      Between 2013 and 2015, a prospective preconception cohort was launched within the Shanghai Birth Cohort to investigate the effects of environmental factors, lifestyle behaviours, genetics and their interplays on couple fecundity. A total of 1179 couples were recruited from two preconception care clinics. Details of the study design and research contents of the preconception cohort were described elsewhere (
      • Zhang J.
      • Tian Y.
      • Wang W.
      • Ouyang F.
      • Xu J.
      • Yu X.
      • Luo Z.
      • Jiang F.
      • Huang H.
      • Shen X.
      Cohort profile: The shanghai birth cohort.
      ). Couples were eligible if they were aged 20 years or older, registered Shanghai residents with no intention to move out of Shanghai within 2 years and planned to conceive spontaneously. Couples who had tried continuously for a natural conception for 12 months but failed or sought infertility treatment were excluded. At recruitment, information on demographic and lifestyle characteristics, environmental factors, and reproductive and medical history was collected through a face-to-face interview using a structured questionnaire. Blood samples were collected from the couples at enrolment after providing informed consent. Women were followed up by telephone calls once every 2 months for 1 year. During each follow-up, information on pregnancy status, miscarriage and its reasons, and contraception use was updated. If women were pregnant or experienced a miscarriage during the follow-up, the information on the last menstrual period (LMP) and gestational age was also recorded. Considering the potential effects of previous endocrine disorders on our analyses, women who had a self-reported history of polycystic ovary syndrome (PCOS [n = 54]), hyperthyroidism [n = 35], hypothyroidism [n = 10] and diabetes mellitus [n = 2]) were excluded. An additional 25 participants with missing information on covariates (age [n = 12], pre-conception body mass index [BMI] [n = 11]), parity [n = 1] and alcohol consumption [n = 1]) were further excluded in the complete case analysis. Eight participants were lost to follow-up. A total of 993 women were included in the final analyses (Supplementary Figure 1). The present study was approved by the Ethics Committees of all involved research institutions and hospitals on 7 January 2013 (number XHEC-C-2013-001), and written informed consent was obtained from all participants.

      Measurement of anti-Müllerian hormone

      Anti-Müllerian hormone levels were measured in serum via enzyme-linked immunosorbent assay (ELISA) using the Ultra-Sensitive AMH/MIS ELISA kit (Ansh Labs, Webster, Texas, USA). The low detection limit was 0.023 ng/ml. In the present study, the detection rate of AMH was 100%.

      Outcome measures

      TTP was used to assess the fecundability (the probability of conception in an effective cycle), defined as the number of months or menstrual cycles taken by a sexually active couple without using birth control methods to conceive (
      • Zhang Q.
      • Wang Y.Y.
      • Zhang Y.
      • Zhang H.G.
      • Yang Y.
      • He Y.
      • Xu J.H.
      • Zhao J.
      • Peng Z.Q.
      • Ma X.
      The influence of age at menarche, menstrual cycle length and bleeding duration on time to pregnancy: A large prospective cohort study among rural chinese women.
      ). At each telephone interview, women reported whether they were pregnant or experienced any other adverse pregnancy events , e.g. spontaneous miscarriage and induced abortion, and the corresponding dates of LMP and events. For women who used contraception intermittently during the follow-up period, only the number of menstrual cycles without contraception was counted. The TTP was calculated using the following formulas:
      • For pregnant women:
        TTP=dateofLMPdateofenrolmentcontraceptivetimeaveragemenstrualcyclelength


      • For non-pregnant women:
        TTP=dateoflastfollowupdateofenrolmentcontraceptivetimeaveragemenstrualcyclelength


      For those who became pregnant during the follow-up period, one additional menstrual cycle was added to TTP (
      • Willis S.K.
      • Wise L.A.
      • Wesselink A.K.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Tucker K.L.
      • Trolle E.
      • Hatch E.E.
      Glycemic load, dietary fiber, and added sugar and fecundability in 2 preconception cohorts.
      ). Infertility was defined as a TTP of more than 12 menstrual cycles (
      • Zegers-Hochschild F.
      • Adamson G.D.
      • de Mouzon J.
      • Ishihara O.
      • Mansour R.
      • Nygren K.
      • Sullivan E.
      • Vanderpoel S.
      International committee for monitoring assisted reproductive technology (ICMART) and the world health organization (WHO) revised glossary of art terminology, 2009.
      ).

      Covariates

      Women were asked whether their menstrual cycle was regular when not using hormonal contraception in the past 6 months. If they reported ‘regular’, then their average cycle length was recorded; otherwise, the longest and shortest cycle lengths were recorded. On the basis of existing research, a directed acyclic graph (Supplementary Figure 2) was constructed to select the potential confounders for adjustment, including woman's age, BMI, education status (below, at and above a bachelor's degree), smoking status (never, passive and active), alcohol consumption (never, occasional and regular), and parity (0 and ≥1).

      Statistical analyses

      Main analyses

      Baseline characteristics with a normal distribution were presented as mean ± SD; otherwise, they were presented as medians and interquartile ranges. Categorical variables were expressed as frequencies and proportions. The population characteristics between pregnant and non-pregnant women were compared using independent Student t-tests and chi-squared tests for continuous and categorical covariates, respectively. Wilcoxon–Mann–Whitney test was used to compare median serum AMH concentrations by pregnancy status. The distributions of AMH concentrations were highly right-skewed and were ln-transformed to improve the normality in the regression analyses. The associations with linear and categorical AMH levels were analysed. Specifically, serum AMH concentrations were categorized into low (<2.78 ng/ml), intermediate (2.78–6.94 ng/ml) and high (≥6.94 ng/ml) levels according to the quartiles.
      The discrete-time Cox proportional hazards model with complementary log-log link function was used to estimate fecundability ratios and the 95% confidence intervals (
      • Scheike T.H.
      • Jensen T.K.
      A discrete survival model with random effects: An application to time to pregnancy.
      ). The fecundability ratio represents the cycle-specific probability of conception. A fecundability ratio less than 1 corresponds to a reduced fecundability, i.e. longer TTP, whereas fecundability ratio more than 1 refers to an increased fecundability, i.e. shorter TTP. Participants were censored if they were lost to follow-up or reached the end of study period without achieving a pregnancy. Crude and covariates adjusted discrete-time Cox analyses were carried out. The covariates-adjusted Kaplan–Meier curves were drawn to illustrate the cumulative probability of pregnancy by AMH groups. The difference between curves was tested via log-rank test (
      • Xie J.
      • Liu C.
      Adjusted kaplan-meier estimator and log-rank test with inverse probability of treatment weighting for survival data.
      ).
      Stratified analyses, as well as a significance test of the interaction term between variables of interest and effect modifiers, were conducted to explore whether woman's age (<35, ≥35 years), BMI (underweight [<18.5 kg/m2], normal [18.5–23.9 kg/m2], and overweight/obese [≥24 kg/m2]) (
      • Xia Y.T.
      • Yan H.M.
      • Wang L.M.
      • Liu S.B.
      • Xu T.L.
      • Shen T.
      • Zhang M.
      • Zhang X.
      • Li C.
      • Huang Z.J.
      • Zhao Z.P.
      • Li J.H.
      A study regarding the control attempts on body weight and related factors among overweight and obese adults in china, 2013.
      ) and menstrual cycle irregularity (no and yes) modified the associations between serum AMH levels and fecundability.
      To examine the possibility of a non-linear association with fecundability, AMH was modelled as a restricted cubic spline (RCS) function with four knots placed at the fixed 5th, 35th, 65th and 95th percentiles (
      • Durrleman S.
      • Simon R.
      Flexible regression models with cubic splines.
      ). Similarly, RCS functions of AMH-fecundability associations stratified by woman's age, cycle regularity and BMI were also modelled to examine the potential effect modification of these variables. All analyses were adjusted for covariates, including women's age, BMI, education status, smoking status, alcohol consumption and parity.

      Sensitivity analyses

      A series of sensitivity analyses were conducted to test the robustness of our results. To exclude potential confounding effects by stress, perceived stress score (PSS-10) was adjusted to test at baseline (
      • Cohen S.
      • Kamarck T.
      • Mermelstein R.
      A global measure of perceived stress.
      ). Given that the fecundability might be affected by male factors, men's age, education, BMI, smoking status and alcohol consumption were further adjusted. Also, the discrete-time Cox models were re-run after excluding 10 participants who had extreme high AMH values (>19.48 ng/ml, corresponding to the 99th percentile). Similarly, 44 women who had extreme low AMH values (<1 ng/ml, corresponding to the 4.5th percentile) were not included in the proportional hazard analyses. Fifty-four participants with the above characteristics were further excluded to see whether the main results were sensitive to the extreme values. In addition, a stratified analysis by semen quality was conducted, which was a combined measure of semen volume, total sperm number, sperm concentration, progressive sperm motility and total sperm motility. These indicators were dichotomized first as ‘normal’ if they were higher than the World Health Organization standard; otherwise, as ‘low’ (
      World Health Organization
      WHO laboratory manual for the Examination and processing of human semen.
      ). The overall semen quality was considered to be poor if at least one of the above five components was ‘low’ (
      World Health Organization
      WHO laboratory manual for the Examination and processing of human semen.
      ). The area under the curve (AUC) of the adjusted receiver operating characteristics (ROC) was used to measure the predictive utility of AMH.
      STATA 16.0 (StataCorp LLC, College Station, Texas, USA) and R (version 4.0.3, R Development Core Team 2020) were used for statistical analyses. Statistical significance level was set at 0.05 (two-sided).

      Results

      Baseline characteristics

      The median TTP of all included women was eight cycles. Among the 1053 enrolled women, 622 (59.1%) became pregnant during the 12-cycle follow-up. A total of 231 participants (21.9%) had TTP of more than 12 menstrual cycles. Overall, women had an average (±SD) age of 29.9 (±3.2) years, were primarily nulliparous (90.9%) and had a bachelor or higher degree (80.1%). Most women were non-smokers (96.7%) and did not drink (99.4%) within the 3 months before enrolment. A total of 11.8% of the women had a pre-pregnancy BMI of 24 kg/m2 or over. A total of 80.1% of participants had regular menstrual cycle (Table 1). The median (IQR) concentration of serum AMH was 4.4 (4.2) ng/ml. Compared with those who were not pregnant at the end of follow-up, pregnant women were younger (29.6 ± 3.1 versus 30.2 ± 3.4) and had a lower rate of menstrual cycle irregularity (17.4% versus 23.9%), whereas no significant differences in other demographic characteristics were found. Meanwhile, the concentrations of AMH did not significantly differ between pregnant and non-pregnant women. The corresponding male characteristics are presented in Supplementary Table 1.
      TABLE 1DEMOGRAPHIC AND REPRODUCTIVE CHARACTERISTICS OF WOMEN IN THE SHANGHAI BIRTH COHORT STUDY
      CharacteristicsTotal
      Including the number of censored patients and pregnant patients.
      (n = 1053)
      Not pregnant (n = 423) n (%)Pregnant (n = 622) n (%)P-value
      P-values based on chi-squared test for categorical variables, and t-test or Wilcoxon–Mann–Whitney test for continuous variables.
      Demographic characteristics
       Women's age, years29.9 ± 3.230.2 ± 3.429.6 ± 3.10.006
      Statistically significant.
       Pre-pregnancy BMI, kg/m2, n (%)0.507
       <18.5163 (15.5)65 (15.4)97 (15.6)
       18.5–23.9766 (72.7)314 (74.2)446 (71.7)
       ≥24124 (11.8)44 (10.4)79 (12.7)
      Education status, n (%)0.085
       Below bachelor degree209 (19.9)93 (22.0)114 (18.3)
       Bachelor degree632 (60.0)258 (61.0)371 (59.6)
       Above bachelor degree212 (20.1)72 (17.0)137 (22.1)
      Smoking status, n (%)0.119
       Never708 (67.2)270 (63.8)433 (69.6)
       Passive311 (29.5)136 (32.2)172 (27.7)
       Active34 (3.3)17 (4.0)17 (2.7)
      Alcohol consumption, n (%)0.124
       Never672 (63.8)255 (60.3)412 (66.3)
       Occasional375 (35.6)166 (39.2)206 (33.1)
       Regular6 (0.6)2 (0.5)4 (0.6)
      Reproductive characteristics, n (%)
       Parity0.591
       0957 (90.9)387 (91.5)563 (90.5)
       ≥196 (9.1)36 (8.5)59 (9.5)
      AMH, ng/ml, median (IQR)
      Information missing for AMH (n = 60).
      4.4 (4.2)4.3 (4.2)4.4 (4.1)0.692
      Menstrual cycle irregularity, n (%)0.010
      Statistically significant.
       No843 (80.1)322 (76.1)514 (82.6)
       Yes210 (19.9)101 (23.9)108 (17.4)
      Data presented as mean ± SD, n (%) or median (IQR).
      AMH, anti-Müllerian hormone; BMI, body mass index; IQR, interquartile range.
      a Including the number of censored patients and pregnant patients.
      b P-values based on chi-squared test for categorical variables, and t-test or Wilcoxon–Mann–Whitney test for continuous variables.
      c Statistically significant.
      d Information missing for AMH (n = 60).

      Association between anti-Müllerian hormone and time to pregnancy

      Compared with women with intermediate AMH levels, the adjusted fecundability ratios for those with low and high AMH were 0.96 (95% CI 0.77 to 1.21) and 1.06 (95% CI 0.84 to 1.32), respectively (Table 2). Further adjustment for perceived stress score and male factors did not alter the present results. Similarly, the associations between AMH levels were identical to the main findings after excluding extremely low or high AMH values (Supplementary Table 2). Although not statistically significant (P = 0.452) (Figure 1), women with high AMH levels had a slightly higher cumulative probability of conception compared with women with intermediate AMH values. Using RCS, no significant non-linear relationship was found between AMH concentration and adjusted fecundability ratio (Figure 2) (P = 0.671). The adjusted receiver operator characteristic curves illustrate the poor predictive ability of AMH (area under the curve 0.491, 95% CI 0.450 to 0.532); similar results were found even after couples with poor semen quality were excluded (area under the curve 0.492, 95% CI 0.442 to 0.541) (Supplementary Figure 3).
      TABLE 2ASSOCIATION BETWEEN SERUM ANTI-MÜLLERIAN HORMONE LEVELS AND FECUNDABILITY
      n (%)Conception n (%)Fecundability ratio
      Probability of conception per cycle. Fecundability ratio less than 1 indicates a reduced fecundability or a longer TTP, whereas fecundability ratio greater than 1 describes increased fecundability or a shorter TTP.
      (95% CI)
      UnadjustedAge-adjusted
      Adjusted for women's age as a continuous covariate.
      Adjusted
      Adjusted for women's age (continuous), pre-pregnancy body mass index (continuous), education status, smoking status, alcohol consumption and parity.
      AMH strata, ng/ml
      Low (<2.78)248 (25.0)151 (25.3)0.93 (0.75 to 1.17)0.99 (0.79 to 1.24)0.96 (0.77 to 1.21)
      Intermediate (2.78–6.94)496 (50.0)300 (50.2)ReferenceReferenceReference
      High (>6.94)249 (25.0)147 (24.5)1.10 (0.88 to 1.37)1.08 (0.86 to 1.35)1.06 (0.84 to 1.32)
      Ptrend0.2320.4720.317
      AMH, anti-Müllerian hormone; Ptrend,P for trend.
      a Probability of conception per cycle. Fecundability ratio less than 1 indicates a reduced fecundability or a longer TTP, whereas fecundability ratio greater than 1 describes increased fecundability or a shorter TTP.
      b Adjusted for women's age as a continuous covariate.
      c Adjusted for women's age (continuous), pre-pregnancy body mass index (continuous), education status, smoking status, alcohol consumption and parity.
      Figure 1
      Figure 1Adjusted cumulative incidence curves indicating the proportion of women becoming pregnant as a function of anti-Müllerian hormone (AMH). The model is adjusted for women's age, pre-pregnancy body mass index, education status, smoking status, alcohol consumption and parity.
      Figure 2
      Figure 2The non-linear relationship between anti-Müllerian hormone (AMH) concentrations and fecundability, fitted by restricted cubic spline. The model is adjusted for women's age, pre-pregnancy body mass index, education status, smoking status, alcohol consumption and parity. aFR, adjusted fecundability ratio.

      Effect modification by woman's age, body mass index, cycle regularity and semen quality on the AMH-fecundability associations

      Stratification analyses failed to find the existence of effect modification by woman's age (P for interaction >0.1) (Table 3). Although positive associations between high AMH level and fecundability were observed among younger women, both low (<2.78 ng/ml) and high (≥6.94 ng/ml) AMH levels were associated with a longer TTP among women aged 35 years and older. The interaction between age and AMH, however, was non-significant. Similarly, the interaction between AMH and BMI was non-significant (P for interaction >0.1) (Table 3); but a clear negative association between AMH concentrations and fecundability in overweight and obese women was found through multivariable RCS functions (Supplementary Figure 4). In contrast, effect modification by menstrual cycle regularity was observed, and the interaction terms with AMH were significant (P for interaction <0.1) (Table 3). Specifically, low AMH levels had reduced fecundability by 57% among women with menstrual cycle irregularity. For semen quality, no significant interaction with AMH levels was detected (Supplementary Table 3 and Supplementary Figure 5).
      TABLE 3EFFECT MODIFICATION BY WOMAN'S AGE, BODY MASS INDEX AND CYCLE REGULARITY ON THE ANTI-MÜLLERIAN HORMONE-FECUNDABILITY ASSOCIATIONS
      Low AMH (<2.78 ng/m)Intermediate AMH (2.78–6.94 ng/ml)High AMH (≥6.94 ng/ml)
      Women's age, years
      <35
      n (%)209 (22.8)467 (51.0)239 (26.2)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      0.93 (0.73 to 1.18)Reference1.10 (0.88 to 1.39)
      ≥35
      n (%)39 (50.0)29 (37.2)10 (12.8)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      0.77 (0.35 to 1.71)Reference0.82 (0.26 to 2.59)
      P for interaction0.252
      Menstrual cycle irregularity
       No
      n (%)219 (27.5)402 (50.5)175 (22.0)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      1.01 (0.80 to 1.28)Reference1.11 (0.86 to 1.42)
       Yes
      n (%)29 (14.7)94 (47.7)74 (37.6)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      0.43 (0.16 to 1.15)Reference1.08 (0.64 to 1.81)
      P for interaction0.064
      Pre-pregnancy BMI, kg/m2
      <18.5
      n (%)42 (26.9)81 (51.9)33 (21.2)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      0.96 (0.50 to 1.85)Reference0.79 (0.41 to 1.52)
      18.5–23.9
      n (%)179 (24.9)356 (49.5)184 (25.6)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      0.92 (0.70 to 1.20)Reference1.16 (0.90 to 1.51)
      ≥24
      n (%)27 (22.9)59 (50.0)32 (27.1)
       aFR (95% CI)
      Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.
      1.05 (0.51 to 2.18)Reference0.93 (0.47 to 1.84)
      P for interaction0.253
      aFR, adjusted fecundability ratio; AMH, anti-Müllerian hormone; BMI, body mass index.
      a Adjusted for women's age (continuous), pre-pregnancy BMI (continuous), education status, smoking status, alcohol consumption and parity.

      Discussion

      In the present study, the association between AMH and fecundability in healthy reproductive-aged Chinese women was examined. Overall, serum AMH levels were not associated with fecundability. The relationship, however, seemed to be modified by pre-pregnancy BMI and menstrual cycle regularity, particularly among women who were overweight or obese and women with irregular cycles.
      The null association between AMH and fecundability in the present study is in general agreement with previous studies (
      • Streuli I.
      • de Mouzon J.
      • Paccolat C.
      • Chapron C.
      • Petignat P.
      • Irion O.P.
      • de Ziegler D.
      Amh concentration is not related to effective time to pregnancy in women who conceive naturally.
      ;
      • Zarek S.M.
      • Mitchell E.M.
      • Sjaarda L.A.
      • Mumford S.L.
      • Silver R.M.
      • Stanford J.B.
      • Galai N.
      • White M.V.
      • Schliep K.C.
      • DeCherney A.H.
      • Schisterman E.F.
      Is anti-mullerian hormone associated with fecundability? Findings from the eager trial.
      ;
      • Depmann M.
      • Broer S.L.
      • Eijkemans M.J.C.
      • van Rooij I.A.J.
      • Scheffer G.J.
      • Heimensem J.
      • Mol B.W.
      • Broekmans F.J.M.
      Anti-mullerian hormone does not predict time to pregnancy: Results of a prospective cohort study.
      ;
      • Steiner A.Z.
      • Pritchard D.
      • Stanczyk F.Z.
      • Kesner J.S.
      • Meadows J.W.
      • Herring A.H.
      • Baird D.D.
      Association between biomarkers of ovarian reserve and infertility among older women of reproductive age.
      ). A recent secondary analysis using data from a multicentre randomized clinical trial found that low AMH levels (≤1.0 ng/ml) before pregnancy was not associated with fecundability (Fecundability odds ratio [FOR] = 1.06, 95% CI 0.80 to 1.41) (
      • Zarek S.M.
      • Mitchell E.M.
      • Sjaarda L.A.
      • Mumford S.L.
      • Silver R.M.
      • Stanford J.B.
      • Galai N.
      • White M.V.
      • Schliep K.C.
      • DeCherney A.H.
      • Schisterman E.F.
      Is anti-mullerian hormone associated with fecundability? Findings from the eager trial.
      ). Also, a study by
      • Steiner A.Z.
      • Pritchard D.
      • Stanczyk F.Z.
      • Kesner J.S.
      • Meadows J.W.
      • Herring A.H.
      • Baird D.D.
      Association between biomarkers of ovarian reserve and infertility among older women of reproductive age.
      failed to support the use of blood AMH levels in assessing fecundability among older reproductive-aged women. Several studies, however, have presented conflicting results on the relationship between AMH and female fecundability. In a study of 100 women aged 30–42 years, low AMH (≤0.7 ng/ml) was found to be associated with reduced day-specific ratio of conception by 62% (OR 0.38, 95% CI 0.08 to 0.91) (
      • Steiner A.Z.
      • Herring A.H.
      • Kesner J.S.
      • Meadows J.W.
      • Stanczyk F.Z.
      • Hoberman S.
      • Baird D.D.
      Antimullerian hormone as a predictor of natural fecundability in women aged 30-42 years.
      ). A significant shorter TTP, however, was observed among women with low AMH levels (≤28.8 pmol/l, approximately ≤4.0 ng/ml) in a study by
      • Hvidman H.W.
      • Bang A.K.
      • Priskorn L.
      • Scheike T.
      • Birch Petersen K.
      • Nordkap L.
      • Loft A.
      • Pinborg A.
      • Tabor A.
      • Jorgensen N.
      • Nyboe Andersen A.
      Anti-mullerian hormone levels and fecundability in women with a natural conception.
      . As for high AMH levels,
      • Hagen C.P.
      • Vestergaard S.
      • Juul A.
      • Skakkebaek N.E.
      • Andersson A.M.
      • Main K.M.
      • Hjollund N.H.
      • Ernst E.
      • Bonde J.P.
      • Anderson R.A.
      • Jensen T.K.
      Low concentration of circulating antimullerian hormone is not predictive of reduced fecundability in young healthy women: A prospective cohort study.
      found that women with AMH above 5.5 ng/ml had a reduced fecundability compared with women with medium levels (2-5.5 ng/ml) in six menstrual cycles of follow-up, but an increased fecundability was reported among women aged 25–42 years with high AMH over 33 pmol/l (approximately >4.6 ng/ml) (
      • Korsholm A.S.
      • Petersen K.B.
      • Bentzen J.G.
      • Hilsted L.M.
      • Andersen A.N.
      • Hvidman H.W.
      Investigation of anti-mullerian hormone concentrations in relation to natural conception rate and time to pregnancy.
      ).
      Such large discrepancies may be attributable to substantial variations in sample size, characteristics of the study population, i.e. women's age, follow-up duration and AMH levels. For example,
      • Hagen C.P.
      • Vestergaard S.
      • Juul A.
      • Skakkebaek N.E.
      • Andersson A.M.
      • Main K.M.
      • Hjollund N.H.
      • Ernst E.
      • Bonde J.P.
      • Anderson R.A.
      • Jensen T.K.
      Low concentration of circulating antimullerian hormone is not predictive of reduced fecundability in young healthy women: A prospective cohort study.
      did not exclude women with diseases affecting fecundability, e.g. PCOS. Inclusion of women with a phenotype overlapping with PCOS seems to be the most likely explanation to their findings. In addition, their participants were less fertile, which may have limited the generalizability of their findings. Moreover,
      • Hvidman H.W.
      • Bang A.K.
      • Priskorn L.
      • Scheike T.
      • Birch Petersen K.
      • Nordkap L.
      • Loft A.
      • Pinborg A.
      • Tabor A.
      • Jorgensen N.
      • Nyboe Andersen A.
      Anti-mullerian hormone levels and fecundability in women with a natural conception.
      measured serum AMH in the first trimester of pregnancy. Given the difference in AMH levels before and during pregnancy, the interpretation of the observed association in that study remains a challenge. Reverse causality was a possibility. In contrast, we measured AMH before pregnancy and excluded women with extremely high or low AMH values (>19.48 ng/ml and <1 ng/ml, respectively). Therefore, our finding confirms that the value of AMH as a predictor of fecundability is also limited in Asian women. This information could be useful for clinical practice.
      The general null association between AMH and female fecundability among healthy women may be partly explained by the physiological role of AMH in human reproduction. Known as the determinant of fecundity, the ovarian reserve encompasses the quantity and quality of the ovarian follicle pool (
      • Petersen K.B.
      Individual fertility assessment and counselling in women of reproductive age.
      ). As the oocyte quality is determined by the amount of DNA damage and the capacity to repair those damages (
      • Maidarti M.
      • Anderson R.A.
      • Telfer E.E.
      Crosstalk between PTEN/PI3K/Akt Signalling and DNA Damage in the Oocyte: Implications for Primordial Follicle Activation.
      ), ageing of the germ cell line as a result of inefficient DNA repair may lead to reduced fecundity (
      • Laven J.S.E.
      • Visser J.A.
      • Uitterlinden A.G.
      • Vermeij W.P.
      • Hoeijmakers J.H.J.
      Menopause: Genome stability as new paradigm.
      ). Therefore, the positive association between AMH and ovarian reserve may not fully explain the female fecundity in the general population. Moreover, although AMH was highly sensitive in predicting the ovarian response to hyperstimulation in assisted reproductive technology (ART), the predictive ability of AMH for fecundity was poor (
      • Dewailly D.
      • Andersen C.Y.
      • Balen A.
      • Broekmans F.
      • Dilaver N.
      • Fanchin R.
      • Griesinger G.
      • Kelsey T.W.
      • La Marca A.
      • Lambalk C.
      • Mason H.
      • Nelson S.M.
      • Visser J.A.
      • Wallace W.H.
      • Anderson R.A.
      The physiology and clinical utility of anti-mullerian hormone in women.
      ). On the other hand,
      • Gnoth C.
      • Schuring A.N.
      • Friol K.
      • Tigges J.
      • Mallmann P.
      • Godehardt E.
      Relevance of anti-mullerian hormone measurement in a routine ivf program.
      reported that AMH was not a valuable tool for predicting high-quality embryo and pregnancy rate in ART settings, either.
      Obesity is a common problem among reproductive-age women. Excess adipose tissue may indirectly affect gonadotrophin-releasing hormone–LH axis secretion, and ultimately results in decreased oocyte quality and even anovulation (
      • Longcope C.
      • Baker R.
      • Johnston Jr., C.C.
      Androgen and estrogen metabolism: Relationship to obesity.
      ;
      • Pasquali R.
      • Pelusi C.
      • Genghini S.
      • Cacciari M.
      • Gambineri A.
      Obesity and reproductive disorders in women.
      ;
      • Burt Solorzano C.M.
      • McCartney C.R.
      • Blank S.K.
      • Knudsen K.L.
      • Marshall J.C.
      Hyperandrogenaemia in adolescent girls: Origins of abnormal gonadotropin-releasing hormone secretion.
      ;
      • Ibáñez L.
      • Ong K.K.
      • López-Bermejo A.
      • Dunger D.B.
      • de Zegher F.
      Hyperinsulinaemic androgen excess in adolescent girls.
      ;
      • Mitchell A.
      • Fantasia H.C.
      Understanding the effect of obesity on fertility among reproductive-age women.
      ). Therefore, obesity is closely related to reduced fecundity. Interestingly, we detected a non-linear negative association between AMH and fecundability in women with a BMI of 24 kg/m2 or over, which suggests that the AMH–fecundability association might be altered by the BMI of participants. Obesity may stimulate androgen synthesis in the ovaries and adrenal glands (
      • Delitala A.P.
      • Capobianco G.
      • Delitala G.
      • Cherchi P.L.
      • Dessole S.
      Polycystic ovary syndrome, adipose tissue and metabolic syndrome.
      ), whereas high-dose androgen will over-recruit follicles, which can promote granulosa cells to secrete AMH to inhibit folliculogenesis (
      • Pierre A.
      • Taieb J.
      • Giton F.
      • Grynberg M.
      • Touleimat S.
      • El Hachem H.
      • Fanchin R.
      • Monniaux D.
      • Cohen-Tannoudji J.
      • di Clemente N.
      • Racine C.
      Dysregulation of the anti-müllerian hormone system by steroids in women with polycystic ovary syndrome.
      ), and, therefore, reduce fecundity. Meanwhile, obesity also can influence fertilization and implantation that lead to prolonged TTP (
      • Norman R.J.
      • Chura L.R.
      • Robker R.L.
      Effects of obesity on assisted reproductive technology outcomes.
      ;
      • Tamer Erel C.
      • Senturk L.M.
      The impact of body mass index on assisted reproduction.
      ). Also, the negative correlation indirectly indicates that there may be a latent or subclinical PCOS phenotype in this group of women. This evidence may partly explain why a negative association between AMH and fecundability was found among overweight and obese women.
      In the present study, we also found that low AMH levels had reduced fecundability by 57% among women with cycle irregularity. It has been shown that cycle irregularity is tightly linked to ovarian ageing (
      • Gizzo S.
      • Andrisani A.
      • Noventa M.
      • Quaranta M.
      • Esposito F.
      • Armanini D.
      • Gangemi M.
      • Nardelli G.B.
      • Litta P.
      • D'Antona D.
      • Ambrosini G.
      Menstrual cycle length: A surrogate measure of reproductive health capable of improving the accuracy of biochemical/sonographical ovarian reserve test in estimating the reproductive chances of women referred to art.
      ), anovulation and hormone metabolism variability (
      • Harlow S.D.
      • Ephross S.A.
      Epidemiology of menstruation and its relevance to women's health.
      ). In a large prospective cohort study (
      • Mutsaerts M.A.
      • Groen H.
      • Huiting H.G.
      • Kuchenbecker W.K.
      • Sauer P.J.
      • Land J.A.
      • Stolk R.P.
      • Hoek A.
      The influence of maternal and paternal factors on time to pregnancy–a dutch population-based birth-cohort study: The gecko drenthe study.
      ), women with menstrual cycle irregularity had a prolonged TTP. Meanwhile, low AMH may reflect lower than normal ovarian reserve. Cycle irregularity may, therefore, act synergistically with low AMH on reduced fecundity. Such a hypothesis, however, is still speculative and needs to be confirmed in future studies.
      The present study has several strengths. First, to the best of our knowledge, this is the first prospective cohort study to evaluate whether the AMH level is associated with female fecundity in Asian women. Second, AMH was measured before pregnancy, which constitutes a temporal order in the cause relationship between AMH and fecundability. Third, we used a large cohort of couples from the general population to assess even relatively minor effects. Finally, in the sensitivity analyses, we further adjusted for factors of male partners, which makes our results less likely to be biased by these factors and increases the robustness of our results.
      Nonetheless, a few limitations are worth noting. First, we excluded participants who were potentially infertile (had tried continuously to conceive spontaneously for more than 12 months but failed or sought infertility treatment) at recruitment. Use of such inclusion and exclusion criteria, on the other hand, limits the generalizability of our findings to women with impaired fecundity. Second, the precise information on the time of pregnancy attempt before recruitment was not well documented, which may have underestimated the TTP. Third, not every couple tried for 12 cycles in our study because some couples did not have effective sexual activities (no sex or using birth controls) for various reasons in some months. Fourth, we did not collect data on timing and frequency of intercourse. The timing of sexual intercourse in relation to ovulation strongly influences the chance of conception (
      • Wilcox A.J.
      • Weinberg C.R.
      • Baird D.D.
      Timing of sexual intercourse in relation to ovulation. Effects on the probability of conception, survival of the pregnancy, and sex of the baby.
      ). Nevertheless,
      • Axmon A.
      • Rylander L.
      • Albin M.
      • Hagmar L.
      Factors affecting time to pregnancy.
      explained that the frequency of intercourse might be an intermediate factor rather than a baseline determinant. Therefore, the lack of information on the intercourse patterns probably had less impact on our study. Fifth, achieving pregnancy was self-reported in our study. Errors in self-reported LMP may be possible, thereby making the TTP estimation more uncertain. Several studies, however, have confirmed the reliability of self-reported LMP (
      • Zielhuis G.A.
      • Hulscher M.E.
      • Florack E.I.
      Validity and reliability of a questionnaire on fecundability.
      ;
      • Mikkelsen E.M.
      • Riis A.H.
      • Wise L.A.
      • Hatch E.E.
      • Rothman K.J.
      • Sørensen H.T.
      Pre-gravid oral contraceptive use and time to pregnancy: A danish prospective cohort study.
      ;
      • Wise L.A.
      • Rothman K.J.
      • Mikkelsen E.M.
      • Stanford J.B.
      • Wesselink A.K.
      • McKinnon C.
      • Gruschow S.M.
      • Horgan C.E.
      • Wiley A.S.
      • Hahn K.A.
      • Sørensen H.T.
      • Hatch E.E.
      Design and conduct of an internet-based preconception cohort study in north america: Pregnancy study online.
      ). Overall, errors due to self-report TTP attainment are supposed to be random and non-differential (
      • Wang B.
      • Zhou W.
      • Zhu W.
      • Chen L.
      • Wang W.
      • Tian Y.
      • Shen L.
      • Zhang J.
      Associations of female exposure to bisphenol a with fecundability: Evidence from a preconception cohort study.
      ), and would, therefore, draw our results towards the null. Finally, we did not carry out antral follicle count and androgen tests in this cohort, which may have led to a missed diagnosis of PCOS and might confound the results.
      In conclusion, serum AMH levels were not associated with fecundability in Chinese women of childbearing age. These findings suggest that regular monitoring of AMH in fecundity prediction among healthy women of reproductive age, particularly in nulliparae, has limited value.

      Acknowledgements

      This study was partly funded by the National Natural Science Foundation of China (41991314 and 81803246), the Shanghai Municipal Health Commission (GWIII-26 and GWV-10.1-XK07) and the Shanghai Jiao Tong University School of Medicine Xinhua Hospital and the National Human Genetic Resources Sharing Service Platform (2005DKA21300). The datasets used, analysed, or both, during the present study are available from the corresponding author on reasonable request. The authors thank all the participants in the Shanghai Birth Cohort for making the present study possible.

      Appendix. Supplementary materials

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      Biography

      Jun Zhang, PhD, MD, is KC Wong Chair Professor at the Shanghai Jiao Tong University School of Medicine, and Director of the Ministry of Education-Shanghai Key Laboratory of Children's Environmental Health. His research interests are reproductive and perinatal epidemiology.
      Key message
      Serum anti-Müllerian hormone (AMH) levels were not associated with fecundability in Chinese women of childbearing age in a large prospective cohort study. This indicates that regular monitoring of AMH in fecundity prediction among healthy reproductive-aged Chinese women is of limited value.