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Anti-Müllerian hormone kinetics in pregnancy and post-partum: a systematic review

Published:February 23, 2017DOI:https://doi.org/10.1016/j.rbmo.2017.02.005

      Abstract

      The aim of this systematic review is to critically appraise the available evidence regarding the kinetics of anti-Müllerian hormone (AMH) during pregnancy and post-partum. A systematic literature search was conducted in MEDLINE, Embase, CENTRAL, Scopus and Web of Science on 14 December 2015, aiming to identify studies providing data on the serum concentration of AMH in women at various stages of gestation and post-partum. There was a total of 1719 participants across eight studies. Seven out of the eight studies reported a decline in serum AMH concentration with advancing gestational age. Further, all four of the studies that evaluated pre- and post-delivery AMH concentrations found that it increased in the post-partum period. This review demonstrated an association between reduced maternal serum AMH concentrations and advancing gestational age, with a subsequent post-partum increase in concentration. These findings suggest that AMH measurements in pregnant women, especially at later stages of pregnancy, should not be used to assess ovarian reserve. Additionally, further longitudinal research would be beneficial, to elucidate the pathophysiological mechanism through which this decline in serum AMH concentration is observed during pregnancy.

      Keywords

      Introduction

      Anti-Müllerian hormone (AMH), also known as Müllerian inhibiting substance, is a member of the TGF-ß family most commonly known for its role in the regression of Müllerian ducts during male fetal sex differentiation. In females, AMH is produced by small antral and pre-antral follicles, and has been shown to inhibit excess recruitment of primordial follicles through reducing responsiveness to FSH (
      • Durlinger A.
      • Visser J.
      • Themmen A.
      Regulation of ovarian function: the role of anti-Mullerian hormone.
      ,
      • Durlinger A.L.L.
      • Gruijters M.J.G.
      • Kramer P.
      • Karels B.
      • Ingraham H.A.
      • Nachtigal M.W.
      • Uilenbroek J.T.J.
      • Grootegoed J.A.
      • Themmen A.P.N.
      Anti-Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary.
      ). Hence, AMH seems to function in the ovary as a paracrine factor, rather than having any systemic hormonal actions (
      • Cook C.L.
      • Siow Y.
      • Taylor S.
      • Fallat M.E.
      Serum müllerian-inhibiting substance levels during normal menstrual cycles.
      ). AMH serum concentration has been shown to be correlated with the ovarian follicular pool, so it is considered to be a marker of ovarian reserve as well as a marker of ovarian follicular activity (
      • de Vet A.
      • Laven J.S.E.
      • de Jong F.H.
      • Themmen A.P.N.
      • Fauser B.C.J.M.
      Antimüllerian hormone serum levels: a putative marker for ovarian aging.
      ,
      • Kwee J.
      • Schats R.
      • McDonnell J.
      • Themmen A.
      • de Jong F.
      • Lambalk C.
      Evaluation of anti-Mullerian hormone as a test for the prediction of ovarian reserve.
      ,
      • van Rooij I.A.J.
      • Broekmans F.J.M.
      • te Velde E.R.
      • Fauser B.C.J.M.
      • Bancsi L.F.J.M.M.
      • de Jong F.H.
      • Themmen A.P.N.
      Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve.
      ).
      In non-pregnant women, the kinetics of AMH have been well studied (
      • 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.
      ,
      • Durlinger A.
      • Visser J.
      • Themmen A.
      Regulation of ovarian function: the role of anti-Mullerian hormone.
      ,
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      ,
      • Nelson S.M.
      • Messow M.C.
      • McConnachie A.
      • Wallace H.
      • Kelsey T.
      • Fleming R.
      • Anderson R.A.
      • Leader B.
      External validation of nomogram for the decline in serum anti-Mullerian hormone in women: a population study of 15,834 infertility patients.
      ,
      • Overbeek A.
      • Broekmans F.J.
      • Hehenkamp W.J.
      • Wijdeveld M.E.
      • van Disseldorp J.
      • van Dulmen-den Broeder E.
      • Lambalk C.B.
      Intra-cycle fluctuations of anti-Mullerian hormone in normal women with a regular cycle: a re-analysis.
      ,
      • van Rooij I.A.J.
      • Broekmans F.J.M.
      • te Velde E.R.
      • Fauser B.C.J.M.
      • Bancsi L.F.J.M.M.
      • de Jong F.H.
      • Themmen A.P.N.
      Serum anti-Müllerian hormone levels: a novel measure of ovarian reserve.
      ,
      • Visser J.A.
      • Themmen A.P.N.
      Anti-Müllerian hormone and folliculogenesis.
      ). Importantly, AMH has been shown to reduce with increasing age consistent with its role as a marker of ovarian reserve (
      • de Vet A.
      • Laven J.S.E.
      • de Jong F.H.
      • Themmen A.P.N.
      • Fauser B.C.J.M.
      Antimüllerian hormone serum levels: a putative marker for ovarian aging.
      ). AMH remains relatively stable throughout the menstrual cycle, with the fluctuations reported in some studies appearing to be of small amplitude (
      • 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.
      ,
      • La Marca A.
      • Broekmans F.J.
      • Volpe A.
      • Fauser B.C.
      • Macklon N.S.
      Anti-Mullerian hormone (AMH): what do we still need to know?.
      ). Further, it has been suggested that younger women might have more significant changes in AMH concentrations throughout their menstrual cycle, whilst older women might have less variation and a lower mean AMH concentration (
      • Sowers M.
      • McConnell D.
      • Gast K.
      • Zheng H.
      • Nan B.
      • McCarthy J.D.
      • Randolph J.F.
      Anti-Mullerian hormone and inhibin B variability during normal menstrual cycles.
      ).
      Serum AMH concentrations have been found to decrease during the long-term use of hormonal contraception, such as the oral contraceptive pill (
      • 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.
      ), and then increase significantly following the cessation of hormonal contraception (
      • van den Berg M.H.
      • van Dulmen-den Broeder E.
      • Overbeek A.
      • Twisk J.W.
      • Schats R.
      • van Leeuwen F.E.
      • Kaspers G.J.
      • Lambalk C.B.
      Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases.
      ).
      Much less is known about the fluctuations of AMH in pregnancy. This is an important area for research because AMH might reflect follicular recruitment during pregnancy. The current evidence regarding AMH kinetics in pregnancy is conflicting, with some studies concluding that it remains stable throughout pregnancy (
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ), whilst others have found that it is more dynamic (
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ). Hence, the aim of this systematic review is to identify, summarize and critically appraise evidence regarding the kinetics of AMH during pregnancy and post-partum.

      Materials and methods

      Search strategy

      A systematic literature search was conducted in MEDLINE, Embase, CENTRAL, Scopus and Web of Science on 14 December 2015 to identify publications relevant to the kinetics of serum AMH during pregnancy. The electronic search was performed using the keywords described in Table 1, which included ‘AMH’ and ‘pregnancy’ as well as synonyms and closely related words in the abstracts, titles and keywords (Table 1). No language or date limits were applied.
      Table 1Search strategy used for identification of eligible studies during electronic search.
      Search stepQuery
      1AMH OR antimulleri* hormone OR anti?muller* hormone OR MIS OR mullerian inhibit* OR antimüllerian hormone OR anti-müllerian hormone
      2Pregnancy OR Gestation OR Pregnant OR Gravida OR delivery OR birth
      31 and 2

      Selection of studies

      Studies were considered eligible regardless of their design, providing they contained data on AMH at different stages of gestation, from the same or different women. Initially 2514 publications were retrieved by two of the reviewers (S.M. and C.V.) and subsequently their titles were examined to exclude irrelevant studies, resulting in 44 potentially eligible studies (Figure 1). The abstracts of these publications were examined, leading to 19 articles whose full text was scrutinised, resulting in the identification of eight studies capable of answering the research question. During this process, duplicate publications were excluded, with the most recent or comprehensive publication analysed.
      In two out of eight studies the association between AMH and gestational age was specifically evaluated (
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ). In the remaining six studies the association of AMH with fetal aneuploidy (n = 2) (
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ), gestational diabetes mellitus (n = 1) (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ), fetal sex (n = 1) (
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ), pre-term birth (n = 1) (
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ) and maternal adiposity (n = 1) (
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ) was examined. Some of these studies reported AMH data separately for case and control groups and these data have also been extracted separately, where available. More specifically, in the study by
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      the cases group included women of white race who delivered before term (n = 105) whilst the control group included women of white race who delivered at term (n = 95). In the study by
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      the cases group included women with gestational diabetes (n = 34) and the control group was comprised of women with healthy, singleton pregnancies, without gestational diabetes mellitus (n = 32). In the study by
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      the cases group included women with pregnancies affected by Down syndrome (n = 145) and the control group included women with pregnancies not affected by Down syndrome (n = 290).

      Data extraction

      Data extraction was performed by two of the reviewers (S.M. and C.V.) and the following information was recorded from each of the eligible studies: study, author, journal name, country of origin, study period, type of study, number of patients, number of measurements per patient, bias-reducing approach employed by authors, main research question addressed, population, mean age, gestational age at AMH measurement, AMH assay used, inter-assay and intra-assay coefficient of variation and mean or median serum AMH concentration in each trimester or post-partum.

      Results

      Eight studies fulfilled the inclusion criteria for the systematic review. Methodological and clinical characteristics of the eligible studies are listed in Table 2, Table 3. The studies were published between 2005 and 2015 and varied in size from 60 to 554 patients, with a total of 1719 patients across the studies. All data used in this systematic review were from pregnant women at various stages of gestation. Three of the studies originated in the USA, four in Europe and one in China.
      There were four case-control studies (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ,
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ,
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ), one of which was longitudinal in design (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ), one longitudinal cohort study (
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ), two cross-sectional studies (
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ,
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ) and one study with a combination of cross-sectional and longitudinal components (
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ). Three studies were designed prospectively (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ), four studies were retrospective (
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ,
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ,
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ), and one was a combination of prospective and retrospective components (
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ) (Table 2). Gestational age at measurement varied across the studies, in accordance with their design.
      Table 2Methodological characteristics of included studies.
      StudyJournalCountry of originStudy periodProspective or retrospectiveType of studyNumber of patientsNumber of measurements per patientControlling for confoundersMain research question addressed
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      Fertility and SterilityUSA2009–2010RetrospectiveCase-control200 women2 per patientPrior history of pre-term birth, fetal gender, maternal age, maternal weight gain between first and second trimesters and smoking during pregnancy, gestational age at the time of blood sampling.

      Maternal race was limited to white.
      Association of pre-term birth with AMH levels
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      EndocrineItalyAugust 2010 to June 2013ProspectiveLongitudinal case-control66 women3 per patientMultivariate analysis controlling for the effect of female age, presence of gestational diabetes mellitus, BMI differences between measurements, newborn weight and placental weightAMH concentrations in the third trimester of pregnancy and postnatally and their association with gestational diabetes mellitus
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      Reproductive Biology and EndocrinologyGermany1995–2012Prospective and retrospective componentsCohort 1: Cross-sectional

      Cohorts 2–4: Longitudinal
      554 patientsCross-sectional (450 women): 1 per patient

      Longitudinal: 3 per patient for 15 women, 2 per patient for 69 women, 5 per patient for 20 women
      Samples were analysed stratified by age groupsAMH fluctuations during pregnancy and post-partum
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      Reproductive SciencesUSANot reportedRetrospectiveCross-sectional107 women1 per patientNot reportedAssociation of fetal sex with maternal AMH levels
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      Fertility and SterilityUKNot reportedProspectiveLongitudinal cohort60 women4 per patientNot reportedAssociation of advancing gestation and maternal adiposity with AMH
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      Journal of Assisted Reproduction and GeneticsUSA2004–2007RetrospectiveCase-control213 women1 per patientOnly singleton pregnancies includedAssociation of reduced ovarian reserve (measured using AMH) with fetal aneuploidy
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      Prenatal DiagnosisChinaNot reportedRetrospectiveCase-control435 patients1 per patientCases were matched with controls for maternal age and gestational ageAssociation of maternal serum AMH levels with the presence of a trisomy 21 (Down Syndrome) pregnancy
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      Human ReproductionItaly/IsraelNot reportedProspectiveCross-sectional84 women1 per patientNot reportedAMH modifications during pregnancy
      Two of the studies were primarily aiming to determine the fluctuations of AMH in pregnancy (
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ), whilst the others were determining the association of AMH in pregnancy with pre-term birth (
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ), fetal sex (
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ), gestational diabetes mellitus (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ), maternal adiposity (
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ) or fetal aneuploidy (
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ).
      The DSL assay was used in one study (
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ), the Immunotech Beckman-Coulter assay was used in one study (
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ), and one study used both assays on their samples (AMHbc and AMHdsl) (
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ). One study used their own laboratory-developed assay (
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ). A further four studies used the most recently available AMH Gen II assay by Beckman-Coulter (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ,
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ). Samples were frozen until time of measurement in three studies (
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ,
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ) and five studies did not report whether their samples were stored prior to measurement (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ,
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ,
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ). Assay sensitivity or lowest limit of detection varied from 0.1 pmol/l to 0.7 pmol/l, although most had a value of 0.6–0.7 pmol/l (n = 5) (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ,
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      ,
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ) and three studies did not report the assay sensitivity (
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ,
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ). The inter-assay and intra-assay coefficients of variation ranged from 5% to 14.2% and 3% to 12.3%, respectively.
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      was the only study to report both intra-assay and inter-assay coefficients of variation greater than 10% (Table 3).
      Table 3Clinical and assay characteristics of the included studies.
      StudyPopulationAge of women (years)Gestational age at measurementAMH assay usedSample storageSensitivity or lowest limit of detection (pmol/l)Inter-assay and intra-assay coefficient of variation (%)
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      Inclusion criteria: women of any age who delivered a singleton after 20 weeks' gestation, who had elected to undergo integrated prenatal screening in Iowa between 2009 and 2010 and who had paired first and second trimester serum samples stored in the serum tissue bank.

      Exclusion criteria: non-spontaneous pre-term birth, non-white race.
      Cases: 28.8 ± 5.2
      Mean ± SD.


      Controls: 28.8 ± 5.5
      Mean ± SD.
      10–13.9 weeks and 15–20.9 weeksAn in-house assay, Reprosource, based on research-use-only materials and reagents from Beckman Coulter-DSLAll samples were frozen at –80°C until time of measurement0.75–9 / 7–12
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      Study group

      Inclusion criteria: singleton pregnancies with gestational diabetes diagnosed by 75 g oral glucose tolerance test between 24 and 28 weeks of gestation

      Exclusion criteria: diabetes mellitus type I and type II, and multiple pregnancies

      Control group: Inclusion criteria: women with singleton healthy pregnancies

      Exclusion criteria: any previous history of metabolic disorders during pregnancy or a previous diagnosis of diabetes mellitus
      Study group: 36.7 ± 4.3
      Mean ± SD.


      Control group: 32.7 ± 4.5
      Mean ± SD.
      28–32 weeks

      34–46 weeks

      40 days after delivery
      Gen II AMH ELISA (Beckman-Coulter)Not reported0.64.63 / 4.02
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      Inclusion criteria: Natural conception without artificial infertility treatment

      Exclusion criteria: History of ovarian surgery, infertility, chemotherapy or radiation.
      30.8 ± 6.2
      Mean ± SD.
      Cross-sectional component:

      First trimester ≤14th week of gestation (n = 58)

      Second trimester 15–28 weeks (n = 53)

      Third trimester ≥29th week of gestation (n = 339)

      Longitudinal components: 15 women had samples taken in each trimester

      69 women were sampled during admission for delivery and within 4 days post-partum

      20 women had blood samples taken just before delivery and during each of the first 4 days post-partum
      Gen II AMH ELISA (Beckman-Coulter, Immunotech, Webster, Texas, USA)Not reported0.6Not reported
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      Inclusion criteria: Women ≥18 with an uncomplicated singleton delivery at ≥37 weeks. All samples were obtained from the Maternal-Fetal Tissue Bank at the University of Iowa.

      Exclusion criteria: None reported
      Not reported≥10 weeks to ≤40 weeksGen II AMH ELISA (Beckman-Coulter)Not reportedNot reportedNot reported
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      Inclusion criteria: Women with spontaneous conception

      Exclusion criteria: Women with previous polycystic ovary syndrome, pre-eclampsia, gestational diabetes, or other metabolic complication of pregnancy developed during index pregnancy
      Not reportedFirst, second and third trimester and ≥12 weeks after deliveryDSL AMH ELISA (Webster, TX)All samples per subject were assayed within the same assayNot reportedNot reported
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      Inclusion criteria: Women with singleton pregnancies who underwent both maternal serum screening for fetal aneuploidy (with sufficient stored serum available) and chorionic villus sampling or amniocentesis (with available cytogenetic results) between 11th and 24th weeks of gestation at the University of North Carolina between 2004 and 2007.

      Exclusion criteria: None reported
      32.9 ± 6.9
      Mean ± SD.
      First or second trimester between 11 and 24 weeksBeckman-Coulter AMH ELISA (AMHbc) and DSL AMH ELISA (Diagnostic Systems Laboratories) (AMHdsl)Stored at −80°CAMHbc: 0.7

      AMHdsl: 0.1
      AMHbc: 9 / 4

      AMHdsl: 5 / 3
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      Inclusion criteria: Women 20–48 years old with Down syndrome pregnancies (cases) or non-Down syndrome pregnancies (controls) were selected from the database of biochemical Down Syndrome screening at the University of Hong Kong.

      Exclusion criteria: None reported
      37
      Median.
      Between 11 and 13 weeks or 15 and 20 weeksGen II AMH ELISA (Immunotech, Beckman-Coulter, France)Samples were stored at −20°CNot reported14.2 / 12.3
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      Inclusion criteria: Group A: Nulliparae healthy women, not seeking pregnancy and with normal BMI; Groups B–E: Primigravidae women with singleton pregnancies at different gestational ages

      Exclusion criteria: Women with a known history of thyroid dysfunction, diabetes mellitus or any personal or familial immune disease.
      A: 18–32

      B: 19–35

      C: 17–34

      D: 20–37

      E: 20–35
      Group A: control non-pregnant women

      Group B: weeks 9–11

      Group C: weeks 21–23

      Group D: weeks 36–38

      Group E: between 48 and 72 h post-delivery
      AMH ELISA (Immunotech, Beckman-Coulter, France)Storage of samples prior to measurement is not reported0.78.7 / 5.3
      a Mean ± SD.
      b Median.

      AMH kinetics during pregnancy

      The results of the studies are presented in detail in Table 4 and Figure 2, Figure 3.
      Table 4AMH values for each trimester in the included studies.
      StudyFirst trimesterSecond trimesterThird trimesterPost-partum
      Gestational age (weeks)AMH value (pmol/l)Gestational age (weeks)AMH value (pmol/l)Gestational age (weeks)AMH value (pmol/l)Timing of measurementAMH value (pmol/l)
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.


      Control group
      10–13.9
      Range (min–max).
      25.70 ± 18.56
      Mean ± SD.
      15–20.9
      Range (min–max).
      21.42 ± 16.42
      Mean ± SD.
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.


      Cases group
      10–13.9
      Range (min–max).
      22.13 ± 17.14
      Mean ± SD.
      15–20.9
      Range (min–max).
      19.99 ± 14.99
      Mean ± SD.
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.


      Control group
      28–32
      Range (min–max).


      34–36
      Range (min–max).
      5.71 (0.71–32.13)
      Median (interquartile range).


      4.28 (0.71–17.85)
      Median (interquartile range).
      40 days7.14

      (0.71–104.96)
      Median (interquartile range).
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.


      Cases group
      28–32
      Range (min–max).


      34–36
      Range (min–max).
      6.43 (0.71–24.99)
      Median (interquartile range).


      5.00 (0.71–27.85)
      Median (interquartile range).
      40 days10.00 (0.71–49.98)
      Median (interquartile range).
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.


      Cross-sectional component
      ≤1412.07 (12.21–22.13)
      Median (interquartile range).
      15–28
      Range (min–max).
      5.71 (3.43–10.07)
      Median (interquartile range).
      ≥29th week of gestation
      Range (min–max).
      3.57 (1.29–7.14)
      Median (interquartile range).
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.


      Longitudinal components
      ≤1419.49 (13.35–23.21)
      Median (interquartile range).
      15–28
      Range (min–max).
      16.85 (11.35–21.06)
      Median (interquartile range).
      ≥29th week of gestation
      Range (min–max).
      9.85 (7.35–12.28)
      Median (interquartile range).
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.


      Post-partum component
      Before delivery (n = 69)4.07 (1.29–8.21)
      Median (interquartile range).
      During first 4 days post-partum (n = 69)3.00 (1.00–6.43)
      Median (interquartile range).
      Day 1 post-partum (n = 20)1.43 (0.29–4.00)
      Median (interquartile range).
      Day 4 post-partum (n = 20)2.57 (1.07–4.14)
      Median (interquartile range).
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      Not reported16.99 ± 14.28
      Mean ± SD.
      Not reported12.93 ± 11.42
      Mean ± SD.
      Not reported5.93 ± 6.64
      Mean ± SD.
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      12.40 ± 1.50
      Mean ± SD.
      11.20 (7.60–20)
      Median (interquartile range).
      26.10 ± 1.30
      Mean ± SD.
      8.60 (3.60–13.0)
      Median (interquartile range).
      35.50 ± 1.30
      Mean ± SD.
      5.50 (2.20–9.20)
      Median (interquartile range).
      17.30 ± 2.90 weeks after delivery
      Mean ± SD.
      14.80 (7.70–26.0)
      Median (interquartile range).
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.


      (Beckman-Coulter values)
      11–14
      Range (min–max).
      20.20 ± 14.90
      Mean ± SD.
      15–24
      Range (min–max).
      9.70 ± 8.40
      Mean ± SD.
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.


      Control group
      11–13
      Range (min–max).
      14.65 ± 8.64
      Mean ± SD.
      15–20
      Range (min–max).
      9.83 ± 7.28
      Mean ± SD.
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.


      Cases group
      11–13
      Range (min–max).
      14.15 ± 10.00
      Mean ± SD.
      15–20
      Range (min–max).
      10.40 ± 7.66
      Mean ± SD.
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      9–11
      Range (min–max).
      14.99 ± 4.00
      Mean ± SD.
      21–33
      Range (min–max).
      17.14 ± 4.57
      Mean ± SD.
      36–38
      Range (min–max).
      13.92 ± 4.28
      Mean ± SD.
      48–72 h post-partum15.35 ± 3.93
      Mean ± SD.
      a Range (min–max).
      b Mean ± SD.
      c Median (interquartile range).
      Figure 2
      Figure 2Anti-Müllerian hormone concentrations during pregnancy or post-partum.
      Figure 3
      Figure 3Anti-Müllerian hormone and gestational age by trimester.

      First to second trimester changes

      Seven of the studies identified in this systematic review provided evidence on the differences between AMH concentrations in the first and second trimesters of pregnancy. Six of the studies demonstrated a significant decrease in AMH during this gestational age, whilst one study demonstrated a non-significant increase in AMH concentrations (
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ).
      Two of the studies collected data longitudinally from the same cohort of patients, throughout their pregnancy (
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ).
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      found that circulating AMH reduced significantly with increased gestational age, with the median first trimester AMH concentrations declining by 2.6 pmol/l, from 11.2 pmol/l to 8.6 pmol/l, in the second trimester.
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      had a longitudinal cohort of 15 women in which they observed a non-significant decline of 2.64 pmol/l from a first trimester median AMH value of 19.49 pmol/l to a second trimester value of 16.85 pmol/l.
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      also performed a larger, cross-sectional analysis of 450 patients which reported a significant decline from the first to the second trimester with median AMH measurements of 12.07 pmol/l and 5.71 pmol/l, respectively.
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      performed a cross-sectional study, which found the mean AMH levels increased from 14.99 ± 4.00 pmol/l in the first trimester to 17.14 ± 4.57 pmol/l in the second trimester. This increase was not statistically significant.
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      performed a case-control study which, in the control group, produced mean AMH values of 25.7 ± 18.56 pmol/l in the first trimester and 21.42 ± 16.42 pmol/l in the second trimester of the pregnancies, which was a statistically significant decline. When considering AMH kinetics in the cases group (women with pre-term birth) there was also a significant decrease in AMH concentrations (first trimester: 22.13 ± 17.14 pmol/l versus second trimester: 19.99 ± 14.99 pmol/l), however the decrease in AMH concentrations from the first to the second trimester was significantly greater in the control group. Similarly,
      • Plante B.J.
      • Beamon C.
      • Schmitt C.L.
      • Moldenhauer J.S.
      • Steiner A.Z.
      Maternal antimullerian hormone levels do not predict fetal aneuploidy.
      performed a case-control study which found significant declines in AMH with increasing gestational age, with AMHbc 20.2 ± 14.9 pmol/l in the first trimester and 9.7 ± 8.4 pmol/l in the second. It should be noted that in this study, first and second trimester AMH concentrations were provided for the whole study population, and no data were provided separately for cases (pregnancies with an aneuploidy embryo) or controls (pregnancies with a euploid embryo).
      In singleton pregnancies not affected by Down syndrome,
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      found a first trimester AMH value of 14.65 ± 8.64 pmol/l and a second trimester value of 9.83 ± 7.28 pmol/l, which represents a statistically significant decrease. In the group of pregnancies with fetuses affected by Down syndrome a significant decrease in AMH concentrations was also observed (first trimester: 14.15 ± 10.00 pmol/l versus second trimester: 10.40 ± 7.66 pmol/l).
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      found a significant fall in AMH between 11 and 15 weeks of pregnancy, with the mean serum AMH falling from 16.99 ± 14.28 pmol/l to 12.93 ± 11.42 pmol/l.

      Second to third trimester changes

      Four studies examined the kinetics of AMH between the second and third trimesters of pregnancy, with all four finding significant decreases in AMH concentrations over this period (
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ,
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      ).
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      found a significant decrease of 3.1 pmol/l in median AMH concentrations from the second trimester (8.6 pmol/l) to the third trimester (5.5 pmol/l).
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      also found a significant decrease from 12.93 ± 11.42 pmol/l to 5.93 ± 6.64 pmol/l over this period.
      The longitudinal component of
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      found significant differences of 7 pmol/l between the second and third trimester values of 16.85 pmol/l and 9.85 pmol/l. The
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      cross-sectional component found a decrease of 2.14 pmol/l from the second trimester (5.71 pmol/l) to the third trimester (3.57 pmol/l). When these results were stratified by age group the ≤27 years group had a significant difference between the median values for the first and third trimesters as well as the second and third trimesters, whilst the 28–34 years age group had significant differences between each trimester (first versus second, first versus third and second versus third). The ≥35 years age group had no significant differences in median AMH values between any trimesters.
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      found a decrease in AMH concentrations between the second and third trimesters from 17.14 ± 4.57 pmol/l to 13.92 ± 4.28 pmol/l, respectively, although this difference was not statistically significant.
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      examined AMH concentrations longitudinally by taking two measurements in the third trimester and another measurement 40 days after delivery. In the control group they found a significant decrease across the third trimester with a median AMH concentration of 5.17 pmol/l at 28–32 weeks and 4.28 pmol/l at 34–36 weeks. A similar, significant decrease in AMH was observed in the cases group (women with gestational diabetes mellitus), from 6.43 pmol/l at 28–32 weeks to 5.0 pmol/l at 34–36 weeks.

      Third trimester to post-partum

      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      also analysed AMH concentrations pre- and post-partum, finding that AMH significantly decreases shortly after birth with a median concentration of 1.43 pmol/l on day 1 post-partum and then significantly increases to 2.57 pmol/l on day 4 post-partum. Similarly,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      found a non-significant increase in AMH in the 48 to 72 h post-partum.
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      took an AMH measurement at a mean of 17.3 ± 2.9 weeks postnatally, which found that AMH concentrations were significantly higher than the values during pregnancy.
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      also found a significant increase from the third trimester median AMH value to the post-partum values in both control and case groups, with changes from 4.28 pmol/l to 7.14 pmol/l and 5.00 pmol/l to 10.00 pmol/l, respectively.

      Discussion

      This systematic review suggests that during pregnancy the serum AMH concentration declines with advancing gestational age. This finding is supported by seven out of eight studies that have been analysed. The only study not completely in line with this conclusion is the
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      study in which an increase between the first and second trimesters was noted. However, this is a cross-sectional study and this might mean that this difference could be confounded by other variables, such as maternal age.
      Furthermore, following delivery it appears that serum AMH concentration increases. This was supported by three of the studies that evaluated pre- and post-delivery AMH concentrations (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ,
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ), but not by
      • Köninger A.
      • Kauth A.
      • Schmidt B.
      • Schmidt M.
      • Yerlikaya G.
      • Kasimir-Bauer S.
      • Kimmig R.
      • Birdir C.
      Anti-Mullerian-hormone levels during pregnancy and postpartum.
      . The reason behind the result observed in the latter study is not clear. It should be noted, however, that the Beckman-Coulter Gen II assay used in that study has been shown to result in inconsistent AMH results under certain sample handling conditions (
      • Han X.
      • McShane M.
      • Sahertian R.
      • White C.
      • Ledger W.
      Pre-mixing serum samples with assay buffer is a prerequisite for reproducible anti-Mullerian hormone measurement using the Beckman Coulter Gen II assay.
      ).
      Reasons for the inverse relationship between gestational age and AMH concentrations are unclear, but there are several possible mechanisms. The reduced concentration of AMH during pregnancy is consistent with the decrease in serum AMH concentration observed during treatment with hormonal contraception (
      • 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.
      ). This may imply that suppressed gonadotrophin release (
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      ) and increased concentrations of circulating progesterone and/or oestrogen during pregnancy (
      • Kuijper E.A.
      • Ket J.C.
      • Caanen M.R.
      • Lambalk C.B.
      Reproductive hormone concentrations in pregnancy and neonates: a systematic review.
      ) could inhibit follicular recruitment.
      Importantly, the decreased AMH concentrations may suggest reduced ovarian follicular activity in pregnancy with a potentially fertility preserving function. However, as AMH still remains detectable at these reduced concentrations we can assume that the ovaries do not completely enter quiescence, with some follicular recruitment remaining. Decreased ovarian follicular activity during pregnancy would be consistent with the findings by some epidemiological studies that increased parity is associated with a delay in menopausal onset (
      • Cramer D.W.
      • Xu H.
      Predicting age at menopause.
      ,
      • Gold E.B.
      • Bromberger J.
      • Crawford S.
      • Samuels S.
      • Greendale G.A.
      • Harlow S.D.
      • Skurnick J.
      Factors associated with age at natural menopause in a multiethnic sample of midlife women.
      ,
      • Whelan E.A.
      • Sandler D.P.
      • McConnaughey D.R.
      • Weinberg C.R.
      Menstrual and reproductive characteristics and age at natural menopause.
      ).
      The post-partum increase in AMH indicates that the presumed inhibition of follicular recruitment during pregnancy is released following birth. Interestingly, an increase is similarly observed in serum AMH following the cessation of hormonal contraceptives (
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      ,
      • van den Berg M.H.
      • van Dulmen-den Broeder E.
      • Overbeek A.
      • Twisk J.W.
      • Schats R.
      • van Leeuwen F.E.
      • Kaspers G.J.
      • Lambalk C.B.
      Comparison of ovarian function markers in users of hormonal contraceptives during the hormone-free interval and subsequent natural early follicular phases.
      ).
      Studies examining AMH concentrations during the post-partum period do not report whether the women were breastfeeding or on hormonal contraceptives, which may confound the results and explain the discrepancies in post-partum AMH values between studies. As association between breastfeeding and AMH concentrations is yet to be studied, a potential downregulating effect of breastfeeding through prolactin on AMH concentration cannot be excluded. Nevertheless, limited evidence suggests normal AMH concentrations in women with hyperprolactinaemia (
      • Barbakadze L.
      • Kristasashvili J.
      Antimullerian hormone in cases of different reproductive pathologies.
      ,
      • Li H.W.
      • Anderson R.A.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Evaluation of serum antimullerian hormone and inhibin B concentrations in the differential diagnosis of secondary oligoamenorrhea.
      ).
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      postulate that the reduction in serum AMH concentration could be associated with haemodilution due to pregnancy-related increased blood volume. Plasma volume expands throughout pregnancy, especially during the second trimester (
      • Pritchard J.A.
      Changes in the blood volume during pregnancy and delivery.
      ), and this is not associated with a proportionate increase in erythrocyte mass, often leading to a dilutional anaemia (
      • Milman N.
      • Bergholt T.
      • Byg K.-E.
      • Eriksen L.
      • Hvas A.-M.
      Reference intervals for haematological variables during normal pregnancy and postpartum in 434 healthy Danish women.
      ). Similarly, there may be a disproportionate increase in plasma volume compared with AMH production, causing a relative decrease in serum AMH concentration, rather than a change in ovarian AMH production.
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      also postulated that the serum AMH decrease in pregnancy could be associated with increased plasma–protein binding, although the exact physiological mechanism by which this might occur is not described.
      Another potential explanation for the decreased serum AMH with increased gestation may be increased maternal adiposity and body mass index (BMI), which have been previously suggested to be negatively associated with AMH serum concentration (
      • Freeman E.W.
      • Gracia C.R.
      • Sammel M.D.
      • Lin H.
      • Lim L.C.
      • Strauss 3rd, J.F.
      Association of anti-mullerian hormone levels with obesity in late reproductive-age women.
      ,
      • Moy V.
      • Jindal S.
      • Lieman H.
      • Buyuk E.
      Obesity adversely affects serum anti-mullerian hormone (AMH) levels in Caucasian women.
      ,
      • Nelson S.M.
      • Stewart F.
      • Fleming R.
      • Freeman D.J.
      Longitudinal assessment of antimullerian hormone during pregnancy-relationship with maternal adiposity, insulin, and adiponectin.
      ). Nevertheless, there is also evidence that refutes such an association (
      • Kriseman M.
      • Mills C.
      • Kovanci E.
      • Sangi-Haghpeykar H.
      • Gibbons W.
      Antimullerian hormone levels are inversely associated with body mass index (BMI) in women with polycystic ovary syndrome.
      ,
      • Skałba P.
      • Cygal A.
      • Madej P.
      • Dąbkowska-Huć A.
      • Sikora J.
      • Martirosian G.
      • Romanik M.
      • Olszanecka-Glinianowicz M.
      Is the plasma anti-Müllerian hormone (AMH) level associated with body weight and metabolic, and hormonal disturbances in women with and without polycystic ovary syndrome?.
      ,
      • Woo H.-Y.
      • Kim K.-H.
      • Rhee E.-J.
      • Park H.
      • Lee M.-K.
      Differences of the association of anti-Mullerian hormone with clinical or biochemical characteristics between women with and without polycystic ovary syndrome.
      ) and hence it is unclear whether BMI and maternal adiposity are responsible for the AMH serum decline. However, the relatively rapid increase of AMH post-delivery might suggest that this is not the most likely cause.
      This review used a systematic approach, included all available evidence, critically evaluated the methodology of the included studies and presented the results homogeneously for comparison. It should be noted that the conclusions drawn by this review must be interpreted with caution considering the fact that a limited number of studies have employed a longitudinal design. Nevertheless, although longitudinal studies are considered optimal for evaluating AMH kinetics during pregnancy, the cross-sectional studies demonstrated the same trends, apart from the
      • La Marca A.
      • Giulini S.
      • Orvieto R.
      • De Leo V.
      • Volpe A.
      Anti-Müllerian hormone concentrations in maternal serum during pregnancy.
      study.
      Furthermore, there is heterogeneity in terms of the population studied. It should be noted that the included studies have not necessarily assessed AMH kinetics on healthy, unselected pregnancies. More specifically, in certain studies specific types of population were analysed such as women with or without: (i) pre-term birth (
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ), (ii) gestational diabetes mellitus (
      • Gerli S.
      • Favilli A.
      • Brozzetti A.
      • Torlone E.
      • Pugliese B.
      • Pericoli S.
      • Bini V.
      • Falorni A.
      Anti-mullerian hormone concentration during the third trimester of pregnancy and puerperium: a longitudinal case-control study in normal and diabetic pregnancy.
      ) and (iii) Down syndrome fetuses (
      • Li H.W.
      • Hui P.W.
      • Tang M.H.
      • Lau E.T.
      • Yeung W.S.
      • Ho P.C.
      • Ng E.H.
      Maternal serum anti-Mullerian hormone level is not superior to chronological age in predicting Down syndrome pregnancies.
      ). Interestingly, a negative association between gestational age and AMH concentration was observed in all these groups.
      The variability in the serum AMH concentrations reported in the studies analysed in this systematic review can also potentially be attributed to heterogeneity in the study populations. AMH is known to decrease with increasing age, so studies with differences in the mean maternal age of participants (Table 3) could be expected to have different distribution of AMH concentrations. Further, other maternal factors such as BMI, smoking status and ethnicity have been reported to affect serum AMH concentrations (
      • 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.
      ,
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      ) and hence differences in these factors between the analysed studies could partially explain the differences in the observed AMH values. Additionally, there were differences in the timing of the measurements and the assay used, which might explain some of the discrepancies observed.
      Importantly, despite these differences, the general trend from the analysed studies is that there is a decline in serum AMH across gestation, which seems to recover post-partum. These differences also do not allow the statistical synthesis of the results from individual studies. More specifically, the various AMH assays used in the eligible studies have been shown to produce quantitatively different results without a straightforward and accurate method of converting them to a common scale (
      • Nelson S.M.
      • La Marca A.
      The journey from the old to the new AMH assay: how to avoid getting lost in the values.
      ). Hence, although the comparison of AMH values between different time points within the same study is valid, pooling these results across different studies would be problematic. A potential method through which the results from individual studies could be compared in a meaningful way would be the assessment of the mean proportion of AMH decline per patient. Unfortunately, these data were not available.
      The results of this review indicate that a large, longitudinal study would be useful to confirm the variation of AMH with gestational age and further assess the potential physiological mechanisms which cause the decline. Repeated measurements in the same subjects, at fixed time points, would give more robust data, eliminating the issues associated with the large AMH inter-individual variability (
      • La Marca A.
      • Grisendi V.
      • Griesinger G.
      How much does AMH really vary in normal women?.
      ,
      • Overbeek A.
      • Broekmans F.J.
      • Hehenkamp W.J.
      • Wijdeveld M.E.
      • van Disseldorp J.
      • van Dulmen-den Broeder E.
      • Lambalk C.B.
      Intra-cycle fluctuations of anti-Mullerian hormone in normal women with a regular cycle: a re-analysis.
      ). Regarding the implications for clinical practice, this systematic review suggests that AMH concentration during pregnancy should not be used as a marker for ovarian reserve, especially using nomograms developed with non-pregnant patient data.
      However, the measurement of AMH during pregnancy could potentially be useful because there is some data suggesting that it could be used to predict pre-term birth, when modelled in conjunction with maternal serum α-fetoprotein and maternal weight change between first and second trimesters (
      • Stegmann B.J.
      • Santillan M.
      • Leader B.
      • Smith E.
      • Santillan D.
      Changes in antimullerian hormone levels in early pregnancy are associated with preterm birth.
      ). AMH has also been reported to be associated with fetal sex by
      • Santillan D.
      • Empey R.
      • Santillan M.K.
      • Tyler E.
      • Hunter S.
      • Smith E.M.
      • Stegmann B.J.
      Influence of fetal sex on maternal anti-mullerian hormone levels.
      , who found that serum AMH concentrations are significantly higher in pregnancies carrying male fetuses compared with female fetuses.
      In conclusion, this review has demonstrated an association between reduced maternal serum AMH concentrations and advancing gestational age. These findings suggest that AMH measurements in pregnant women, especially at later stages of pregnancy, should not be used to assess ovarian reserve. Furthermore, future research on a longitudinal cohort is needed in order to more accurately assess AMH concentrations during pregnancy and elucidate whether ovarian activity is indeed reduced. If this hypothesis is confirmed, further research might explore the physiological mechanisms which cause this decreased ovarian activity during pregnancy.

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      Biography

      Christos A. Venetis is an obstetrician/gynaecologist and a Subspecialist in Reproductive Medicine (ESHRE). He obtained a PhD in Reproductive Endocrinology and Infertility (2014) from the Aristotle University of Thessaloniki, Greece with the Highest Distinction. His research interests include ovarian stimulation, reproductive endocrinology, endometrial receptivity and evidence-based medicine.
      Key message
      By systematically reviewing the available evidence, this paper suggests that anti-Müllerian hormone (AMH) serum concentration declines during pregnancy and increases to pre-pregnancy concentrations following delivery. The exact physiological mechanism of this decline is still unknown. For this reason AMH should not be used for assessing ovarian reserve during pregnancy.