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Seven out of 10 couples treated by IVF achieve parenthood following either treatment, natural conception or adoption

Open AccessPublished:August 23, 2016DOI:https://doi.org/10.1016/j.rbmo.2016.08.010

      Abstract

      The aim of this study was to explore the achievement of parenthood 8 years after starting IVF, considering multiple pathways to parenthood during and after IVF treatment. Medical data on 6507 couples who began IVF between 2000 and 2002 were obtained from the databases of eight French IVF centres. Information on long-term outcome was available for participants in the 2008–2010 postal survey. Multiple imputation methods were used to account for missing data. Eight years after starting IVF, 71% (95% CI 69 to 74) of treated couples had a child. This included 41% live births after IVF in the IVF centre, 7% live births after another treatment or after IVF in another centre, 12% live births after spontaneous conception and 11% adoptions. This study provides a longitudinal overview of paths to parenthood among couples successfully and unsuccessfully treated by IVF. These results should give hope to infertile couples as seven out of 10 couples finally became parents. However, IVF is not the only path to parenthood, and couples should be informed of the other possible avenues.

      Keywords

      Introduction

      Infertility is estimated to affect one couple out of four (
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      ), and the number of couples seeking medical help has clearly increased in recent decades (
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      Seeking medical help to conceive.
      ). In Canada, for example, the prevalence of past-12-month infertility has tripled between 1984 and 2010 (
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      • Cook J.L.
      • Yuzpe A.A.
      • Tough S.
      • Collins J.
      Estimating the prevalence of infertility in Canada.
      ). Assisted reproductive techniques, and especially IVF, are now widely used in developed countries (
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      • D'Hooghe T.
      • Ferraretti A.P.
      • de Mouzon J.
      • Erb K.
      • Castilla J.A.
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      Assisted reproductive technology in Europe, 2011: results generated from European registers by ESHREdagger.
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      • Sunderam S.
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      • Folger S.G.
      • Jamieson D.J.
      • Warner L.
      • Barfield W.D.
      Assisted Reproductive Technology Surveillance – United States, 2013.
      ). The success of IVF has long been measured on the basis of pregnancy rate per one IVF cycle, but this indicator has been debated (
      • Min J.K.
      • Breheny S.A.
      • MacLachlan V.
      • Healy D.L.
      What is the most relevant standard of success in assisted reproduction? The singleton, term gestation, live birth rate per cycle initiated: the BESST endpoint for assisted reproduction.
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      • Pinborg A.
      • Loft A.
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      • Nyboe Andersen A.
      What is the most relevant standard of success in assisted reproduction?: Is there a single ‘parameter of excellence’?.
      ). Several proposals have been made for considering success as delivery of healthy babies. With patient counselling in mind (
      • Malizia B.A.
      • Hacker M.R.
      • Penzias A.S.
      Cumulative live-birth rates after in vitro fertilization.
      ,
      • Moragianni V.A.
      • Penzias A.S.
      Cumulative live-birth rates after assisted reproductive technology.
      ), a more relevant approach has been developed by reporting success rates in terms of cumulative live-birth rate (CLBR) per woman during her entire treatment (
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      Final ART success rates: a 10 years survey.
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      • Maheshwari A.
      • McLernon D.
      • Bhattacharya S.
      Cumulative live birth rate: time for a consensus?.
      ,
      • Malizia B.A.
      • Dodge L.E.
      • Penzias A.S.
      • Hacker M.R.
      The cumulative probability of liveborn multiples after in vitro fertilization: a cohort study of more than 10,000 women.
      ,
      • McLernon D.J.
      • Maheshwari A.
      • Lee A.J.
      • Bhattacharya S.
      Cumulative live birth rates after one or more complete cycles of IVF: a population-based study of linked cycle data from 178 898 women.
      ). This CLBR indicator gives a more long-term view of the chance of success by considering not just a single IVF cycle but all the IVF cycles undergone by a woman. For instance, in a recent Japanese study, the CLBR was estimated to be 38% (
      • Bodri D.
      • Kawachiya S.
      • De Brucker M.
      • Tournaye H.
      • Kondo M.
      • Kato R.
      • Matsumoto T.
      Cumulative success rates following mild IVF in unselected infertile patients: a 3-year, single-centre cohort study.
      ).
      On completion of the various IVF cycles undertaken by couples, leaving the IVF centre childless is usually perceived as the end of any hope of parenthood. It is timely, however, to challenge such a view and to explore the long-term outcome of couples leaving an IVF centre childless. Indeed, patients often ask about their chances of conceiving naturally, i.e. without any medical help (
      • Cahill D.J.
      • Meadowcroft J.
      • Akande V.A.
      • Corrigan E.
      Likelihood of natural conception following treatment by IVF.
      ), and some studies have shown that spontaneous pregnancy can occur after unsuccessful IVF treatment (
      • Cahill D.J.
      • Meadowcroft J.
      • Akande V.A.
      • Corrigan E.
      Likelihood of natural conception following treatment by IVF.
      ,
      • Osmanagaoglu K.
      • Collins J.
      • Kolibianakis E.
      • Tournaye H.
      • Camus M.
      • Van Steirteghem A.
      • Devroey P.
      Spontaneous pregnancies in couples who discontinued intracytoplasmic sperm injection treatment: a 5-year follow-up study.
      ). Moreover, some couples shift their parental project to adoption as another path to fulfill their desire for parenthood (
      • Sydsjö G.
      • Ekholm K.
      • Wadsby M.
      • Kjellberg S.
      • Sydsjo A.
      Relationships in couples after failed IVF treatment: a prospective follow-up study.
      ). Few studies have been able to provide a full overview of these different paths to parenthood among unsuccessfully treated couples (
      • de La Rochebrochard E.
      • Quelen C.
      • Peikrishvili R.
      • Guibert J.
      • Bouyer J.
      Long-term outcome of parenthood project during in vitro fertilization and after discontinuation of unsuccessful in vitro fertilization.
      ,
      • Walschaerts M.
      • Bujan L.
      • Isus F.
      • Parinaud J.
      • Mieusset R.
      • Thonneau P.
      Cumulative parenthood rates in 1735 couples: impact of male factor infertility.
      ,
      • Wischmann T.
      • Korge K.
      • Scherg H.
      • Strowitzki T.
      • Verres R.
      A 10-year follow-up study of psychosocial factors affecting couples after infertility treatment.
      ). Indeed, studies on the long-term outcome of couples treated by IVF require follow-up over several years. Such a long-term approach is hampered by a high risk of loss to follow-up, even when costly longitudinal protocols are used (
      • Chen K.F.
      • Colantuoni E.
      • Siddiqi F.
      • Dinglas V.D.
      • Sepulveda K.A.
      • Fan E.
      • Pronovost P.J.
      • Needham D.M.
      Repeated attempts using different strategies are important for timely contact with study participants.
      ,
      • Cotter R.B.
      • Burke J.D.
      • Stouthamer-Loeber M.
      • Loeber R.
      Contacting participants for follow-up: how much effort is required to retain participants in longitudinal studies?.
      ,
      • Robinson K.A.
      • Dinglas V.D.
      • Sukrithan V.
      • Yalamanchilli R.
      • Mendez-Tellez P.A.
      • Dennison-Himmelfarb C.
      • Needham D.M.
      Updated systematic review identifies substantial number of retention strategies: using more strategies retains more study participants.
      ). These methodological issues may explain the sparse results published so far.
      The aim of this study was to provide a long-term overview of the different paths to parenthood 8 years after starting IVF. It considers births achieved after several cycles of IVF treatment in the centre (the CLBR), births achieved after other subsequent treatments, as well as spontaneous births obtained without medical assistance. To develop a full perspective of paths to parenthood, adoption was also taken into account as another way for couples to fulfill their desire to become parents.

      Materials and methods

       Population and sources of data

      DAIFI (the French acronym for outcome after IVF) is a retrospective cohort (
      • Troude P.
      • Bailly E.
      • Guibert J.
      • Bouyer J.
      • de La Rochebrochard E.
      Who does not participate in a follow-up postal study? a survey of infertile couples treated by in vitro fertilization.
      ). It is an exhaustive database of all 6507 couples who began IVF between 2000 and 2002 in eight French IVF centres (among the 93 IVF centres in metropolitan France). This study received approval from the French Data Protection Authority on 9 September 2005 (authorization number 05–1334).
      Data collection included two complementary sources: medical data obtained from the IVF centres and information based on a postal questionnaire. In this paper, information from the postal questionnaire was used to explore long-term outcome among unsuccessfully treated couples. A full presentation of the postal survey is available elsewhere, including a detailed analysis of participation (
      • Troude P.
      • Bailly E.
      • Guibert J.
      • Bouyer J.
      • de La Rochebrochard E.
      Who does not participate in a follow-up postal study? a survey of infertile couples treated by in vitro fertilization.
      ).

       Medical data collected in the whole cohort

      Medical data were obtained from the IVF centre databases. All IVF treatments carried out in the centres between 2000 and 2007 were exhaustively recorded for the 6507 couples of the cohort. Medical data included sterility assessments for the couple (age, origin, type and duration of infertility), information on each IVF treatment carried out in the centre (number of oocytes retrieved, number of embryos obtained, number of embryos transferred, pregnancy after fresh or frozen embryo transfer) and on the outcome of any ensuing pregnancies. On the basis of these medical data, two groups were identified among the 6507 couples of the cohort: 2691 couples successfully treated in the centre and leaving it with a child, and 3816 couples unsuccessfully treated in the centre and leaving it childless (Figure 1).

       Long-term outcome data among unsuccessfully treated couples

      Long-term outcome was explored in the postal questionnaire carried out between 2008 and 2010. Different steps toward parenthood were considered: live birth after another treatment at a later date (further IVF treatment in another centre or another treatment such as sperm insemination) and live birth after spontaneous conception. As well as these paths to ‘biological’ parenthood, the study also explored adoptive parenthood as an alternative path for the couple to fulfill their desire to have a child.
      In the postal survey, to increase chances of contact, every effort was made to obtain updated validated mailing addresses through the central hospital billing department and through the French postal system. Of the 3816 couples unsuccessfully treated in the IVF centre, 2274 couples (60%) were contacted in the postal survey 8 years after registration in the IVF centre (Figure 1).
      To increase the chance of response among contacted couples, effective ‘response-enhancement’ strategies were used (
      • Edwards P.
      • Roberts I.
      • Clarke M.
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      • Pratap S.
      • Wentz R.
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      Increasing response rates to postal questionnaires: systematic review.
      ,
      • MacDonald S.E.
      • Newburn-Cook C.V.
      • Schopflocher D.
      • Richter S.
      Addressing nonresponse bias in postal surveys.
      ). In particular, a relatively short, colour-printed questionnaire designed to be user-friendly was distributed to participants, and stamped-addressed envelopes were provided. If necessary, a reminder was sent, including a second copy of the questionnaire, requesting an explanation of non-participation. Of the 2274 couples contacted by mail, 1100 couples (48%) returned a completed questionnaire (Figure 1). This response rate was moderate but consistent with the expected response rate in patient surveys considering that, in this study, patients were interviewed about past events (
      • Asch D.A.
      • Jedrziewski M.K.
      • Christakis N.A.
      Response rates to mail surveys published in medical journals.
      ). Because of this non-participation, classic epidemiological statistical tools did not seem appropriate for analysing the data from the postal survey, and cutting edge statistical methods were, therefore, used.

       Strategy of analysis

      The postal survey was analysed on the basis of post-survey adjustment methods developed to produce unbiased results for datasets affected by non-participation (
      • Donders A.R.
      • van der Heijden G.J.
      • Stijnen T.
      • Moons K.G.
      Review: a gentle introduction to imputation of missing values.
      ,
      • Graham J.W.
      Missing data analysis: making it work in the real world.
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      Missing data analysis using multiple imputation: getting to the heart of the matter.
      ,
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      Statistical Analysis with Missing Data.
      ,
      • MacDonald S.E.
      • Newburn-Cook C.V.
      • Schopflocher D.
      • Richter S.
      Addressing nonresponse bias in postal surveys.
      ,
      • Ranstam J.
      • Turkiewicz A.
      • Boonen S.
      • Van Meirhaeghe J.
      • Bastian L.
      • Wardlaw D.
      Alternative analyses for handling incomplete follow-up in the intention-to-treat analysis: the randomized controlled trial of balloon kyphoplasty versus non-surgical care for vertebral compression fracture (FREE).
      ,
      • Schafer J.L.
      • Graham J.W.
      Missing data: our view of the state of the art.
      ,
      • Wang C.
      • Hall C.B.
      Correction of bias from non-random missing longitudinal data using auxiliary information.
      ). In this analysis, non-participants in the postal survey were included in the estimation of long-term parenthood achievement using multiple imputation by chained equations (
      • Azur M.J.
      • Stuart E.A.
      • Frangakis C.
      • Leaf P.J.
      Multiple imputation by chained equations: what is it and how does it work?.
      ,
      • Royston P.
      • White I.R.
      Multiple Imputation by Chained Equations (MICE): implementation in stata.
      ,
      • van Buuren S.
      • Boshuizen H.C.
      • Knook D.L.
      Multiple imputation of missing blood pressure covariates in survival analysis.
      ).
      Values of non-participants were imputed on the basis of their medical characteristics. The model of imputation relies on a multivariate logistic regression describing medical factors associated with parenthood achievement (P < 0.20) among unsuccessfully treated couples who participated in the postal survey. To account for uncertainty in the imputed values, imputation was repeated several times for each participant (multiple imputation). To test the stability of our results obtained through multiple imputation strategy, a sensitivity analysis was conducted. A supplementary auxiliary parameter was introduced in the model: a deprivation score (the Carstairs index) as an indicator of couples' socioeconomic level. This index was based on the characteristics of the couple's area of residence collected in the 1999 French census and available for 88% of the study sample (3373/3816).
      The confidence interval of the overall parenthood achievement rate was calculated using an estimation of the standard error carried out by the delta method (
      • Buehler R.J.
      Confidence intervals for the product of two binomial parameters.
      ). All statistical analyses and imputations were conducted using STATA/SE 12.0 (Stata Press, College Station, TX, USA), particularly the mi impute chained command of Stata software.

      Results

       Characteristics of the study population and CLBR

      In the whole cohort (n = 6507), the median age of the women at first oocyte retrieval was 33 years (quartiles Q1–Q3 [30–37]) and the median age of the men was 35 years (Q1–Q3 [31–39]) (Table 1). For one-third of couples (2108/6470), infertility was caused by male factor, for 36% (2353/6470) a female factor, mixed factors for 18% (1176/6470) and unexplained for 13% (833/6470) of couples. The median number of IVF attempts at the IVF centre was two (Q1-Q3 [1–3]). The treatment ended successfully with a live birth for 41% (2691/6507) of the couples of the cohort. The CLBR was thus 41% (95% CI 40 to 43).
      Table 1Characteristics of couples and outcome of IVF treatment in the IVF centre (n = 6507).
      Distribution (%)
      Woman's age (years) at first IVF
       <3024
       30–3437
       35–3928
       ≥4011
      Man's age (years) at first IVF
       <3014
       30–3434
       35–3929
       ≥4023
      Origin of infertility
       Female36
       Male33
       Couple18
       Unexplained13
      Year of first IVF
       200027
       200138
       200235
      Number of IVF cycles during treatment
       142
       227
       316
       ≥416
      Outcome of IVF treatment in the centre
       Live birth41
       No live birth59

      Long-term parenthood achievement after unsuccessful IVF treatment

      At the end of treatment at the IVF centre, 59% (3816/6507) of treated couples remained childless. Of these unsuccessfully treated couples, 1100 participated in the postal survey (Figure 1). These unsuccessfully treated couples who participated in the survey included 561 couples who finally later succeeded in having a child (biologically or by adoption) and 539 couples who still remained childless. The characteristics of these two groups are described in Table 2, which also shows the proportion of couples who had a child (biologically or by adoption) according to the couples' characteristics. For instance, 69% (134/194) of women under 30 years later succeeded in becoming parents, whereas this percentage was 33% (44/134) for women older than 40 years.
      Table 2Characteristics according to long-term biological and adoptive parenthood achievement among the 1100 couples unsuccessfully treated in the IVF centre and who participated in the postal survey.
      Distribution of couples whoProportion of couples who had a biological or adopted child (n = 1100) %
      did not have a child (n = 539) %had a biological or adopted child (n = 561) %P χ2
      Woman's age (years) at first oocyte retrieval<0.001
       <30112469
       30–34364355
       35–39362542
       ≥4017833
      Year of first oocyte retrieval<0.001
       2000192456
       2001364356
       2002453444
      Origin of infertility0.631
       Female393951
       Male322949
       Couple181852
       Unexplained111455
      Number of embryos obtained at first IVF0.157
       0151245
       1–2222049
       3–5353551
       >5273356
      Outcome of first IVF
      Variable corresponding to the step at which the first IVF failed, in five categories: less than two oocytes retrieved but no transfer; two or more oocytes retrieved but no transfer; embryos transferred but no embryo frozen and no pregnancy; embryos transferred and frozen but no pregnancy; pregnancy after fresh or frozen embryo transfer which resulted in an ectopic pregnancy, spontaneous abortion or stillbirth.
      0.009
       0–1 oocyte3235
       ≥ 2 oocytes91052
       Transfer686349
       Frozen161853
       Pregnancy4870
      Number of oocyte retrievals0.071
       1262853
       2272752
       3182256
       ≥ 4292245
      At least one embryo transferred during all IVFs in the centre0.055
       No9641
       Yes919452
      a Variable corresponding to the step at which the first IVF failed, in five categories: less than two oocytes retrieved but no transfer; two or more oocytes retrieved but no transfer; embryos transferred but no embryo frozen and no pregnancy; embryos transferred and frozen but no pregnancy; pregnancy after fresh or frozen embryo transfer which resulted in an ectopic pregnancy, spontaneous abortion or stillbirth.
      Factors associated with long-term parenthood achievement among unsuccessfully treated couples are presented in Table 3. The probability of parenthood achievement decreased strongly with increasing age of the woman. It was also associated with year of first oocyte retrieval, outcome of the first IVF, number of IVFs and IVF centre. Using these factors in the multiple imputation model, the proportion of couples achieving parenthood (biologically or by adoption) was estimated to be 51% (95% CI 48 to 54). Another multiple imputation analysis was also conducted by considering only biological parenthood (Supplementary Table 1), leading to a biological parenthood achievement rate of 33% (95% CI 30 to 36). Sensitivity analysis gave similar results to the initial analysis, as the proportion of long-term parenthood achievement was estimated at 50% (95% CI 47 to 54) when considering biological and adoptive parenthood (versus 51% in the initial analysis) and at 33% (95% CI 29 to 38) when considering only biological parenthood (versus 33% in the initial analysis also).
      Table 3Factors associated in logistic regressions with parenthood achievement (biologically or by adoption) among the 1100 couples unsuccessfully treated in the IVF centre and who participated in the postal survey.
      nUnivariate analysisMultivariate analysis
      Adjusted for all variables in the table and for IVF centre.
      OR95% CIPOR95% CIP
      Woman's age (years) at first oocyte retrieval<0.001<0.001
       <30134/1941.801.26 to 2.581.961.35 to 2.85
       30–34243/43911
       35–39140/3330.590.44 to 0.780.530.39 to 0.72
       ≥4044/1340.390.26 to 0.590.350.23 to 0.54
      Year of first oocyte retrieval<0.001<0.001
       2000132/23611
       2001241/4330.990.72 to 1.361.050.74 to 1.49
       2002188/4310.610.44 to 0.840.580.41 to 0.82
      Outcome of first IVF
      Variable corresponding to the step at which the first IVF failed, in five categories: less than two oocytes retrieved but no transfer; two or more oocytes retrieved but no transfer; embryos transferred but no embryo frozen and no pregnancy; embryos transferred and frozen but no pregnancy; pregnancy after fresh or frozen embryo transfer which resulted in an ectopic pregnancy, spontaneous abortion or stillbirth.
      0.0110.01
       0–1 oocyte9/260.550.24 to 1.250.650.27 to 1.56
       ≥2 oocytes54/1041.120.74 to 1.691.000.64 to 1.58
       Transfer351/71511
       Frozen101/1891.190.86 to 1.640.960.67 to 1.37
       Pregnancy46/662.391.38 to 4.112.671.50 to 4.76
      Number of oocyte retrievals0.0720.01
       1158/29911
       2153/2970.950.69 to 1.310.910.65 to 1.29
       3125/2241.130.80 to 1.601.060.73 to 1.54
       ≥ 4125/2800.720.52 to 1.000.600.42 to 0.86
      a Adjusted for all variables in the table and for IVF centre.
      b Variable corresponding to the step at which the first IVF failed, in five categories: less than two oocytes retrieved but no transfer; two or more oocytes retrieved but no transfer; embryos transferred but no embryo frozen and no pregnancy; embryos transferred and frozen but no pregnancy; pregnancy after fresh or frozen embryo transfer which resulted in an ectopic pregnancy, spontaneous abortion or stillbirth.

       Overall parenthood achievement during or after IVF treatment and paths to parenthood

      Forty-one per cent (2691/6507) of couples become parents during IVF treatment in the centre and, among unsuccessfully treated couples, 51% became parents after having left the IVF centre; therefore, it was estimated that 71% (0.41 + (1 − 0.41) x 0.51, 95% CI 69 to 74) of couples finally became parents during or after IVF treatment. The different paths to parenthood were explored on the basis of proportions observed in the postal survey. It included three main components (Figure 2): 48% of couples who became parents through medical treatment (in the IVF centre or afterwards), 12% after spontaneous conception and 11% through adoption.
      Figure 2
      Figure 2Long-term parenthood outcome of couples treated by IVF.
      Among the 539 couples remaining childless at the time of the survey, 27% (143/534) had undertaken steps to adopt a child without success, 5% (29/534) were still considering adoption as a further step that could be undertaken, 41% (219/534) had considered adoption but finally decided against it and 27% (143/534) declared that adoption was never an option for them. The success rate of adoption was 60% (211/354) when considering couples who had become parents through adoption (211) and those who had unsuccessfully tried to adopt (143).

      Discussion

      In a large cohort of French couples treated by IVF and retrospectively followed up for 8 years, 71% finally succeeded in becoming parents, biologically and by adopting. Few studies have considered globally all the paths to parenthood among IVF couples, and most series have been relatively small (
      • de La Rochebrochard E.
      • Quelen C.
      • Peikrishvili R.
      • Guibert J.
      • Bouyer J.
      Long-term outcome of parenthood project during in vitro fertilization and after discontinuation of unsuccessful in vitro fertilization.
      ,
      • Lande Y.
      • Seidman D.S.
      • Maman E.
      • Baum M.
      • Dor J.
      • Hourvitz A.
      Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years.
      ,
      • Sydsjö G.
      • Svanberg A.S.
      • Lampic C.
      • Jablonowska B.
      Relationships in IVF couples 20 years after treatment.
      ,
      • Wischmann T.
      • Korge K.
      • Scherg H.
      • Strowitzki T.
      • Verres R.
      A 10-year follow-up study of psychosocial factors affecting couples after infertility treatment.
      ). Our results are similar to those of a German study conducted among 208 couples who began IVF in between 1994 and 1997, in which 66% of couples had become parents 10 years after starting IVF (
      • Wischmann T.
      • Korge K.
      • Scherg H.
      • Strowitzki T.
      • Verres R.
      A 10-year follow-up study of psychosocial factors affecting couples after infertility treatment.
      ). Another study conducted among 1131 French couples had reported an overall cumulative parenthood rate of 60% 4–9 years after consulting for infertility (
      • Walschaerts M.
      • Bujan L.
      • Isus F.
      • Parinaud J.
      • Mieusset R.
      • Thonneau P.
      Cumulative parenthood rates in 1735 couples: impact of male factor infertility.
      ). Considering the shorter mean length of follow-up, and that the study population was restricted to couples with male infertility, this last result seems roughly in agreement with our estimation of 71%. Nonetheless, one Israeli study conducted among 134 couples who started IVF in between 2001 and 2002 has reported that 93% of couples had become parents 5–7 years after starting IVF (
      • Lande Y.
      • Seidman D.S.
      • Maman E.
      • Baum M.
      • Dor J.
      • Hourvitz A.
      Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years.
      ). This higher parenthood achievement rate may probably be explained by the younger age of women included in the Israeli study (<35 years). A Norwegian study has also reported a higher rate of couples who became parents (83%) 10 years after starting IVF, but it was conducted among only 66 couples (
      • Sundby J.
      • Schmidt L.
      • Heldaas K.
      • Bugge S.
      • Tanbo T.
      Consequences of IVF among women: 10 years post-treatment.
      ). The heterogeneity of study populations and of lengths of follow-up probably explained variations in the previously reported proportions of couples who became parents. To the best of our knowledge, this paper is the first to estimate the overall cumulative parenthood achievement rate during and after IVF treatment in a large sample taking into consideration all couples treated by IVF whatever their age and origin of infertility. Moreover, the sensitivity analysis gave some reassuring evidence on the stability of the results obtained through multiple imputation strategy.
      The chance of achieving parenthood decreases among older women, and further research will be needed to explore variations in parenthood achievement according to age. In our study population, 39% of women were aged 35 years or older at the beginning of IVF treatment, which is consistent with the proportion (41%) observed in the French national data for the year 2000 (
      • Nyboe Andersen A.
      • Gianaroli L.
      • Nygren K.G.
      Assisted reproductive technology in Europe, 2000. Results generated from European registers by ESHRE.
      ). The age of women treated by IVF tends to increase, with 46% of women aged 35 years or older in the French national data for the year 2011 (
      • Kupka M.S.
      • D'Hooghe T.
      • Ferraretti A.P.
      • de Mouzon J.
      • Erb K.
      • Castilla J.A.
      • Calhaz-Jorge C.
      • De Geyter C.
      • Goossens V.
      Assisted reproductive technology in Europe, 2011: results generated from European registers by ESHREdagger.
      ). This increasing age observed among treated couples reflects the general demographic trend to delay childbearing described in European countries (
      • Billari F.C.
      • Liefbroer A.C.
      • Philipov D.
      The postponement of childbearing in Europe: driving forces and implications.
      ,
      • Te Velde E.
      • Habbema D.
      • Leridon H.
      • Eijkemans M.
      The effect of postponement of first motherhood on permanent involuntary childlessness and total fertility rate in six European countries since the 1970s.
      ).
      Although most couples became parents, IVF is far from being the only path to parenthood. In our study, the proportion of couples who became parents after treatment in the IVF centre (the CLBR) was 41%, an estimation very close to the 38% observed in a Japanese study (
      • Bodri D.
      • Kawachiya S.
      • De Brucker M.
      • Tournaye H.
      • Kondo M.
      • Kato R.
      • Matsumoto T.
      Cumulative success rates following mild IVF in unselected infertile patients: a 3-year, single-centre cohort study.
      ). In the long term, however, 71% of couples finally achieved their parenthood project biologically or by adoption. Of the couples unsuccessfully treated in the IVF centre, 51% became parents after discontinuation of IVF treatment in this centre. This result is close to the rate reported in another small French study, where 46% of unsuccessfully treated couples became parents (
      • de La Rochebrochard E.
      • Quelen C.
      • Peikrishvili R.
      • Guibert J.
      • Bouyer J.
      Long-term outcome of parenthood project during in vitro fertilization and after discontinuation of unsuccessful in vitro fertilization.
      ).
      The probability of achieving parenthood biologically or by adoption after unsuccessful treatment was higher if the woman was younger, if during IVF treatment she had an ectopic pregnancy, a spontantous abortion or a stillbirth, and if she had less than four IVF attempts in the IVF centre participating in the study. These factors could be mainly related to biological parenthood, as similar results were achieved when restricting the analysis to biological parenthood (Supplementary Table 1). Few results have been published on factors affecting parenthood achievement after unsuccessful treatment. In another French study, male and female ages less than 35 years and duration of infertility less than 24 months were associated with a higher cumulative biological parenthood rate, but it was conducted only in couples with male infertility (
      • Walschaerts M.
      • Bujan L.
      • Isus F.
      • Parinaud J.
      • Mieusset R.
      • Thonneau P.
      Cumulative parenthood rates in 1735 couples: impact of male factor infertility.
      ). Duration of infertility and female age have been reported to be associated with spontaneous pregnancy after failed assisted reproduction techniques in some studies (
      • Khalili M.A.
      • Kahraman S.
      • Ugur M.G.
      • Agha-Rahimi A.
      • Tabibnejad N.
      Follow up of infertile patients after failed ART cycles: a preliminary report from Iran and Turkey.
      ,
      • Osmanagaoglu K.
      • Tournaye H.
      • Camus M.
      • Vandervorst M.
      • Van Steirteghem A.
      • Devroey P.
      Cumulative delivery rates after intracytoplasmic sperm injection: 5 year follow-up of 498 patients.
      ,
      • Osmanagaoglu K.
      • Collins J.
      • Kolibianakis E.
      • Tournaye H.
      • Camus M.
      • Van Steirteghem A.
      • Devroey P.
      Spontaneous pregnancies in couples who discontinued intracytoplasmic sperm injection treatment: a 5-year follow-up study.
      ).
      In our study, when considering the whole cohort, about 12% of couples became parents after spontaneous conception. This spontaneous live-birth rate seems to be intermediate compared with other published rates. In studies that have considered the different paths to parenthood, some have reported a lower spontaneous live birth rate of about 7% (
      • Lande Y.
      • Seidman D.S.
      • Maman E.
      • Baum M.
      • Dor J.
      • Hourvitz A.
      Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years.
      ,
      • Pinborg A.
      • Hougaard C.O.
      • Nyboe Andersen A.
      • Molbo D.
      • Schmidt L.
      Prospective longitudinal cohort study on cumulative 5-year delivery and adoption rates among 1338 couples initiating infertility treatment.
      ) and others a higher rate of about 15% (
      • Sundby J.
      • Schmidt L.
      • Heldaas K.
      • Bugge S.
      • Tanbo T.
      Consequences of IVF among women: 10 years post-treatment.
      ,
      • Walschaerts M.
      • Bujan L.
      • Isus F.
      • Parinaud J.
      • Mieusset R.
      • Thonneau P.
      Cumulative parenthood rates in 1735 couples: impact of male factor infertility.
      ). Although caution is required owing to heterogeneity of the populations, length of follow-up and outcome measures, other previously published studies have suggested that spontaneous live birth might finally concern one to two couples out of 10 (
      • Brandes M.
      • Hamilton C.J.
      • de Bruin J.P.
      • Nelen W.L.
      • Kremer J.A.
      The relative contribution of IVF to the total ongoing pregnancy rate in a subfertile cohort.
      ,
      • Brandes M.
      • Hamilton C.J.
      • van der Steen J.O.
      • de Bruin J.P.
      • Bots R.S.
      • Nelen W.L.
      • Kremer J.A.
      Unexplained infertility: overall ongoing pregnancy rate and mode of conception.
      ,
      • Cahill D.J.
      • Meadowcroft J.
      • Akande V.A.
      • Corrigan E.
      Likelihood of natural conception following treatment by IVF.
      ,
      • Ludwig A.K.
      • Katalinic A.
      • Jendrysik J.
      • Thyen U.
      • Sutcliffe A.G.
      • Diedrich K.
      • Ludwig M.
      Spontaneous pregnancy after successful ICSI treatment: evaluation of risk factors in 899 families in Germany.
      ,
      • Osmanagaoglu K.
      • Collins J.
      • Kolibianakis E.
      • Tournaye H.
      • Camus M.
      • Van Steirteghem A.
      • Devroey P.
      Spontaneous pregnancies in couples who discontinued intracytoplasmic sperm injection treatment: a 5-year follow-up study.
      ,
      • Shimizu Y.
      • Kodama H.
      • Fukuda J.
      • Murata M.
      • Kumagai J.
      • Tanaka T.
      Spontaneous conception after the birth of infants conceived through in vitro fertilization treatment.
      ). It is possible that some of these spontaneous live births were obtained with a new male partner (
      • Kjaer T.
      • Albieri V.
      • Jensen A.
      • Kjaer S.K.
      • Johansen C.
      • Dalton S.O.
      Divorce or end of cohabitation among Danish women evaluated for fertility problems.
      ). In our postal study, however, only a low proportion (7%, 16/219) of spontaneous live births had been conceived with a new male partner.
      Finally, in our study, about 11% of couples became parents through adoption. This estimation is in agreement with previous studies in which the proportion of IVF-treated couples who adopted ranged from 4–15% (
      • Lande Y.
      • Seidman D.S.
      • Maman E.
      • Baum M.
      • Dor J.
      • Hourvitz A.
      Couples offered free assisted reproduction treatment have a very high chance of achieving a live birth within 4 years.
      ,
      • Pinborg A.
      • Schmidt L.
      • Nyboe Andersen A.
      Crude 5-year follow-up on delivery and adoption rates among 1338 new couples treated with ART (abstract).
      ,
      • Pinborg A.
      • Hougaard C.O.
      • Nyboe Andersen A.
      • Molbo D.
      • Schmidt L.
      Prospective longitudinal cohort study on cumulative 5-year delivery and adoption rates among 1338 couples initiating infertility treatment.
      ,
      • Sundby J.
      • Schmidt L.
      • Heldaas K.
      • Bugge S.
      • Tanbo T.
      Consequences of IVF among women: 10 years post-treatment.
      ,
      • Walschaerts M.
      • Bujan L.
      • Isus F.
      • Parinaud J.
      • Mieusset R.
      • Thonneau P.
      Cumulative parenthood rates in 1735 couples: impact of male factor infertility.
      ,
      • Walschaerts M.
      • Bujan L.
      • Parinaud J.
      • Mieusset R.
      • Thonneau P.
      Treatment discontinuation in couples consulting for male infertility after failing to conceive.
      ,
      • Wischmann T.
      • Korge K.
      • Scherg H.
      • Strowitzki T.
      • Verres R.
      A 10-year follow-up study of psychosocial factors affecting couples after infertility treatment.
      ). Only one study has reported a higher proportion (21%), but this was a cumulative rate over a long follow-up period of 20 years (
      • Sydsjö G.
      • Svanberg A.S.
      • Lampic C.
      • Jablonowska B.
      Relationships in IVF couples 20 years after treatment.
      ). Differences in adoption regulations from one country to another could partly explain disparities between published rates. However, adoption is much more an international process than a national one. For example, in France, 90% of children adopted are born abroad (
      • Halifax J.
      • Villeneuve-Gokalp C.
      Adoption in France: who are the adopted children and who are the adopters?.
      ).
      In conclusion, this study provides a complete longitudinal overview of paths to parenthood among couples successfully and unsuccessfully treated by IVF. These results should give hope to infertile couples, as seven out of 10 couples finally became parents 8 years after starting IVF treatment. However, IVF is not the only path to parenthood and couples should be informed of the other possible avenues.

      Acknowledgements

      The authors wish to thank Elisabeth Morand (INED) for her advice on statistical analysis. This project was supported by the Agence Nationale de la Recherche [n° ANR-06-BLAN-0221-01 ]. DAIFI Group members include: Institut National d'Etudes Démographiques (INED) – Institut National de la Santé et de la Recherche Médicale (INSERM) – Université Paris Sud XI: Elise de La Rochebrochard (national coordinator), Annie Bachelot, Estelle Bailly, Jean Bouyer, Juliette Guibert, Henri Leridon, Patricia Thauvin, Laurent Toulemon, Pénélope Troude; Auvergne: Rusudan Peikrishvili, Jean-Luc Pouly (CHU Estaing, Clermont-Ferrand); Basse-Normandie: Isabelle Denis, Michel Herlicoviez (CHU Clémenceau, Caen); Franche-Comté: Christiane Joanne, Christophe Roux (CHR Saint-Jacques, Besançon); Haute-Normandie: Catherine Avril, Julie Roset (Clinique Mathilde, Rouen); Ile-de-France: Joëlle Belaisch-Allart, Olivier Kulski (Centre Hospitalier des 4 Villes, Sèvres); Jean-Philippe Wolf, Dominique de Ziegler (Cochin, Paris); Philippe Granet, Juliette Guibert (Institut Mutualiste Montsouris, Paris); Provence-Alpes-Côte d'Azur: Claude Giorgetti, Géraldine Porcu (Institut de Médecine de la Reproduction, Marseille).

      Appendix. Supplementary material

      The following is the supplementary data to this article:
      • Table S1

        Factors associated in logistic regression with biological parenthood outcome among the 1100 couples unsuccessfully treated in the IVF centre and who participated in the postal survey.

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      Biography

      Pénélope Troude is a public health MD. She has a PhD in epidemiology. She works in the Public Health department of an university hospital and is involved in improvement of care quality. She is working on evaluation of professional practices, care organization, outcomes and medical management of infertile couples.