1 Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, 2 International Health Foundation, Europalaan 506, 3526 KS Utrecht, 3 Department of Reproductive Medicine, Division of Obstetrics, Neonatology and Gynaecology, University Medical Center Utrecht, Postbus 85500, 3508 GA Utrecht and 4 Department of Gynaecology and Obstetrics, Erasmus Medical Center, Postbus 2040, 3000 CA Rotterdam, The Netherlands
5 To whom correspondence should be addressed. e-mail: f.v.leeuwen{at}nki.nl
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Abstract |
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Key words: epidemiology/IVF treatment/menopausal transition/natural menopause/retrieved oocytes
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Introduction |
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Early ovarian depletion is likely to be reflected by a low number of retrieved oocytes (poor oocyte response) after gonadotrophin stimulation in IVF treatment. This is supported by the fact that in older women, fewer oocytes are retrieved after stimulation with gonadotrophins during IVF treatment than in younger women (Navot et al., 1991; Cahill et al., 1994
; Seifer et al., 1999
; Check et al., 2000
). Thus, a low number of retrieved oocytes after gonadotrophin stimulation for IVF would be expected to be associated with an earlier start of the menopausal transition. Indeed, in a small casecontrol study, we recently observed that the retrieval of a low number of oocytes at first IVF treatment was associated with greater risk of early menopause (≤46 years of age) (de Boer et al., 2002
).
In the present, much larger, study, we examine whether women who had a poor oocyte response at their first IVF attempt enter the different menopausal transition stages earlier, or reach natural menopause earlier, than women of similar ages with a normal oocyte response. We also investigated whether poor quality of the retrieved oocytes is predictive of early menopausal transition or early natural menopause.
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Materials and methods |
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Between 1997 and 2000, all women received a questionnaire, an information letter and a study brochure. A total of 19 242 women received the 23-page study questionnaire, asking each participating subject for their written informed consent for data abstraction from the medical records. Seventy-three percent of the women returned the questionnaire. The upper part of Figure 1 displays a graphical presentation of the OMEGA study population.
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Furthermore, women were asked whether they used HRT for menopausal complaints, whether their menstrual cycle had ceased for 311 months prior to completion of the questionnaire and whether this was due to pregnancy/lactation or other reasons. In addition, women were also asked whether or not their last vaginal bleeding had occurred at least 12 months before completion of the questionnaire. Menopause was considered natural if it was not the result of (or possibly related to) surgery (hysterectomy, oophorectomy) or due to chemotherapy/radiotherapy for cancer treatment.
Trained research assistants abstracted data from the medical files on: gynaecological history, subfertility diagnosis, fertility hormones used prior to IVF treatment, and detailed information about each subsequent IVF treatment (all fertility drugs and the corresponding dosages used during IVF treatment, the number of retrieved oocytes, occurrence of complications and whether or not the treatment resulted in a pregnancy).
Analytic cohort
To be eligible for the cohort study presented here, women had to have a regular menstrual cycle pattern at the time of their first visit to the gynaecologist. Women were defined as having a regular menstrual cycle pattern when they were able to predict the next menstrual cycle always or almost always within 4 days and when their mean menstrual cycle length was between 21 and 35 days. Of all initial 10 215 IVF-treated women who returned the questionnaire and for whom medical record data were available, 6872 women reported to have had a regular menstrual cycle pattern at the time of the first visit to the gynaecologist. The lower part of Figure 1 presents the distribution of the source population (n = 10 215) according to menstrual cycle characteristics and various exclusion criteria. Finally, 4601 women were eligible for the present study.
Subsequently, we examined whether, at the end of the follow-up period (at the completion of the questionnaire, follow-up time ranged from 0.5 to 16.2 years), women had kept their regular menstrual cycle pattern (premenopausal) or whether they had reached the menopausal transition or the natural menopause.
Definitions of variables and methods of analysis
In the analysis, we compared the odds of having entered the menopausal transition or having reached natural menopause between women with a normal response and women with a poor response or a cycle cancellation due to insufficient follicle growth (anticipated poor response) at their first IVF attempt. Type of response was taken as a proxy for oocyte quantity. By comparing only the number of retrieved oocytes at first IVF treatment, and not at subsequent IVF attempts, the effects of previous ovarian stimulation and adaptation of stimulation regimens based on previous response experiences were largely avoided. Considering the number of retrieved oocytes and a mean fertilization rate of 5060%, four oocytes are needed to reach an average of two embryos available for transfer (Bancsi et al., 2002). Therefore, women who had ≤3 oocytes retrieved at their first IVF attempt were defined as poor responders. Normal response was defined as the collection of >3 oocytes at the first retrieval. Anticipated poor response was defined as an attempt at ovarian stimulation in women who eventually did not undergo an IVF puncture because of insufficient or no follicle growth. If the first IVF cycle was cancelled due to risk of ovarian hyperstimulation syndrome (OHSS), the woman was included in the normal responders category (>3 oocytes). Furthermore, we examined the odds of having entered the menopausal transition or reaching the natural menopause according to the actual number of retrieved oocytes. However, when we used the number of oocytes as a continuous variable, we had to exclude those women whose first cycle was cancelled because of insufficient or no follicle growth or risk of OHSS.
Subfertility diagnoses (based on medical record information) were divided into four categories: tubal (endometriosis included), male, unexplained subfertility (causes related to disturbances of the menstrual cycle included) and other or unknown subfertility causes. Each woman was categorized into only one category of subfertility diagnosis, i.e. the one which was assumed to contribute most to the subfertility. Duration of subfertility was determined by the period between start of involuntary childlessness and the date of first visit to the IVF centre.
We categorized women into four different menopausal transition stages using somewhat arbitrary definitions based on the literature and the data that were available. We decided to define women as having entered the menopausal transition when they were no longer able to predict the next menstrual cycle within 4 days while still having a mean menstrual cycle length of 2135 days (early menopausal transition) (group a). For the subsequent middle stage of the menopausal transition, an additional criterion was a change in mean menstrual cycle length: women whose next menstrual cycle was not predictable within 4 days and who had a mean cycle length of <21 or >35 days (middle menopausal transition) (group b). Women whose menstrual cycle had ceased 311 months prior to the completion of the questionnaire (unless this was due to lactation/pregnancy or surgery such as hysterectomy) were categorized into the late menopausal transition (group c). Women who (had) used HRT for menopausal complaints were considered as a separate category because they could not be assigned to one of the stages of the menopausal transition (group d). Women whose last vaginal bleeding had occurred at least 12 months prior to the completion of the questionnaire (unless this was due to lactation/pregnancy or surgery such as hysterectomy, or due to chemotherapy/radiotherapy for cancer treatment) were considered as having reached the natural menopause. Women who considered themselves as post-menopausal but used HRT at that same time were included in the HRT subgroup. Women whose menstrual cycle pattern could not be categorized into either the premenopausal group, the various menopausal transition stages, natural menopause or HRT subgroup were categorized into the so-called other group.
Women were defined as smokers when they had smoked more than one cigarette a day for at least 1 year at the time of the first oocyte retrieval.
The following three oocyte quality measures were used for the analyses of the results. Live birth rate (LBR) per started cycle, defined as any birth event in which at least one baby is born alive divided by the number of started IVF cycles (as a percentage), relates to the overall clinical effectiveness of the entire treatment cycle, including the ovarian response to stimulation, the ovum pick-up procedure, whether or not fertilization takes place, early embryonic development in vitro and the technique of the embryo transfer. The LBR per embryo transfer, which has the number of embryo transfers as denominator, is only related to the last phases of the treatment cycle which depend more directly on the oocyte quality. The ability of the embryo to implant into the uterus can also be regarded as a reflection of oocyte quality. It is defined by the number of gestational sacs visualized with ultrasound divided by the number of embryos replaced (Van Kooij et al., 1996). Since this information was not available, we used the LBR per transferred embryo as a proxy of the implantation rate. The LBR per transferred embryo was defined as the number of babies born alive divided by the number of embryos replaced. For example, if the birth of a set of twins was the result of the transfer of two embryos, the LBR per embryo was 100%. If one child was born after four embryos had been transferred, the LBR per embryo was 25%. These examples demonstrate that several implantations may take place in one woman. These implantation successes cannot be taken as independent observations, a phenomenon known as overdispersion (Cox, 1970
). The Williams procedure (Williams, 1982
) for dependency was used to correct for this phenomenon (Van Kooij et al., 1996
).
All descriptive analyses were processed with SPSS® (version 10.0, SPSS Inc., Chicago, IL, USA). Because no normal distribution could be assumed, the comparison of the median number of retrieved oocytes between women who entered the menopausal transition or had reached natural menopause and women with a regular menstrual cycle pattern was analysed and tested by the MannWhitney U-test. Differences between group means and distributions over categories were tested by Students t-test or 2 test. A two-sided P-value <0.05 was considered statistically significant.
We also estimated the age-specific prevalences of having reached the menopausal transition or natural menopause, for normal and (anticipated) poor responders separately. Three year age-specific moving averages were used for graphical presentation. The age-specific prevalence curve for the normal responders was based on the estimates between the ages of 29 and 46 years. For the poor and anticipated poor responders, the age-specific prevalence curve was based on the estimates between the ages of 35 and 48 years. All other age-specific prevalences were based on fewer than 50 women and were therefore omitted in the graphical presentation.
Multinomial logistic regression analysis was used to determine the odds ratios for having entered various stages of the menopausal transition or having reached natural menopause according to the number of retrieved oocytes at first IVF treatment. Since we did not have information as to when women had entered the menopausal transition, the outcome used in the analysis was whether or not women had entered the various stages of the menopausal transition at the end of follow-up. Although we had information as to when women had reached the natural menopause, for reasons of comparability we used a uniform outcome measure and also determined whether or not women had reached the natural menopause according to the number of retrieved oocytes at first IVF treatment. It is important to emphasize that our measure of disease occurrence is actually a prevalence measure instead of an incidence measure. Odds ratios, two-sided P-values, and 95% confidence intervals (CIs) were calculated with a normal response at first IVF treatment as the reference category. In a multivariate multinomial logistic regression model, it was determined whether or not it was necessary to adjust for potential confounders, such as the womans age at time of filling out the questionnaire (continuous), the age at which the first IVF treatment took place (3 years age groups), calendar year of IVF treatment (continuous), subfertility diagnosis (four categories), live birth after IVF (yes/no), smoking habits (yes/no and one category containing unknown smoking status), the number of IVF cycles per woman (continuous) and the number of ampoules of HMG/FSH used for ovarian stimulation during the first IVF attempt (four categories). Potential confounders were evaluated by adding each confounder separately into the logistic model. If this resulted in a >10% change in the odds ratio (compared with the crude odds ratio), the confounder was included in the final multinomial logistic model (Rothman and Greenland, 1998).
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Results |
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The menopausal transition group was divided into the following four tentative subgroups: (a) 209 (5%) were classified in the early menopausal transition group; (b) 182 (4%) in the middle menopausal transition group; (c) 40 (1%) in the late menopausal transition; and (d) 116 (3%) women were categorized into the HRT subgroup. Apparently, few women had entered the late menopausal transition group or had reached natural menopause. Figure 2 presents the menstrual cycle characteristics at the end of follow-up according to type of oocyte response at first IVF treatment.
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Discussion |
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We also found that smokers at the time of the first oocyte retrieval were more likely to have entered the menopausal transition or to have reached natural menopause. These findings are in line with the literature, which consistently shows that smoking decreases menopausal age (Jick and Porter, 1977; McKinlay et al., 1992
; Torgerson et al., 1994
; van Noord et al., 1997
; Harlow and Signorello, 2000
). In addition, women with a(n) (anticipated) poor response during their first IVF attempt were more often smokers than women with a normal response. This observation is in line with studies which showed that cigarette smoke components might influence oocyte quantity and quality directly or indirectly (Zenzes et al., 1995
; Zenzes, 2000
).
Defining the menopausal status of women is a difficult task for researchers and depends greatly on the source and completeness of the data. Many definitions of the menopausal status are based upon the work of Treloar (1981) and Vollman (1977
). Terms such as premenopause, perimenopause, climacteric, menopause and menopausal transition are often used in different ways and regularly create confusion. The World Health Organization (WHO Scientific Group, 1996
) recommended the use of the terms premenopause, perimenopause and the menopausal transition. According to the WHO, the menopausal transition is the time before the final menstrual period when variability in the menstrual cycle is usually increased. However, this definition remains vague since variability was not defined.
The criterion of variability or predictability is used in many studies defining menopausal status (Cooper and Baird, 1995; McKinlay, 1996
; Harlow et al., 2000b
; Mitchell et al., 2000
; Gold et al., 2001
). Except for the study of Mitchell et al. (2000
) and the STRAW workshop (Soules et al., 2001
), most of these studies lack any specific description of these terms.
Brambilla et al. (1994) and Dudley et al. (1998
) suggested that difficulties in predicting the next menstrual cycle could be one of the early signs of approaching menopause. Furthermore, in several studies, the occurrence of amenorrhoea for 311 months is used as a criterion for the menopausal transition or late perimenopause (McKinlay et al., 1992
; Brambilla et al., 1994
; Guthrie et al., 1996
; Dennerstein et al., 1997
; Dudley et al., 1998
; Harlow et al., 2000b
; Gold et al., 2001
). In addition to the predictability of the next menstrual cycle and the mean cycle length, all participating women in the OMEGA-project were asked to report whether they used HRT. Since HRT in The Netherlands is nearly always prescribed to treat menopausal complaints, and not just to prevent osteoporosis during premenopause, we decided to include these women in the menopausal transition group. Since no questions were included in the questionnaire about the reasons for OC use, we were not able to distinguish women who used OCs for treating menopausal complaints. Therefore, women who used OCs 1 year prior the completion of the questionnaire (n = 978) and those with missing data on OC use (n = 181) were excluded from the analyses. To investigate the possibility of selection bias, we analysed the distribution of the oocyte response at first IVF treatment in these excluded women. Of all the excluded women due to reasons of OC use (n = 1159), 78% had more than three oocytes at their first oocyte retrieval (normal response), 16% had a poor response (three or fewer oocytes) and in 5% the first IVF treatment was cancelled due to anticipated poor response. The percentages of (a)n (anticipated) poor and normal response are similar to those observed for the eligible women in our study, rendering selection bias unlikely.
One hundred and fifty-six (3%) women were categorized into the so-called other group (i.e. menstrual cycle characteristics unknown). Women who had a poor response or anticipated poor response were more likely to have entered this group. We cannot exclude the possibility that the women in this subgroup who reported their menstrual cycle as unknown or did not report their menstrual cycle at all might actually have reached the menopausal transition or the natural menopause. Any resulting bias is likely to be small due to the small proportion of women concerned.
For the present study, we only selected cohort members who had a regular menstrual cycle at the time of the first visit to the gynaecologist. Since our main interest was to study the womens reproductive ageing from cycle regularity to irregularity, in relation to the number of retrieved oocytes at the first IVF attempt, we excluded women who had an irregular menstrual cycle at the first visit to the gynaecologist. Furthermore, we used both the mean menstrual cycle length and the predictability to define the regularity of the menstrual cycle at the time of the first visit to the gynaecologist. We did so to avoid possible misclassification, assuming that the reported mean menstrual cycle length would be less reliable if women were not able to predict their next menstrual cycle.
According to our results, the association between oocyte response and risk of entering the menopausal transition after a median follow-up of 5.5 years was stronger for the later stages of the menopausal transition and for the natural menopause. While poor responders at first IVF treatment had a 15-fold increased risk of natural menopause, their risk of entering the early menopausal menopausal transition was only 2-fold increased. When we considered women in the early menopausal transition as premenopausal, the age-adjusted odds ratios for having entered the menopausal transition/natural menopause for poor and anticipated poor responders increased to 3.9 (95% CI 3.05.1) and 4.3 (95% CI 3.16.1) respectively, as compared with normal responders at their first IVF treatment. Misclassification of menopausal transition according to the current menstrual cycle pattern is less likely to have occurred for women who were categorized into the middle and late menopausal transition. Many aspects of the female reproductive ageing process are not well understood, and it remains difficult to design a classification system which is adequate and widely applicable. It is indeed not certain whether less predictability of the menstrual pattern is the first sign of the menopausal transition, as we assumed in the definition of early menopausal transition.
By comparing only the number of retrieved oocytes at first IVF treatment, and not at subsequent IVF attempts, most of the effects of previous ovarian stimulation and adaptation of stimulation regimens based on previous response experiences were avoided. However, in The Netherlands, stimulation regimes for IVF treatment have changed over the past years and women might, before they underwent IVF treatment, already have received gonadotrophin stimulation followed by intrauterine insemination, after which the stimulation protocols for IVF treatment might have been adapted. Therefore, we added the number of ampoules of HMG/FSH used during IVF treatment and year of IVF treatment as possible confounders in the multinomial logistic regression analyses. Both possible confounders did not change our risk estimates by more than 10% and were therefore not included in the final multinomial logistic regression analysis.
When interpreting our results, the strengths and limitations of the study design need to be considered. For 3227 IVF-treated women (Figure 1) participating in the OMEGA-project who returned the questionnaire, data from the medical files could not yet be obtained. Since this was due to limited project funding resulting in a random sample of records not yet completed, it is highly unlikely that this has led to selection bias. With respect to selection bias due to non-response to the mailed questionnaire, the following information is useful. From an anonymous sample of the non-responding women (n = 1672), we abstracted data from the medical files. Of the non-responding women to the OMEGA questionnaire, 72% had a normal oocyte response at their first IVF attempt, 19% had a poor response and 9% had an anticipated poor response. The percentages of (anticipated) poor responders among the non-responding women are somewhat higher than those found in the present study. These results suggest that women with a low response or an anticipated poor response at their first IVF attempt (and therefore a lower probability of having a live birth) were less inclined to participate. However, non-response bias could only have occurred if non-responding women who had a(n) (anticipated) poor response would also have entered the menopausal transition more or less frequently than responding women. We investigated this in a group of 213 women who initially did not respond to the OMEGA questionnaire, but who eventually did respond after a phone call. In this group of women, the percentages across oocyte response categories (75% normal response, 16% poor response and 10% anticipated poor response) were very similar to those of women who persisted in non-response also after a telephone call. Reassuringly, the age-adjusted odds ratios for reaching the menopausal transition/natural menopause were comparable with those for the total group of responders, 1.8 (95% CI 0.65.0) for a poor oocyte response and 2.9 (95% CI 0.99.0) for anticipated poor response. This finding renders selection bias unlikely.
Furthermore, since in the OMEGA questionnaire information on menstrual cycle characteristics was collected retrospectively, women might have been misclassified according to their menstrual cycle pattern. However, we would expect the proportion of misclassified women to be the same among those with a normal response and a(n) (anticipated) poor response. This so-called non-differential bias would have attenuated the observed risk estimates.
In conclusion, our results indicate that women with a low number of retrieved oocytes at first IVF treatment have an increased risk of reaching the menopausal transition or natural menopause in the decade after the first IVF treatment.
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Acknowledgements |
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FOOTNOTES |
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References |
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Submitted on May 23, 2002; resubmitted on February 17, 2003; accepted on March 19, 2003.