Effect of female age on the diagnostic categories of infertility
Assisted Reproduction Unit, Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK
1 Correspondence address. Tel: +44-1224-553582; Fax: +44-1224-551072; E-mail: abha.maheshwari{at}abdn.ac.uk
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Abstract |
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BACKGROUND: As more women choose to delay childbearing, increasing numbers of them face age-related fertility problems. We aimed to explore the association between age and diagnosed causes of female infertility.
METHODS: Anonymized data (age of male and female partner, year of first visit, diagnosis, duration and type of infertility) were obtained on all couples attending Aberdeen Fertility Centre from 1993–2006. The prevalence of different causes of infertility was determined for women <35 and 
35 years of age at the time of their first clinic visit. Binary logistic regression and multinomial regression were used to determine the association between age and diagnostic categories of infertility.
RESULTS: Of a total of 7172 women, 26.9% were over the age of 35 years and 51.4% of the total had primary infertility. The mean female age was 31.2 (5.2 SD) years. There was an association between female age and the cause of female infertility (likelihood ratio, P < 0.001). More women over 35 had unexplained infertility (26.6 versus 21.0%, P < 0.001). Compared with women under 30 years, the adjusted odds ratio (95% confidence intervals, CI) of the following diagnoses in women over 35 were: unexplained infertility = 1.8 (1.4–2.2), ovulatory dysfunction = 0.3 (0.3–0.4) and tubal factor = 2.2 (1.7–2.7).
CONCLUSIONS: The causes of infertility in older women are different from those in younger women. Women over 35 years of age are nearly twice as likely to present with unexplained infertility.
Key words: infertility/diagnosis/advanced reproductive age/unexplained infertility/ovarian ageing
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Introduction |
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The purpose of a diagnostic fertility workup is to establish the cause, offer a prognosis and plan further treatment. Basic investigations include tests for ovulation, semen analysis and tubal patency. Previous epidemiological studies have shown that in a subfertile population, 25–35% couples have male factor infertility, 14–22% have tubal factor, 10–27% have ovulatory dysfunction, 10–17% have unexplained infertility and 5–6% have endometriosis (Hull et al., 1985
; Templeton et al., 1990; Collins, 1997).
Female age is the single most important determinant of spontaneous as well as treatment-related conception, with a gradual decline in fertility especially after the age of 35 years (Menken et al., 1986; Templeton et al., 1996). Demographic studies have shown that more women are delaying childbearing at the present time than previously (Botting Dunnell, 2003). This trend is expected to cause a corresponding rise in the mean age at which women first present with infertility. It is unclear as to whether women who present to fertility clinics at an older age have a different diagnostic profile from that in younger women. In particular, it has been suggested that older women may be more likely to be diagnosed with unexplained infertility and that this is due to the negative effect of age on ovarian reserve (Gleicher and Barad, 2006).
Miller et al. (1999) found a lower prevalence of ovulatory dysfunction but a trend towards an increased risk of unexplained infertility in older women (age = 40–45 years) versus younger women (age = 20–29 years). Their results were based on small numbers (n = 217) from a tertiary care centre and were not representative of a general subfertile population. There is a lack of large population-based studies on potential differences in diagnostic categories of infertility in women of different age groups. With more women planning to have children later in life, this information is critical in terms of planning investigations, offering a prognosis and developing a management plan.
While there is no universally accepted definition of advanced reproductive age, 35 years is considered as a watershed in fertility terms (American Society of Reproductive Medicine, 2006a). Similar considerations have informed the National Institute of Clinical Excellence (NICE, 2004) recommendations that women over 35 years of age should be referred early from primary care for investigations and treatment.
In this study, we aimed to use population-based data from women from a defined geographical region attending a single fertility clinic in order to: (i) investigate trends in the age of female partner at first attendance to a secondary care referral unit over a period of 14 years; (ii) compare the causes of infertility in older (35 years) versus younger women (<35 years); (iii) assess the influence of the female age on the diagnostic categories of infertility and (iv) explore the most common diagnosis in older women.
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Materials and Methods |
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This study is based on data collected from a secondary referral centre in a geographically defined stable population. The Aberdeen Fertility Centre (AFC) is unique in that it caters to all infertile couples in Grampian, a region in Scotland which does not possess any other National Health Service or private fertility clinics. Investigations and management of all the patients seen in the AFC are performed according to a standard protocol. Women are referred to this clinic by general practitioners after at least 1 year of regular unprotected intercourse (definition of infertility, NICE, 2004
). Ovulation is diagnosed by timed mid-luteal serum progesterone (calculated according to the shortest and longest length of cycle). Progesterone tracking is done if required. Semen analysis is reported as per World Health Organization (WHO, 1992) guidance. Tubal patency is checked by either hysterosalpingography (HSG) or diagnostic laparoscopy and dye test. If HSG is inconclusive, laparoscopy is performed. Endometriosis is diagnosed by laparoscopy according to the revised American Fertility Society scoring. Women with minimal and mild endometriosis are categorized as endometriosis. Unexplained infertility was diagnosed if there was evidence of (i) ovulation, (ii) patency of tubes and (iii) adequate sperm production (American Society of Reproductive Medicine, 2006b). These definitions were consistent across the board and were uniform throughout the 14 years. Clinical data are collected on standardized history sheets and entered contemporaneously onto a dedicated electronic database by a single data entry clerk. Periodic checks are performed for accuracy of data entry. For the purpose of this study, we analysed the data collected from 1 January 1993 to 31 December 2006 comprising clinical records on 7172 infertile couples where the female was aged between 20 and 50 years. This is a relational database where women rather than episodes are recorded. Each woman is given a unique code number on the databank. Repeat visits are clearly recoded. Each patient has been counted only once and this study is based on the data from the first visit only. The following variables were extracted for analysis: date of first visit, history of previous conception, duration of infertility, age of both partners and the causes of infertility.
Analysis
Extracted variables were analysed using the Statistical Package for Social Sciences (SPSS version 15 for Windows). Comparisons were made between women aged <35 years and 35 years at the time of their first clinic visit. Independent t-tests or Mann–Whitney tests were used to compare the two groups as appropriate. The chi-square test was used to compare the proportion of women in each diagnostic category between the two groups. Analysis was stratified by type of infertility (primary or secondary). Binary logistic regression was used to quantify the effect of female age on various diagnostic categories. Adjustment was made for confounders including the age of the male partner, diagnosis of male factor, duration and type (primary/secondary) of infertility. As data were collected over a 14 year period, we also adjusted for the year of first clinic visit in order to overcome the effect of change in practice over the time. Multinomial regression was done to identify the commonest diagnosis in older women. For the purpose of this study, we have concentrated on female causes of infertility, i.e. all diagnostic categories except for male factor infertility. A value of P < 0.05 was considered significant.
Power calculation
We hypothesized that women aged 35 years or more were more likely to have a diagnosis of unexplained infertility than women <35 years of age. Assuming the prevalence of unexplained infertility to be 20% in women under 35 years, we estimated that a total of 824 women (412 in each group) would provide 90% power at the 5% level of significance in terms of demonstrating a difference of 10% (20–30%) between the two groups in the proportion of women with a diagnosis of unexplained infertility.
An anonymized dataset was used for analysis. We wrote to the local research ethics committee (North of Scotland Research Ethics Committee) and were advised that a full ethical application was not required as the dataset used for this analysis was completely anonymous. Permission for data retrieval was obtained from the AFC Database Steering Committee.
Data
Records of 7172 couples were obtained from the AFC Database, all of which had year of first visit and age of the female partner. Cases where diagnosis was uncertain (n = 417) were excluded from analysis. Details of the numbers of cases available for analysis are shown in Tables I–IV. Presence of diagnosis was labelled in the database as 1, whereas absence was labelled as 0.
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Results |
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The mean age of the female partner at referral was 31.2 (5.2 SD) years and the mean male age was 33.8 (6.5 SD) years. Mean female age rose from 29.4 years (4.7 SD) in 1992 to 32.4 years (5.3 SD) in 2006 (P < 0.001). The mean age of the male partner also increased from 31.6 years (5.8 SD) in 1992 to 35.3 years (6.5 SD) in 2006 (P < 0.001).
The overall prevalence of the different causes of infertility was as follows: ovulatory dysfunction = 1374/6752 (20.3%), male factor infertility = 2315/6737 (34.4%), tubal factor infertility = 1316/6740 (19.5%), unexplained infertility = 1514/6745 (22.4%) and endometriosis = 277/6740 (4.1%). With the exception of male factor infertility, these diagnostic categories were mutually exclusive except in 174 women, who had more than one diagnosis (tubal, endometriosis and ovulatory). A total of 1717 couples (23.9%) had an exclusive diagnosis of male factor infertility.
Just over a quarter (26.9%, n = 1929) of women were over the age of 35 years at their first clinic visit and half of the total presented with primary infertility (51.4%). Demographic characteristics of older and younger women (<35 and 35 years) are shown in Table I. The median and lower quartile for the duration of infertility was the same in both groups; however, the upper quartile was different, indicating a more widespread duration of infertility in older women (Table I).
Ovulatory dysfunction
Fewer women over 35 had a diagnosis of ovulatory dysfunction as compared to their younger counterparts (11.4 versus 23.6%, P < 0.001) (Table II). This difference persisted even when the data were stratified by the type of infertility (primary versus secondary) (Table III). The adjusted odds [95% confidence interval (CI)] of a diagnosis of ovulatory dysfunction at 35–39 years were 0.3 (0.3–0.4) as compared to a woman under 30 (Table IV).
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Endometriosis
Overall younger women were more likely to have endometriosis than older women (4.5 versus 3.1%, respectively) (P = 0.01) (Table II). Stratifying by the type of infertility (primary and secondary) showed no difference in the proportion of women over and under 35 with a diagnosis of endometriosis (Table III). The adjusted odds (95% CI) of having a diagnosis of endometriosis at 35–39 years were 0.9 (0.6–1.5) as compared to a woman under 30 (Table IV).
Tubal factor
A higher proportion of older women had tubal factor as a primary diagnosis than older women (24.8 versus 17.6%, respectively) (P < 0.001) (Table II). When stratified by the type of infertility (primary versus secondary), increased incidence of tubal factor infertility was only present for women with secondary infertility (Table III). The adjusted odds (95% CI) of having a diagnosis of tubal factor at 35–39 years were 2.2 (1.7–2.7) as compared to a woman less than 30 (Table IV).
Unexplained infertility
Older women were more likely to have a diagnosis of unexplained infertility in comparison with those who were younger (26.6 versus 21.0%, respectively P < 0.001) (Table II). The difference persisted within the sub groups of primary and secondary infertility (Table III). The adjusted odds (95% CI) of having a diagnosis of unexplained infertility at 35–39 years were 1.8 (1.4–2.2) as compared to a woman <30 (Table IV).
Association between age and the diagnosis of infertility
Multinomial regression revealed an association between female age and diagnosis of female infertility (likelihood ratio test, P < 0.001). Older women (aged 35–39) were less likely to have ovulatory dysfunction and more likely to have unexplained and tubal factor infertility than women aged <30 years (Table V).
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Discussion |
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Male and female age of referral to a fertility clinic has increased over time. Women over 35 years are less likely to present with ovulatory dysfunction. The odds of being diagnosed with unexplained and tubal factor infertility are almost twice as high in women over 35 years of age in comparison with those under 30 years. The duration of infertility was more widespread in older women.
This study is based on a large dataset from a secondary care setting which caters to a stable population from a clearly defined geographical area, with few (<6%) missing data. As such, it is likely to be genuinely population based. Prevalence of the various causes of infertility in this population corresponds to previously reported clinic based data from the UK (Hull et al., 1985).
As a consequence of its retrospective nature, this study suffers from the usual limitations of relying on routinely collected data. Changes in clinical practice and diagnostic methods over time may also have introduced an element of bias. In an attempt to minimize this, we have adjusted for the year of first clinic attendance in our final analysis. Our clinic has standardized protocols both in terms of referrals by General Practitioners as well as investigations by all clinic doctors. Cases where tubal work up was omitted due to older age and a perceived need for early IVF are excluded from analysis as in the database they will be counted as missing values.
Miller et al. (1999) found that a diagnosis of ovulatory dysfunction was more common in younger age group, which is consistent with our findings. However, they could only show a trend towards an increased prevalence of unexplained infertility in older women. The present study, with a larger sample size is able to demonstrate a statistically significant association between age and unexplained as well as tubal factor infertility. In addition, we are able to stratify our analysis by the type (primary versus secondary) of infertility. Our initial power calculation (412 women in each category) was based on the assumption of detecting 10% difference in the prevalence of unexplained infertility in the two age groups. However, the actual difference was found as 6.6%. To detect a difference of 5% in the prevalence of unexplained infertility we need 1504 women in each group. Clearly our sample size is larger than this, which increases the authenticity of the findings. Moreover, the patients studied by Miller et al. (1999) were derived from a tertiary referral centre, whereas our data are more representative of a general population.
Hull et al. (1985) showed a reduction in conception rates after the age of 35 years. There are already existing recommendations (NICE, 2004; American Society for Reproductive Medicine, 2006a) that women over 35 should be classed as having advanced reproductive age and referred more promptly for early investigations and active treatment. Our data suggest that there is a reduction in the diagnosis of ovulatory dysfunction by one-third, but a two-fold rise in unexplained and tubal infertility beyond the age of 35 years. Although, the differences are more marked at the age of over 35 years, the increase in incidence of unexplained and tubal factor infertility is evident from the age of 30 years onwards, as is decreased incidence of ovulatory dysfunction. This might suggest that the artificial dividing line of 35 years could be revisited.
Even the most sophisticated diagnostic assessment cannot reveal all potential barriers to fertility (American Society for Reproductive Medicine, 2006b). Whether ‘unexplained infertility’ is genuinely unexplained (Gleicher and Barad, 2006) has been debated in the literature. Women with regular cycles and documented ovulation can experience reduced fertility (Faddy et al., 1992; te Velde and Pearson, 2002) and deterioration of oocyte quality with age. Approximately, 10% of women experience early menopause before the age of 45 years (van Noord et al., 1997). Assuming the hypothesis of fixed time interval of 13 years between decline in fertility and menopause (Faddy, 2000; Nikolaou and Templeton, 2003), these women will have subfertility due to ovarian ageing before 32 years and accelerated decline in fertility before 37 years. For lack of symptoms such women would be erroneously diagnosed as unexplained infertility (Nikolaou and Templeton, 2003, 2004).
Diminished ovarian reserve has been suggested as a putative cause of unexplained infertility. If this is indeed the case, it might be clinically helpful to distinguish women with true ‘unexplained infertility’ from those with ovarian senescence by means of more precise diagnostic tests. However, despite the plethora of tests in the literature, there does not, at present, appear to be an ideal test of ovarian reserve (Maheshwari et al., 2006). It is difficult to extrapolate from results of relevant published studies which are based on relatively young women (<38 years old) undergoing assisted reproduction treatment.
Other possible causes of unexplained infertility in older women can be higher body mass index (BMI) (BMI is known to be increased with age), decreased coital frequency and other lifestyle factors, such as smoking and stress (Homan et al., 2007). However, women can be counselled about these causes and with lifestyle modifications the situation can change, whereas we do not have any effective treatment, as yet, for diminished oocyte quality. Unexplained infertility and age of the woman at conception are both independent factors associated with poorer reproductive outcome (Hecht et al., 1996; Pandian et al., 2001; Tough et al., 2002).
A possible explanation for a higher incidence of ovulatory dysfunction in the younger women could be the fact that those with irregular cycles may present early for investigations and treatment. A larger proportion of older women, particularly those presenting with secondary infertility, have a diagnosis of tubal factor infertility. This could be due to the increased risk of acquiring pelvic infection with age (Bewley et al., 2005) or the effect of previous salphingectomy due to ectopic pregnancy. Earlier research has shown that previous terminations per se are not associated with impaired fertility in later life (Lurie et al., 1994; Debby et al., 2003).
A higher proportion of women in the older group had increased duration of infertility, which would be explained by the fact that women in this population with secondary infertility present later at the clinics.
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Conclusion |
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This study suggests that the prevalence of different causes of female infertility is associated with age. A diagnosis of unexplained and tubal factor infertility is commoner in women over 35 years of age. The increased incidence of tubal factor is more prevalent in women presenting with secondary infertility: this is more likely due to prior ectopic pregnancy. There is a need to distinguish older women with genuine unexplained infertility from those with age-related diminished ovarian reserve. In the absence of an efficient test of ovarian ageing, we should be aware that some women with declining ovarian function could present as unexplained infertility.
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Submitted on August 24, 2007; resubmitted on December 6, 2007; accepted on December 14, 2007.
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