Selection Bias in Determining the Age Dependence of Waiting Time to Pregnancy

Tina Kold Jensen1, Thomas Scheike2, Niels Keiding2, Inger Schaumburg3 and Philippe Grandjean1

1 Department of Environmental Medicine, Institute of Public Health, University of Southern Denmark, Odense, Denmark.
2 Department of Biostatistics, University of Copenhagen, Copenhagen, Denmark.
3 Department of Occupational and Environmental Medicine, Skive Hospital, Skive, Denmark.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Many studies have found decreased fecundability, that is, the ability to conceive in a menstrual cycle, with increasing female age. To evaluate the effect of maternal age on waiting time to pregnancy, the authors reviewed hospital charts of all pregnant women attending prophylactic antenatal care at Odense University Hospital, Denmark, during 1972–1987. Only the first pregnancy of each woman and only planned pregnancies were included (n = 14,754). The fecundability odds ratio (FR) was calculated as the odds of a conception in a menstrual cycle among the older women divided by the odds among women aged 15–24 years. The FR for women aged 25–29 years was 1.12 (95% confidence interval (CI): 1.04, 1.20), for women aged 30–34 years it was 1.15 (95% CI: 1.01, 1.30), and for women above 34 years the FR was 2.44 (95% CI: 1.84, 3.22) after adjustment for confounders. The increased fecundability with age is contrary to previous studies and may be explained by selection bias, as sterile women were not included. In addition, some very fertile young women who became pregnant by accident before efficient birth control methods were available and therefore were excluded from time to pregnancy studies may now use oral contraceptives until they plan a pregnancy later in life and are included. Am J Epidemiol 2000;152:565–72.

age factors; fertility; infertility; time factors

Abbreviations: CI, confidence interval; FR, fecundability odds ratio.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Fecundability is defined as the biologic ability of a couple to conceive in a menstrual cycle. If pregnancies are planned and the couples use safe contraceptive methods until a well-defined point in time, fecundability can be determined as the time to pregnancy, that is, the number of months or cycles it takes a sexually active couple to conceive from the time of discontinuation of birth control. Time to pregnancy may be easily determined by self-administered standardized questionnaires or by interview. Recall times up to several years have been considered reliable on a population level (1GoGo–3Go). However, sterility is not considered in retrospective time to pregnancy surveys, as only women who achieved a pregnancy are included. In addition, only couples with planned pregnancies are included, as no waiting time can be determined if the pregnancy occurred by accident.

The effect of age on fecundability is of great relevance in societies where pregnancies are carefully planned or postponed for reasons such as education and employment. If the risk of subfertility (usually defined as time to pregnancy above 1 year) increases with age, this should be considered when deciding upon fertility treatment or deferral of childbearing. Historical studies (4Go, 5Go) indicate an age-related decrease in birth rates (fertility) with age. Similar data may be obtained from developing countries (6Go, 7Go) where fertility has been reported to decline among married women not practicing contraception. Thus, compared with the fecundability of Hutterite women aged 20–24 years, a decrease by 6 percent was observed for women aged 25–29 years, by 14 percent for women aged 30–34 years, and by 31 percent for women aged 35–39 years (8Go). Other studies (9GoGoGoGoGoGoGoGoGoGoGoGo–21Go) have also reported a decreased fecundability and/or increased risk of subfertility with increasing age of the woman. However, some retrospective studies failed to show an effect of age (22GoGo–24Go). An apparent age-associated decrease in fecundability could be affected by selection bias, as some women who become pregnant at a later age may represent a less fertile subgroup that failed to become pregnant earlier. Some studies refer to the age at conception (17Go, 21Go), although the age at the start of the conception attempt would be more appropriate. Several studies (15GoGoGoGoGo–20Go) have not considered this issue and failed to indicate the time at which age was determined.

Opportunities to examine associations between age and fecundability are rare because of the lack of appropriate cohorts of women. We studied the effect of maternal age on fecundability in a population-based sample of 14,754 pregnant Danish women attending a large maternity clinic during 1972–1987 (25Go).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
At the Department of Gynecology and Obstetrics at Odense University Hospital, Denmark, records were kept of all pregnant women who attended prophylactic antenatal care between 1972 and 1987. The county of Funen is served by the University Hospital and six smaller community hospitals. The primary catchment area of the University Hospital varied slightly during this period, and all women could in principle give birth at the hospital of their choice. Records from women residing in the Odense municipality and adjacent municipalities were entered into a data file (n = 40,666). Seventy-four percent of the women lived in the municipality of Odense (26Go).

Some women had more than one pregnancy during the study period. These observations cannot be considered independent, so only the first pregnancy recorded for each woman during the observation period was included in the present analyses (n = 28,629) (figure 1).



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FIGURE 1. Selection of the study population for time to pregnancy (TTP) analyses, Odense, Denmark, 1972–1987.

 

Questionnaires and interviewers
At the first routine antenatal examination (at the 20th week of gestation), reproductive, medical, educational, occupational, and lifestyle histories were recorded by a medical secretary. All data were part of routinely collected information. The medical secretaries were salaried staff at the hospital clinic. They interviewed the pregnant women and recorded the information on preprinted records. One of the preprinted questions was the following: "From the time you wanted a pregnancy until it occurred how much time passed?" Answers were recorded in months. The covariates obtained by interview and their categorization are shown in table 1. Five medical secretaries were long-term employees at the hospital clinic, and they filled in 15,711 of the 28,629 forms (54.9 percent) (figure 1). Each secretary was trained in asking the questions and coding the answers. Information on the time to pregnancy was missing from 2.0 percent of all the forms filled in by these five medical secretaries. Among the other medical secretaries, some of whom had been working only briefly with antenatal care, the information on time to pregnancy was missing from 14.5 percent of the records. Over the study period, their percentage of missing answers increased, and their coding of answers was therefore considered less reliable. As the major risk factors (table 2) were equally distributed among the two groups of medical secretaries, the 15,711 forms filled in by the five main medical secretaries (figure 1) represent the study population examined in the present study. One of the main medical secretaries had coded 4,041 records during 1977–1987, and analyses were repeated by including only forms filled in by her.


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TABLE 1. Covariates assessed by interview at the first antenatal examination, Odense University Hospital, Denmark, 1972–1987

 

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TABLE 2. Characteristics of the study population in relation to time to pregnancy (TTP), including the adjusted fecundability odds ratio and the odds ratio for subfecundity, Odense University Hospital, Denmark, 1972–1987*

 
Pregnancies reported as a result of contraceptive failure or with no information on time to pregnancy were excluded, thus leaving 14,754 (93.9 percent) of the pregnancies for the final analyses (figure 1). Some couples may have changed their attitude toward the pregnancy and have reported it as planned even though it occurred as a result of birth control failure. Attempts to minimize this potential bias were made by repeating the analyses after exclusion of women who became pregnant during the first cycle.

Statistical analyses
We censored time to pregnancy after 12 months, which is normally the time at which infertility treatment is started. Age was classified as 15–24, 25–29, 30–34, and above 34 years. In addition, a continuous age variable was examined, and mothers under the age of 22 years were compared with older mothers in 2-year age intervals.

Potential confounders were examined in bivariate analyses by comparing couples achieving pregnancy within 12 months with those who took longer (subfertile). Multivariate logistic regression models were then fitted to the data to assess the effect of risk factors on fecundability in the presence of covariates. Two approaches were taken. First, the length of time to conception was treated as a dichotomous variable with 12 months as the cut-off point, using multiple logistic regression and calculating the odds ratio for subfertility (time to pregnancy above 12 months). The second approach was to analyze by survival analysis techniques equivalent to logistic regression with the total number of observed cycles with the outcome pregnant/not pregnant (27Go). Fecundability denotes the probability of obtaining a clinically recognized pregnancy in a menstrual cycle among couples not pregnant in previous cycles. The fecundability odds ratio (FR) measures the odds of a conception among the older group of women divided by the odds among the young group of women. An initial logistic regression model was run with the covariates associated with delayed conception in the bivariate analyses, including the identity of the recording medical secretary and the municipality. If a variable was missing, the case or the cycle was excluded from the analyses. The FR and odds ratio are presented with 95 percent confidence intervals.

The women who became pregnant and gave birth before the end of 1987 represent a right truncated version of the true waiting-time distribution, as women with long waiting times starting to conceive in 1987 would not be represented in this study population. Similarly, the women entering the study in 1972 represent a left truncated version. As temporal trends may have occurred, we minimized this potential bias by repeating all analyses including only the period 1974–1985 and, as we censored time to pregnancy at 12 months, we thereby excluded women with long/short waiting times at both ends of the study period. Furthermore, we repeated the analyses using a newly developed model that takes into account this problem (27Go). As these approaches did not change the reported associations, we present the analyses of the larger number of pregnancies without taking into account the potential effect of calendar year.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Characteristics of the population are shown in table 2. The mean age of the women at the start of the conception attempt was 24.5 (standard deviation, 4.2) years. Seventy-one percent were nulliparous, and 77.2 percent had no previous spontaneous or induced abortions.

The majority of the women in the study apparently conceived very quickly: 42.4 percent conceived within the first month, 66.2 percent became pregnant in 3 months, 78.8 percent in 6 months, and 88.6 percent within 1 year. The mean time to pregnancy was 2.3 months.

The ages of the mother and father at the start of their conception attempt were closely correlated, and no independent effect of paternal age was detected. Older women had a higher parity and body mass index, and they were more often employed in management and less often in industry. A recent history of irregular menstruation and long cycles more often occurred in younger women.

Multivariate models were used to calculate the association between age and fecundability (FR) and the odds of subfertility (odds ratio) while controlling for potentially confounding variables (i.e., paternal age, body mass index, use of oral contraceptives as the most recent method of birth control, smoking status, parity, previous induced or spontaneous abortions, occupation of both parents, municipality of residence, duration and regularity of the menstrual cycle, the cycle at which the woman became pregnant, and the identity of the recording medical secretary). As iterations to adjust for time trends did not change the associations already seen, we excluded calendar year in the final models.

After adjustment and using women aged 15–24 years as the comparison group, we found that the FR for women aged 25–29 years was 1.12 (95 percent confidence interval (CI): 1.04, 1.20); for women aged 30–34 years, 1.15 (95 percent CI: 1.01, 1.30); and for women above 34 years, 2.44 (95 percent CI: 1.84, 3.22). Moreover, the estimated odds ratio of failure to conceive within 1 year decreased with age (table 2). While the effect of parity was controlled for in these calculations, additional analyses for nulliparous and multiparous women were performed separately (table 3). Among both nulliparous and multiparous women, the increase in fecundability occurred gradually from the age of 22 and onward (test for trend: nulliparous women, p = 0.0005; multiparous women, p = 0.0001). When age was included as a continuous variable, the FR increased by 0.03 (95 percent CI: 1.02, 1.04) when age increased by 1 year (female age was nearly normally distributed because of the way the database was selected; see Discussion).


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TABLE 3. Fecundability odds ratio (FR) among women in different age categories with different parity after control for the age of the father, the cycle at which the women became pregnant, occupation of both parents, municipality, number of previous spontaneous or induced abortions, body mass index before pregnancy, duration and regularity of menstrual cycle, smoking status of the women during pregnancy, use of oral contraceptives as last method of birth control, and the recording secretary, Odense University Hospital, Denmark, 1972–1987

 
The records filled in by the most experienced medical secretary alone confirmed the association between female age and fecundability (FR (25–29 years) = 1.23, 95 percent CI: 0.97, 1.56; FR (30–34 years) = 1.06, 95 percent CI: 0.69, 1.64; FR (>34 years) = 2.05, 95 percent CI: 0.59, 7.15). Repeating all analyses by including only the period 1974–1985 to avoid truncation bias did not change the effect of female age and neither did exclusion of pregnancies occurring during the first month (FR (25–29 years) = 1.12, 95 percent CI: 1.01, 1.23; FR (30–34 years) = 1.09, 95 percent CI: 0.92, 1.29; FR (>34 years) = 1.61, 95 percent CI: 1.04, 2.27).


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Increasing maternal age at the beginning of the conception attempt was associated with a higher fecundability and a lower relative risk of failure to conceive within 1 year (subfertility) among both nulliparous and multiparous women. The fecundability odds ratio was more than doubled in women above 34 years compared with women aged 15–24 years. This surprising outcome must be considered in the light of possible bias.

In retrospective studies, such as this, sterile couples are not included. If the proportion of couples with sterility increases with age without a concomitant increase in time to pregnancy, an age effect on fecundability will not be detected. If a fraction of the women were subfertile until their middle thirties when they became sterile, this could explain our findings that older women who did achieve pregnancy appeared more fertile than younger women who achieved pregnancy. These issues cannot be settled with the design used in the present study.

Exclusion of pregnancies reported as unplanned may also be a source of bias. The more fertile couples are more likely to have birth control failures or accidental pregnancies, and consequently they are more likely to be excluded from the study. If younger women more frequently chose varying or less effective methods of birth control, their fecundability would be underestimated. However, by looking at the women who reported that their pregnancy was unplanned (4.2 percent) or who reported a waiting time of 0 months (39.8 percent), the magnitude of this bias can be ruled out. The percentages of unplanned pregnancies increased with increasing age of the mother, which does not explain the effect of age. Some very fertile young women who became pregnant by accident before efficient birth control methods were available and who therefore were excluded from time to pregnancy studies may now use oral contraceptives until they plan a pregnancy in their thirties when they appear in time to pregnancy studies with a short waiting time, thereby explaining the effect of age found in this study.

Some couples may have changed their attitude to the pregnancy and reported it as planned even though it occurred as a result of a birth control failure. In this regard, it is notable that the proportion of women conceiving during the first month was higher than in previously published retrospective studies (16, 23, 24, 28–33). Bias would result if this tendency were different among younger and older women, which it was not. In addition, the magnitude of this bias was reduced by repeating the analyses after exclusion of women who became pregnant during the first month.

Medical treatment of subfertility may have improved during the study period from 1972 to 1987, thereby reducing the waiting time for some couples or introducing a sample of subfertile couples who would have been considered sterile before the treatment was introduced. If older women started treatment before younger women, this could cause a treatment-induced reduction of their time to pregnancy compared with younger women. Moreover, if younger women had a higher success rate of treatment, they would appear in this analysis with very long time to pregnancy values, whereas the older women would not appear at all. However, the magnitude of this potential bias was reduced by censoring the time to pregnancy at 1 year when fertility treatment is usually introduced.

Apart from these general bias problems in retrospectively collected time to pregnancy data, our study had significant strengths compared with previously published studies. It was a large, well-defined, population-based study comprising a wide socioeconomic and age range with time to pregnancy being ascertained in early pregnancy. In addition, the statistical model used was highly sensitive, as the per cycle probability of conception was calculated rather than dichotomizing the women into only two classes. However, there are several potential limitations in the study design.

We included only the first pregnancy recorded in the database for each woman during the study period. That is much more likely to be the first pregnancy of that woman at the end of the study period and more likely to occur in a younger woman. Therefore only 230 women over 34 years were included in the database. However, the decrease in time to pregnancy appeared already from the age of 23 years, and choosing a random sample of women in the database showed a similar decrease in time to pregnancy with age. One potential source of bias was the inclusion of all women from different municipalities who gave birth at Odense University Hospital. A selection bias could be introduced if women living in municipalities outside Odense had chosen to give birth in Odense because they had high-risk pregnancies. Thus, women living outside Odense and giving birth in Odense had a longer time to pregnancy and were older. However, analyses that were based on women living only within the municipality of Odense or that included the municipality as a dummy variable in the multiple regression analysis showed the same associations between female age and fecundability.

An additional limitation of our study was the lack of information on several potential confounders, as data were antecedent. Study subjects were not asked about their frequency or timing of intercourse or about the use of contraception apart from oral contraceptives. Some couples may have used other birth control methods from the termination of oral contraceptive use until the conception attempt. However, a longer time to pregnancy among former users of oral contraceptives was found with the effect diminishing after 3 months, which is in accordance with previously published studies (16Go, 23Go). In addition, the bias is relevant only if the tendency to use other birth control methods for a period after oral contraceptive termination differed between older and younger women. If the frequency of intercourse is related to age, it is most likely to decrease with increasing age, thereby reducing fecundability among older couples. Furthermore, no information on female caffeine and alcohol intake, as well as male lifestyle factors, was available. Previously published results on the effect of these factors have, however, not shown any clear patterns (17Go, 18Go, 24Go, 30Go, 34GoGo–36Go).

Overall, among the potential biases mentioned, the major reason for the surprising age-related increase in fecundability is the fact that the population included only women who had achieved a pregnancy. Thus, this finding is probably caused by selection bias, as the frequency of sterile women may increase with age. These considerations are highly relevant when analyzing the associations of fecundability with age, and these sources of bias need to be taken into consideration when interpreting retrospectively collected time to pregnancy data in general.


    ACKNOWLEDGMENTS
 
This study was supported by a grant from the Danish Medical Research Council and the Danish Medical Health Insurance Foundation.

The authors are indebted to Dr. Jes Westergaard and his staff at the Department of Gynecology and Obstetrics, Odense University Hospital. Vajna Berntsen, Pernille Kjærsgaard, and Axel Skythe skillfully handled the data entry.


    NOTES
 
Reprint requests to Dr. Tina Kold Jensen, Department of Public Health, Imperial College of Medicine at St. Mary's, Norfolk Place, London W2 1PG, United Kingdom (e-mail: t.koldjensen{at}ic.ac.uk


    REFERENCES
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 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication September 18, 1998. Accepted for publication November 22, 1999.