Fertility patterns after appendicectomy: historical cohort study

Participants

We identified all women in the Swedish Hospital Inpatient Registry who underwent appendicectomy before the age of 15 years between 1964 and 1983. The inpatient registry contains information on date and type of each operation and the discharge diagnosis for patients treated in somatic care wards in Swedish hospitals.

On the basis of the discharge diagnosis the patients were divided into three groups: non-perforated appendix, perforated appendix, and normal appendix at exploration. Patients with a diagnosis indicating another disease that needed surgical treatment were excluded as these operations were necessary explorations. Patients with a gynaecological condition at operation were also excluded as these diseases could affect fertility.

The study included 9840 women who had been operated on before they were 15 years old and who were aged 15 years at the start of follow up and were nulliparous (22 patients were excluded because they had died, emigrated, or given birth after the operation but before the age of 15). The discharge diagnosis was appendicitis in 6714 patients (899 (13%) with perforated appendix and 5815 without), while 3126 patients (32%) had a normal appendix removed.

For each patient we selected five controls at random from the women in the Swedish Fertility Registry who had the same birth date as the patients. This nationwide registry provides fertility data for all women who were Swedish citizens in 1960 or who were born in Sweden since 1960. Information regarding the date of all live births and the date of emigration or death was obtained for the patients and the controls. The latest update of the registry for the purpose of this study was 31 December 1995.

For technical reasons the 49 200 randomly selected controls were matched on the birth date whereas the patients were eligible first at age 15. Between birth and age 15 some control women had emigrated (n=625), died (n=979), or given birth (n=6). These 1610 women were excluded. Thus the final analysis included 9840 cases and 47 590 controls.

All women were followed from 15 years old until date of first birth. Nulliparous women were censored at date of emigration or death or at the latest update of the registry. The childbearing pattern of the women was also assessed from the distribution of parity at the date of emigration or death or at the latest update of the registry.

Statistical methods

The dependent variable considered in most analyses was age at first birth. We analysed this variable by survival methods because of the varying length of follow up. Simple comparisons between groups were performed on the basis of survival curves computed by the Kaplan-Meier method. These curves describe the cumulative proportion of primiparous women at each age, taking into account the varying length of follow up. Tests for the equality of such curves were carried out by the log rank test. Age specific rates of first birth were calculated by using the life table approach.

Cox proportional hazards regression models were used to compare the average age specific rates of first birth in different groups of women. In the multivariate models the hazard ratio was adjusted for any differences in the distribution of the covariates between the groups of women. The matching variable of birth date was included explicitly as an explanatory variable in these analyses. The results are given as hazard ratios (95% confidence intervals). A ratio larger than 1 implies a larger probability of an early first birth than in the reference group.

The standard Cox model assumes proportional hazards at all ages for the treated groups or in the present case the same ratios of rate of first birth at all ages compared with the reference group. Inspection of the curves of the age specific rates of first birth showed that this assumption was not fulfilled. Therefore we also obtained estimates in three different age intervals that allowed different relative birth rates among treated groups.

Because of the long study period we also analysed the influence of year of operation. Separate analysis were performed for operations that had been performed in 1964-8, 1969-73, 1974-8, and 1979-84 with adjustment for year of birth. Age at operation was deliberately omitted from these analysis because with data covering short periods there will be a strong correlation between year of birth and age at operation, which makes it unsuitable to include both variables in the same model.

Fig 1

Kaplan-Meier plot of cumulative proportion of parous women at each age for 9840 women who underwent appendicectomy before age 15 and 47 590 age matched controls

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The variable parity (number of children at latest registry update) is dependent on age (birth year) and length of follow up. Therefore formal testing of differences between groups was performed after adjustment for birth year (standard regression analysis for continuous variables and logistic regression for dichotomous variables). In these regressions we also adjusted for lost years of follow up because of emigration or death by the inclusion of the length of follow up in the models.

Age at first birth

Women with a history of perforated appendix in childhood and the control women had similar fertility, as shown from the Kaplan-Meier plots of the cumulative proportion of primiparous women (fig 1; log rank test P=0.20). Women who had had a normal appendix removed or had a non-perforated appendix tended to have their first child at an earlier age than control women (fig 1; log rank test P<0.001). The higher rate of the first birth in the women who had had a normal appendix removed was present only before the age of 25 years, as shown by the age specific rates of first birth (fig 2).

Fig 2

Age specific rates of first birth among women who underwent appendicectomy before age 15 and among age matched controls according to life table analysis. Figure shows average birth rate in a given 2 year age interval

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Multivariate analysis of fertility

The influence of the diagnosis at operation, the women's year of birth, and age at operation was analysed with univariate and multivariate Cox proportional hazards regression models (table 2). Women with perforated appendix had a similar fertility as the control women while women with a normal appendix or non-perforated appendix gave birth to their first child at a higher rate.

Differences in fertility at different ages of follow up

The ratio of the age specific rates of first birth of the women who underwent operation and the control women were not proportional at all ages (fig 2). We therefore also performed separate analyses for the age intervals 15-19, 20-24, and >=25 years at follow up (table 3). Relative to the control women, patients with a history of perforated appendix had a (non-significant) lower birth rate at 15-19 years and at 20-24 years but not at age >=25 years.

In the younger age groups women who had had a normal appendix removed gave birth to their first child at a higher rate compared with control women. From age 25 there was no difference between cases and controls. Patients with non-perforated appendix also had an increased birth rate until the age of 25 years and no difference thereafter. As expected, women belonging to younger birth cohorts had a lower rate of first births (tables 2 and 4). Age at operation had no influence on the rate of first birth (tables 2 and 3).

Influence on fertility of year of operation

The analysis based on year of operation produced stable results (table 4). The hazard ratios associated with perforated appendix were close to 1 in all periods and not significantly differently different from 1. Results for other groups were also quite similar over time. The slightly higher hazard ratio in the most recent period for women who had had a normal appendix removed may partly be due to the shorter follow up for these patients.

Number of children at end of follow up

The mean parity at the latest update of the fertility registry was higher in women with normal appendix or non-perforated appendix compared with the controls (1.61 and 1.36 v 1.27; P<0.001). Women with perforated appendix had a similar number of children as the control women (1.21 v 1.27; P=0.38).

The similar fertility among women with a history of perforated appendix and the control women is also shown from the similar proportions of childless women (38.5% v36.4%; P=0.48) and of women with three or more births (13.6% v14.8%; P=0.63) (table 4). Compared with the controls, nulliparity was less common among women with a history of non-perforated appendix (33.8%) and removal of normal appendix (26.6 %), while multiparity (parity 3+) was more common (16.5%and 23.1%, respectively).