Long term effects of hysterectomy on mortality: nested cohort study

Introduction

Several new technologies may reduce the need for hysterectomy,1 yet the procedure remains common in many countries. For example, about 600 000 hysterectomies are carried out in the United States annually,2 with more than 25% of women having the operation by age 60.3 Although the number of hysterectomies carried out by the NHS in England and Scotland has fallen by 25% since 1998,4 5 around 47 500 women still had the procedure in 2002. Around 20% of women in the United Kingdom have a hysterectomy by age 55.6 Any long term effects of hysterectomy are therefore important, particularly on all cause mortality and on cardiovascular disease and cancer, the most common causes of death.

The only study to date to examine all cause mortality found no evidence of an association with hysterectomy. But the study may have misclassified hysterectomy status, and follow up was short (5.6 years).7

Studies of cardiovascular sequelae have produced conflicting evidence. One study found that hysterectomy with preservation of both ovaries was weakly associated with an increased risk of non-fatal myocardial infarction.8 Another study found that after hysterectomy with or without preservation of the ovaries, women had an increased 10 year risk of myocardial infarction or coronary death (according to the Framingham score) than women with an intact uterus and ovaries.9 Conversely, another study found no excess risk of myocardial infarction in premenopausal women after hysterectomy or after unilateral oophorectomy, although it did find an increased risk in post-menopausal women after hysterectomy with or without unilateral oophorectomy.10

Another study found an increased risk of non-genital (mainly rectal and thyroid) cancer among women after hysterectomy compared with those with an intact uterus, although the authors concluded that hysterectomy was not associated with a substantial effect on cancers in general.11 Several studies have found a reduced risk of ovarian cancer after hysterectomy without bilateral oophorectomy12 13 and a decreased risk of breast cancer after hysterectomy (with or without oophorectomy).14 15 Conversely, a study found that renal cell carcinoma was significantly more common among women who had had a hysterectomy compared with those who did not have the operation.16

Using data from the Royal College of General Practitioners' oral contraception study, we examined the long term risk of hysterectomy on mortality.

Methods

Results

One woman died from a Mullerian tumour more than 26 years after hysterectomy. We found no further information on the death certificate or in the oral contraception study's database to explain the anomaly. We excluded this woman and her matched non-exposed comparator from the cohort, leaving 7410 women for analysis.

Hysterectomy not elsewhere classified (code R696) was the most common type of hysterectomy recorded (2526 women, 68.2%). Both groups had similar characteristics at baseline (table 1). The median age of the cohort at time of operation was 43.7 years (interquartile range 38.9-48.1 years). The hysterectomy group had a significantly higher mean parity than that of the non-hysterectomy group (2.55 (SD 1.3) versus 2.47 (SD 1.3) births, P = 0.01).

Both groups were followed-up for a mean length of 250.3 (SD 87.1) months. By the end of follow-up, 623 (8.4%) women had died; 233 from cancer, 160 from cardiovascular disease, and 230 from other causes.

None of the Kaplan-Meier plots for survival from all cause mortality and mortality due to cardiovascular disease or cancer showed significant differences between groups (plots not shown). We found no obvious deviations from the proportional hazards assumption in the Kaplan-Meier plots for each potential confounding factor. For each of our outcomes we present hazard ratios only for variables identified important for the final model.

After stepwise adjustment, women who were younger at hysterectomy had a non-significant 18% reduction in risk of all cause mortality, compared with young women who did not have a hysterectomy (table 2). Smoking and a history of hypertension or non-gynaecological cancer were each independently associated with all cause mortality in younger women. Women who were older when they had a hysterectomy had an adjusted 6% reduced risk of all cause mortality compared with older women not having the procedure. In older women, smoking and a history of hypertension, cardiovascular disease, gynaecological cancer, or non-gynaecological cancer was independently associated with death from any cause. All cause mortality was significantly reduced among older women who had used oral contraceptives.

Hysterectomy was not associated with a significantly altered risk of mortality due to cardiovascular disease regardless of age (table 3). Smoking and a history of cardiovascular disease or non-gynaecological cancer among younger women was associated with future death from cardiovascular disease. Among older women, smoking and a history of hypertension or cardiovascular disease was associated with an increased risk of death from cardiovascular disease. The risk of death from cardiovascular disease was 40% lower among older women who had ever used oral contraceptives compared with never users (adjusted hazard ratio 0.60, 95% confidence interval 0.39 to 0.92).

Women who were younger at operation had a non-significant reduced risk of death from cancer than similarly aged women who did not have a hysterectomy (adjusted hazard ratio 0.81, 0.55 to 1.19; table 4). A history of non-gynaecological cancer, however, was associated with a significantly increased risk of death from cancer. In contrast, women who were older when they had their hysterectomy had almost the same risk of death from cancer as similarly aged women not having the procedure (adjusted hazard ratio 1.02, 0.69 to 1.49). In the older group, death from cancer was significantly more likely among women who smoked or had a history of gynaecological or non-gynaecological cancer, and was lower in previous users of oral contraception.

Discussion

In this study, hysterectomy was not associated with an increased long term risk of death from any cause, cardiovascular disease, or cancer.

Information on hysterectomy and potential confounding variables was provided prospectively by doctors participating in the oral contraception study. Information bias would therefore have occurred if they reported information differently on the basis of a woman's hysterectomy status. Such bias is, however, unlikely as the purpose of the oral contraception study is to examine the effects of oral contraception rather than those of hysterectomy. Information about cause of death was mainly based on information from death certificates, often without post mortem. This may have affected cause specific analyses, although many certificates were based on recent illness before death, and any inaccuracies are likely to be non-differential between the groups. The mean length of follow-up was more than 20 years, enabling us to investigate medium to long term risks of mortality associated with hysterectomy, based on a substantial number of deaths.

Some women in the original oral contraception study cohort were not flagged, mainly because they left the study before flagging occurred. We have shown previously that the large losses to general practitioner follow-up incurred by the main study have not substantially biased the results for overall mortality.21 The previous analysis also showed that women in the oral contraception study tend to be healthier than the general population.21 Thus, although comparisons within the group are valid, caution should be exercised when extrapolating the results to all women who have had a hysterectomy. Other studies are needed to confirm or refute our findings.

Our results may have been affected by residual confounding, partly from the imprecise ascertainment of some factors. For example, social class was evaluated in three broad categories, and at one point in time—possibly when effects were not most influential. Furthermore, some factors were not measured at all—for example, use of hormone replacement therapy after hysterectomy, which may affect the risk of subsequent mortality. Information about use of hormone replacement therapy after hysterectomy was not available for women who left the main oral contraception study after the operation. Current understanding, however, is that hormone replacement therapy may be associated with a balance of higher risk of serious disease (such as breast cancer, stroke, and pulmonary embolism) than benefits (such as reduced risk of colorectal cancer and fractures of the neck of the femur).22 More women who have had a hysterectomy than those who have not use hormone replacement therapy.23 It is unlikely, therefore that the reduced risk of all cause mortality among the hysterectomy group was due to confounding from subsequent use of hormone replacement therapy.

Smoking status was based on information obtained at recruitment to the oral contraception study. The status of many women is likely to have changed. Assuming a pattern similar to national trends24 (that is, substantially more middle aged women stopping smoking than starting), the prevalence of smoking among the cohort will have fallen. This was the case in a subset of women in the oral contraception study who participated in a health survey in the mid-1990s.25 The effects of smoking, therefore, are likely to be underestimated. Since we found no significant relation between smoking and hysterectomy, however, our measurement of smoking is unlikely to have affected the risk estimates between hysterectomy and subsequent mortality.

The finding of a lower risk of death among ever users of oral contraceptives in women who were older when they had their hysterectomy (but not younger) was unexpected, and is not readily explained. It may be a chance finding.

We have been able to find only one study that looked at the long term risk of all cause mortality after hysterectomy, and that found no overall effect.7 In our study, hysterectomy was not associated with a significantly altered risk of death due to cardiovascular disease. Other studies have examined non-fatal cardiovascular outcomes, with conflicting results.8 10 Some studies have considered the effects of oophorectomy with hysterectomy. We do not know how many of the women in our study with hysterectomy had a concurrent unilateral or bilateral oophorectomy. If hysterectomy with oophorectomy has different effects from hysterectomy without oophorectomy, the effects of different combinations will have been masked. Even if this information was available, it is often difficult to know how many women become menopausal soon after hysterectomy. We were therefore unable to carry out separate analyses using menopausal status.

Previous studies have looked at risk of specific cancers such as ovarian and breast cancer after hysterectomy, rather than all cancer mortality. The reduced risk of ovarian cancer after hysterectomy found in one study26 may have been due to a screening effect, as surgery provides an opportunity to detect abnormal ovaries. Such effects would persist for as long as it takes visible premalignant abnormalities to produce symptoms of cancer.26 This bias could have occurred in our study, although it is not clear how long such a protective effect might have influenced our risk estimates of all cancer mortality.

Most women in our study had a hysterectomy for non-malignant reasons. They would no longer be at risk of endometrial, cervical, or ovarian cancer if they also had bilateral oophorectomy. Cancers comprise more than a third of deaths in middle aged women, with many at gynaecological sites. The observed lower risk of death (although not statistically significant) from all causes and from cancer among young women who had a hysterectomy was therefore unsurprising. Our results ignore any non-fatal, physical, psychological, and social costs to the individual after hysterectomy. The results should therefore not be used to argue that hysterectomy be used as a public health measure to reduce women's risk of death later in life. Instead, patients should be reassured that hysterectomy will not put their lives at risk later in life.