Pre-eclampsia and the risk of cancer

This issue of the BMJ includes a study which examines the relation between pre-eclampsia and cancer.¹ Many researchers have suggested that pre-eclampsia or hypertension in pregnancy is associated with a reduced risk or no excess risk of cancer in the mother.^2-8 However this week's study by Paltiel et al shows an increased risk of cancer after pre-eclampsia.¹

Despite decades of research, there is still confusion over the cause of pre-eclampsia. It is relatively common, affecting 3-5% of pregnancies, and is a leading cause of morbidity and mortality both in the mother and unborn child.⁹ Several observational studies in European and North American populations have examined the relation between pre-eclampsia (or hypertension) in pregnancy and cancer.^2-8 Unfortunately some were based on a small number of cancers in the pre-eclampsia group, not all adjusted for known confounders, and the length of follow up varied. Most of these studies found a reduced risk of breast cancer after pre-eclampsia or hypertension in pregnancy,^2-4,⁶,⁷ and one study found no significant association.⁸ Some authors have hypothesised that the observed reduction in risk of maternal breast cancer may be due to reduced maternal oestrogen, increased α fetoprotein, or raised androgen concentrations.³,¹²,¹³ One cohort study found a decreased risk of death from all cancers in the mother, and this risk was further decreased when pre-eclampsia developed before term. The authors hypothesised that this reduction was due to the lower prevalence of smoking and reduced oestrogen levels in mothers with pre-eclampsia.⁵

Studies investigating the relation between preeclampsia (or hypertension) in pregnancy and breast cancer that also provide risk estimates are shown in a forest plot (figure). Although we need to be cautious in interpreting results from case-control and cohort studies together, the overall picture is useful as it illustrates that the results of the present study clearly contrast with previous studies. Wherever possible, the risks shown are those corrected for known confounders and are for women followed up from first pregnancy. The main problems in interpreting any observational study relate to the potential for residual confounding and bias. Many established and probable risk factors for breast cancer exist,¹⁴ and it is important to correct for as many of these confounders as possible when interpreting the results of such studies.

Figure 1.

Forest plot of studies examining the association between pre-eclampsia or hypertension in pregnancy and breast cancer

Paltiel et al present the results of a cohort study of pre-eclampsia with analysis of results restricted to three large hospitals in West Jerusalem where recording of pre-eclampsia was complete (37 033 women).¹ The median follow up was 29 years. The incidence of cancer increased marginally after pre-eclampsia (hazard ratio 1.27 (95% confidence interval 1.03 to 1.57). Site-specific increases were noted for cancers of the breast, stomach, lung/larynx, and ovary. The hazard ratio for breast cancer after pre-eclampsia was 1.38 (1.0 to 1.89), adjusted for age at baseline and parity. In women followed up from first birth (n = 22 716), there was a further increase in age adjusted risk of breast cancer (hazard ratio 1.75 (1.19 to 2.58)).

The authors suggest their results may be partly explained by the longer period of follow up in their study. Previous cohort studies have been based on shorter periods (median 13 years,⁵ mean 16 years⁷ and mean 19 years⁶). It would be helpful if the authors could calculate hazard ratios by decade of follow up, to see if this changes significantly with increasing length of follow up.

Pre-eclampsia⁹-¹¹

Definition—raised blood pressure and proteinuria

Pathophysiology—intense vasospasm; activation of coagulation cascade; plasma volume contraction; organ hypoperfusion

Pre-disposing factors—first pregnancy, previous pregnancy with pre-eclampsia, hypertension, diabetes, increased insulin resistance, black race, increased testosterone, genetics, pregnancy with new father, high maternal weight

It is possible that different risk factors for pre-eclampsia exist among different populations, and that, as Paltiel et al propose,¹ certain populations are at increased risk of cancer after pre-eclampsia. Certain families are more at risk of cancer and, in particular, some genes confer a greatly increased risk of breast cancer. BRAC 1 and 2 genes are more common in Ashkenazi Jewish populations than in Western populations, though only about 2% of Ashkenazi Jewish women carry these genes.¹⁴

The available evidence therefore suggests that women in Europe and North America probably have a reduced risk of cancer after pre-eclampsia, at least in the short term. With increasing time, this risk might reverse. It is also possible that women from the Middle East have some common underlying risk factors for certain cancers and pre-eclampsia, possibly related to genetics or lifestyle factors. Unfortunately any explanation for these results is speculative, so further good quality population based studies with long periods of follow up are necessary.