In the HYPITAT trial, induction of labour was shown to be superior to expectant management in women with pregnancy-induced hypertension or mild pre-eclampsia at term [5
]. The key finding of the additional analyses presented here is that the risk of developing high-risk situations depends on the level of cervical ripeness only when women are managed expectantly, in which case a favourable cervix indicates a lower risk of high-risk situations. If labour is induced, the likelihood of high-risk situations is not associated with cervical favourability. As a consequence of this finding, the likelihood of a high-risk condition after expectant management is specifically higher in women with an unripe cervix, which implies that induction of labour is more beneficial to these women. We therefore conclude that labour induction, compared with expectant management, results in a stronger risk reduction for women with gestational hypertension or pre-eclampsia at term who have an unfavourable cervix, with the reduction being most pronounced in women with an unripe cervix.
To our knowledge this study is the first report of the interaction between cervical length and treatment in pregnancy-related hypertension. To replicate this finding in a new data set one would need to have 335 women in each group to be able to find the odds ratio of 1.37 with 80% power at 10% one-sided type I error [9
]. The details of this sample size calculation are presented in Appendix S1
At first glance, this finding may appear to be counterintuitive, if one considers the widely held belief that the decision to induce labour should only be made when the cervix is favourable; because successful induction of labour is related to cervical ripeness [7
]. Many studies have unequivocally shown that the rate of labour arrest and caesarean delivery is high in the presence of an unripe cervix [10
]. This makes obstetricians reluctant to induce labour in women with an unfavourable cervix. In our analyses, we showed a comparable risk of caesarean delivery after labour induction between women with favourable and unfavourable cervices (). However, as we could analyse the trial data, we had the opportunity to evaluate and compare the parallel association between cervical ripeness and risk of caesarean delivery in comparable women who were managed expectantly. This analysis showed that women with an unripe cervix were at an increased risk of caesarean delivery with expectant management, and that the risk was higher with expectant management than with labour induction.
Nearly 80 years ago, Calkins et al. [13
] recognised the importance of cervical assessment in labour induction. For a number of years, preinduction cervical assessment has been accomplished through the use of various measurements and scoring systems, the Bishop score being the one most commonly used. Cervical assessment using the Bishop score was described initially in its application to non-complicated pregnancies in multiparous women [7
]. Later, it was shown to predict induction success in nulliparous women as well [12
]. There have also been attempts to modify the Bishop score and to create better prediction models for the success of labour induction. Laughon et al. [8
], for example, have recently demonstrated that when assessing the cervix, a combination of dilatation, station and effacement was at least as predictive as the Bishop score. A problem, however, is that Laughon et al., just like Bishop and many other researchers, have only looked at the outcome of the induction strategy. Their approach does not assess the effect of cervical status on the outcome of expectant management. As our analysis shows, an unripe cervix is more predictive for an early onset of spontaneous labour in women managed expectantly than for the occurrence of caesarean delivery in women in whom labour is induced. Indeed, the decision for induction of labour is made after a comparison of the consequences of induction versus expectant management, and both should be considered when including cervical ripeness in this clinical decision.
We hypothesised that the main mechanism by which labour induction reduces the risk of a high-risk situation may be through its effect on the time from admission to delivery. We could show that a longer time to delivery is associated with a higher risk of entering into a high-risk situation. This evidence supports the hypothesis that the main reason for better outcomes of labour induction compared with expectant management is that induction shortens the time to delivery and therefore decreases the chance of deterioration of the maternal condition. In both treatment strategies, a shorter cervix was associated with a shorter time to delivery. Women with a long cervix generally deliver later and would be at a higher risk of maternal complications, especially if managed expectantly. Labour induction dramatically shortens the time to delivery and almost invariably results in delivery within 4 days. As a result, women with an unripe cervix, who are at the highest risk when managed expectantly, would have a reduced risk similar to that of other women and hence would obtain the highest benefit.
Evaluation of the occurrence of HELLP syndrome in both groups over time corroborates this hypothesis. We observed that more cases of HELLP syndrome occurred in the expectant management group and most of them occurred within the 2-week period after randomisation. In the women with induced labour all HELLP syndrome cases were observed in the first 2 days, and by terminating the pregnancy using labour induction, the occurrence of more cases of HELLP was prevented.
The HYPITAT study has been criticised because it used a composite outcome measure of high-risk situations, including blood pressures in the high ranges [14
]. In this analysis we observed that the endpoint was diagnosed earlier in the induction group than in the expectant management group, which can probably be explained by the fact that women in the induction group are monitored more closely during the first days after randomisation than women in the expectant management group. Nevertheless, despite more monitoring and earlier detection of deterioration in the induction of labour group, more women developed high-risk situations in the expectant management group.
We think that our findings may also hold true for other indications of labour induction in which a progressive disease like pre-eclampsia is present. In such a setting, induction of labour is generally applied because the expected risk of continuation of pregnancy from either a maternal or a fetal perspective is larger than the expected risk of immediate delivery. Consequently, an unripe cervix, which predicts a long time to the onset of spontaneous labour, increases the risk for maternal or neonatal complications. In the case of a ripe cervix, on the other hand, spontaneous labour is likely to start soon, and the risk of such complications is reduced.