Our study showed that an increase in the oxytocin recovery interval is associated with a reduction in postpartum blood loss in parturients undergoing a CD for labour arrest following oxytocin augmented labour. Amongst the presumed risk factors for PPH, we found morbid obesity to be associated with an increase in blood loss at delivery. Moreover, the total amount and duration of oxytocin administered for labour augmentation were associated with the higher use of additional interventions to control postpartum bleeding.
At the study institution, oxytocin is typically discontinued after a CD is indicated for labour arrest. There is variability in the duration of the oxytocin-free period prior to the CD depending on the availability of an operating room and personnel and prioritization of cases. These conditions provided us with an opportunity to investigate the clinical implications of a varying oxytocin-free period following augmented labour. We included women who received oxytocin for labour augmentation for more than two hours to select those who received sufficient oxytocin to induce OTR desensitization. The length of this inclusion criterion was based on studies of pregnant human myometrium in vitro showing that two hours of exposure to oxytocin resulted in a substantial decline in subsequent oxytocin-induced contractions.10,14 We also based our parameter on a clinical study in which higher doses of oxytocin were required to achieve adequate uterine tone in women exposed to oxytocin.15 Clinically, OTR desensitization from augmented labour is associated with an increased risk of PPH depending on the dose and duration of oxytocin administered during labour.8–10,13,16,17,24 Although we did not observe more blood loss with increasing oxytocin administration during labour, an increased use of additional interventions suggests that there was poor uterine tone at delivery.
Various studies in the literature have described OTR desensitization10–13; however, little is known about the potential implications of OTR resensitization. Cell-based studies have shown that OTR resensitization following oxytocin pretreatment occurs in a time-dependent manner following discontinuation of oxytocin. An oxytocin recovery interval of four hours markedly enhanced oxytocin-OTR binding as compared with a 45-min duration,25 while an increase in the interval from 5-15 min led to an increase in effective oxytocin responsiveness.26 A more recent study found that increasing the recovery period from 30-90 min did not improve the contractile response to oxytocin in myometrial samples in vitro.27 The discrepancies between these results may be a consequence of differing cell types, culture conditions, and oxytocin pretreatment regimens. Furthermore, the recycling or synthesis of OTRs may depend, at least in part, on cell signals mediated by in vivo factors not reproduced in the in vitro studies. These issues highlight the difficulty of studying OTR resensitization in vitro and extrapolating results to the clinical setting.
Following OTR desensitization during labour augmentation, the oxytocin recovery interval in our study represented the anticipated time interval during which resensitization can occur. The time-dependent reduction in postpartum blood loss may have resulted from OTR resensitization, which restores the myometrial responsiveness to oxytocin administered for PPH prophylaxis. These clinical findings parallel the time-dependent restoration of OTR responsiveness to subsequent oxytocin challenges following oxytocin pretreatment in in vitro studies.25,26
In addition to the oxytocin recovery interval, morbid obesity was associated with EBL. The role of obesity as a risk factor for PPH remains debated.28–30 The contrasting results may be due to differences in the covariates, such as ethnicity, mode of delivery and oxytocin exposure in the statistical models, or the outcomes used to define PPH. We observed that the blood loss in morbidly obese women was about 600 mL greater than that in non-morbidly obese mothers; however, this was not associated with the need for more interventions to manage the blood loss. Interestingly, studies finding an association between PPH and obesity used blood loss (≥ 1,000 mL) to define PPH,28,29 whereas the study with an opposing finding used PPH requiring blood transfusion as their outcome.30 Obese women have different signalling pathways modulating OTR function and ligand binding as well as alterations in OTR membrane viscosity and fluidity due to high cholesterol levels. Hence, they are likely to have impaired oxytocin-induced myometrial contractility, predisposing them to dysfunctional labour and PPH.31
Other PPH risk factors in our study were not found to be associated with the study outcomes. Prior studies examining the association of chorioamnionitis with PPH have been conflicting.8,17,32 We did not find an association despite the fact that our cases were confirmed by pathology reports. The lack of an association with some other previously identified risk factors may be the result of the low number of cases in our study with macrosomia, preeclampsia, multiple pregnancy, and polyhydramnios. Consideration of other factors contributing to blood loss is also needed. Patients who waited a shorter time for their CD may have been at higher risk of adverse obstetric outcomes that increase the likelihood of PPH. To this end, multivariable models and selection criteria were used.
There were some limitations to our study. For example, we cannot eliminate residual confounders completely, particularly those contributing to blood loss to a subclinical extent without any notable impact on PPH risk. These are not clearly defined in the literature but may convolute the association examined, since we measured the quantity of blood loss rather than the occurrence of PPH. Nevertheless, we carefully controlled for PPH risk factors, including the use of oxytocin as a continuous variable to account for its contribution to blood loss more accurately. We excluded potential confounders such as early or late gestation, the use of general anesthesia, and uterine rupture. Hence, our multivariable model and selection criteria gave us the incentive to examine the association between oxytocin recovery interval and blood loss.
The hematocrit variation method to estimate blood loss was used because it provides more accurate results than visual estimations. Specifically, visual estimations have been shown to be subjective and dependent on the experience of the observer, and they tend to underestimate actual blood loss.21,33–35 Nevertheless, the hematocrit variation method is not without its limitations. It is possible that estimating blood loss using this method may lead to overestimation in morbidly obese women. Although it is known that indexed blood volume decreases in a non-linear manner with increasing body weight,36 it is unclear how this relates to the morbidly obese and pregnant population. Secondly, following the decrease in estrogen in the immediate postpartum period, there is diuresis of fluids accumulated during pregnancy and a relative elevation of the hematocrit.37 Since the EBL relies on the difference between pre- and post-CD hematocrit levels, a postpartum elevation in hematocrit from this physiologic phenomenon can artificially lower the EBL. Additional fluids can also alter patients’ hematocrit level. A final limitation to our study is that, although the quantified reduction in blood loss was statistically significant, the clinical consequences of this blood loss were uncertain based on our secondary outcomes (i.e., little need for blood transfusion or additional uterotonics).
In summary, the study showed that an increase in the oxytocin recovery interval is associated with a reduction in postpartum blood loss. This suggests that, once a CD is considered for labour arrest, cessation of oxytocin for augmented labour may reduce the amount of postpartum blood loss. The extent of the reduction in blood loss found in this study likely does not warrant a mandatory recovery interval beyond what typically occurs. Nevertheless, particular attention must be given to morbidly obese women, as they are at a significantly higher risk of bleeding than non-obese parturients. Further investigations may be needed to assess the impact of the recovery interval on the need for additional interventions to manage blood loss as well as the implications of a recovery interval on patients at higher risk for PPH, such as morbidly obese parturients.