The number of parturients who give birth at an advanced maternal age (≥35 years) has been increasing these days worldwide (Chan and Lao, 2008; Matthews and Hamilton, 2014; Office for National Statistics for Births in England and Wales, 2018). It has been verified that advanced maternal age increases the likelihood of intrapartum complications of cesarean section and postpartum hemorrhage (PPH) (Lao et al., 2014; Kanmaz et al., 2019). Therefore, elderly parturients with prior history of cesarean delivery (CD) comprise a critical proportion of CD.

When a caesarean section is performed, it is common practice in hospitals to give the parturient oxytocin after the delivery of the fetus. A rapid oxytocin I.V. bolus, even in small dose, is linked to either mild or severe adverse effects, such as, hypotension, myocardial ischemia, and hemodynamic collapse, especially among women with various cardiac conditions. Oxytocin infusion is advantageous in maintaining uterine tone (UT) throughout the operative and postoperative periods because of oxytocin’s short half-life. Thereby, numerous practitioners would rather infuse than inject to administer a certain dose of oxytocin.

For elective CD, the minimum effective dose of I.V. oxytocin administration has been determined by a few studies. The effective doses of ED90 oxytocin infusion for non-laboring parturients in elective CD were 16.2 and 17.4 IU h⁻¹ in order for adequate UT (George et al., 2010; Lavoie et al., 2015). However, the dose of intravenous oxytocin infusion following delivery in CD remains inconclusive based on parturients’ situation, and consequently, it is inappropriate to apply a universal dose to all cases (Heesen et al., 2019). An in vitro study indicated that the occurrence rate of multiphasic spontaneous myometrial contractions had likely been increased with increasing parturients’ maternal age and their decreasing spontaneous activity (Smith et al., 2008). Bobrowski and Bottoms (1995) performed a retrospective review of over 8 years in 9,556 cases of delivery of singleton pregnant women, with ages ranging from 20 to 29 or above 35 years, and showed the highest age-related increases in oxytocin use (1.7 times). Furthermore, prior CD has been shown to predispose parturients to an increased risk of maternal morbidity, especially PPH (Ma et al., 2016). The aim of this dose–response research was to find the optimum oxytocin infusion rate for preventing uterine atony during CD in elderly parturients with prior history of CD.

Following the enrollment and randomization, a total of 120 parturients completed the study (Figure 1). The six groups did not show a significant baseline difference in the aspects of their demographic characteristics, preoperative Hb, preoperative HCT, or surgery time (Table 1).

The percentage of parturients with adequate UT at 3 min after oxytocin infusion is shown in Figure 2. The dose–response curve of oxytocin to prevent uterine atony is shown in Figure 3. The estimated ED50 and ED90 were 14.6 (95% CI 12.0–18.4) IU h⁻¹ and 27.7 (95% CI 22.5–39.4) IU h⁻¹, respectively.

The UTSs after oxytocin infusion at 3, 6, and 9 min are presented in Figure 4. When compared with the UTSs of those who received 8, 12, 16, and 20 IU h⁻¹ oxytocin (p < 0.05), the UTSs of parturients receiving 0 IU h⁻¹ were significantly lower at 3 min. Parturients receiving 16 and 20 IU h⁻¹ had significantly higher UTSs at 3 min than those receiving 0, 4, and 8 IU h⁻¹ oxytocin (p < 0.05). When compared with the UTSs of those receiving 0 IU h⁻¹ (p < 0.05), the UTSs of parturients receiving 16 IU h⁻¹ were significantly higher at 6 and 9 min. When compared with the UTSs of those receiving 0, 4, and 8 IU h⁻¹ oxytocin (p < 0.05), the UTSs of parturients receiving 20 IU h⁻¹ were significantly higher at 6 and 9 min (Figure 4).

The secondary outcomes are summarized in Table 2. The rescue oxytocin dose and delivery-PD time decreased with increasing oxytocin infusion dose (p < 0.05) (Table 2). No statistically significant differences were observed in terms of total I.V. crystalloid volume, EBL, and supplemental second-line uterotonic agents between the different groups. PPH was not observed in the study, and none of the parturients required a blood transfusion perioperatively.

No statistical difference was observed in terms of hypotension incidence, tachycardia, vomiting, headache, nausea, chest distress, and flushing between the different groups (Table 3). The side effects reported were not aggravated and quickly alleviated after symptomatic treatment or after the end of oxytocin infusion.

This dose–response research obtained the primary finding that ED50 and ED90 of oxytocin infusion during caesarean delivery were 14.6 (95% CI 12.0–18.4) IU h⁻¹ and 27.7 (95% CI 22.5–39.4) IU h⁻¹, respectively, in elderly parturients with a prior history of CD. In addition, the rescue oxytocin dose and delivery-PD time decreased with the increasing oxytocin infusion dose. Parturients in the group of 20 IU h⁻¹ oxytocin infusion were in need of the least rescue oxytocin bolus and delivery-PD time among the six groups. The ED90 of oxytocin infusion was deduced from the probit analysis and outside the dose range of this study; however, several previous studies have suggested that 30 IU h⁻¹ of oxytocin infusion is safe during CD (Munn et al., 2001; Committee on Practice Bulletins-Obstetrics, 2017; Ghulmiyyah et al., 2017; Ahmadi, 2018). Therefore, we recommend 27.7 IU h⁻¹ of oxytocin as the optimal dose to avoid uterine atony when elderly parturients who have had prior history of CD are going through a CD.

In the last decade, considerable research have been conducted as to how much and in what ways oxytocin should be administered at the third stage of CD (Heesen et al., 2019; Baliuliene et al., 2021; Phung et al., 2021). Although consensus regarding the optimal oxytocin dose and mode is lacking, adverse hemodynamic effects of 5 IU oxytocin bolus have been verified (Baliuliene et al., 2021). Thomas et al. (2007) found that 5 IU oxytocin bolus when compared with infusion resulted in significantly increased heart rates and decreased mean arterial pressure, but blood loss did not significantly vary. Miyoshi et al. (2021) came to the same conclusion and advised us to discard the I.V. bolus injection of oxytocin when cesarean section (CS) was performed, particularly when non-laboring women were going through an elective CS. Therefore, most practitioners would rather choose the way of infusion to administer oxytocin than use a bolus for safety considerations.

Previous studies have estimated that the ED90 of oxytocin as an infusion was 16.2 and 17.4 IU h⁻¹ for preventing uterine atony in parturients scheduled for CD without labor (George et al., 2010; Lavoie et al., 2015). In this study, we found that the ED90 of an oxytocin infusion was raised to 27.7 IU h⁻¹ in elderly parturients with prior history of CD. Patel et al. (2017) demonstrated that in comparison with 3-month-old mice, 8-month-old mice had less connexin-43 mRNA expression and oxytocin receptor in the myometrium, which was in collaboration with a more frequent yet shorter duration of spontaneous myometrial contractions and a weaker contractile reaction to oxytocin. Another animal study reached the conclusion that the myometrium of young laboring rats appear ready to contract to the maximum extent, while blunted contractions occur in the myometrium of older non-laboring rats and the contractile potential has to be stimulated (Elmes et al., 2015). Clinical research has also shown that elderly parturients required more oxytocin for preventing uterine atony (Bobrowski and Bottoms, 1995; Wei et al., 2020). Our previous study estimated the ED50 of oxytocin was greater in the parturients with a history of prior caesarean delivery than in the parturients without a history of prior caesarean delivery (Wei et al., 2021). Therefore, uterine scarring and advanced maternal age may be responsible for the increased requirements of oxytocin in elderly parturients with a prior history of CD.

In this study, we found that the UTSs at 3, 6, and 9 min were increased when the oxytocin infusion dose was increased. In the meanwhile, the UTS increased with increasing oxytocin infusion time in each group. Both the increase in the dose of oxytocin infusion and the extension of the time of oxytocin infusion will increase the concentration of oxytocin in the blood, which will enhance the maternal uterine contractions. Previous investigations have indicated that larger infusion doses of oxytocin turn out more productive than smaller doses to avoid potential remedies for PPH, especially in the case of CD (Roach et al., 2013). The results of the current study are consistent with previous findings.

Oxytocin is linked to hemodynamic side effects ranging from myocardial ischemia, arrhythmias, vomiting, hypotension, chest pain, nausea, headache, to flushing. However, such side effects have connections with oxytocin doses and its administration rates (Jonsson et al., 2010). There was no statistical difference observed in the oxytocin-related adverse events among the different dose infusion groups. This may be attributed to the small dose difference of only 4 IU h⁻¹ between the groups in this study. The oxytocin-related side effects were not aggravated and quickly alleviated after symptomatic treatment or after the end of oxytocin infusion.

Limitations still exist with this research even though its findings have significant clinical implications. Above all, the analyses of the side effects at the time interval ≥3 min after oxytocin was administered may have been disturbed in participants who were treated with rescue oxytocin doses; despite this, inadequate UT and bleeding were not allowed to persist without remedies because of ethics. In addition, the ED90 of the oxytocin infusion dose was deduced from the probit analysis and outside the dose range of this study. However, we can conclude from previous studies that the administration of 27.7 IU h⁻¹ oxytocin during CD was a safe clinical practice (Munn et al., 2001; Committee on Practice Bulletins-Obstetrics, 2017; Ghulmiyyah et al., 2017; Ahmadi, 2018). Although it was the senior attending obstetricians who conducted the evaluation of adequate UT in this research, there might still exist problems of variability and subjectivity with uterine palpation. Nevertheless, there are no reliable and objective methods of clinical UT assessment. Subjective assessments have been adopted in previous studies assessing UT during CD too (Qian et al., 2019; Drew et al., 2020).

In summary, we demonstrate that the ED50 and ED90 of oxytocin infusion in preventing uterine atony during elective CD were 14.6 and 27.7 IU h⁻¹, respectively, in elderly parturients with prior history of CD. An oxytocin infusion rate of 27.7 IU h⁻¹ is suggested to prevent uterine atony during CD in elderly parturients with prior history of CD. We suggest that guidelines for oxytocin administration should differentiate between elderly parturients with prior history of CD and non-laboring patients.