Labor pain is a common physiological phenomenon during pregnancy and occurs due to uterine contractions. However, it causes tension, anxiety, and weak contractions of puerpera that result in prolonged labor, fetal hypoxemia, acidosis, or fetal distress [1, 2]. Labor analgesia has been widely accepted in recent years, with lifestyle improvement. Currently, labor analgesia mainly includes non-drug and drug analgesics [3, 4]. Non-drug labor analgesia has no adverse effects on the labor process and fetus, however, the analgesic effect is poor or inaccurate and is adequate only for mild or moderate labor pain. Thus, drug labor analgesics are widely used for labor analgesia [5, 6]; especially opioid-based drugs are preferred for peri-and postoperative pain management [7, 8]. Sufentanil, a derivative of fentanyl, has a strong analgesic effect and a long analgesic duration. Thus, it is a commonly used drug for drug labor analgesia [9, 10].

ATP-binding cassette B1 (ABCB1), also known as the multiple drug resistance 1 (MDR1) gene encodes a transporter of the blood-brain barrier (BBB) that participates in opioid tolerance [11, 12]. Polymorphisms rs1128503 (1236C$>$T, p.G412G, exon 12) and rs1045642 (3435C$>$T, p.I1145I, exon 26) are the most continually studied mutations in different populations [13, 14]. The TT genotypes of these two polymorphisms are related to decreased expression of ABCB1 protein, which restricts opioid distribution [12]. The rs1128503 genotype is associated with the analgesic effect and sufentanil dose in lung cancer patients [15]. However, the correlation between ABCB1 gene polymorphisms and analgesic effect and adverse reactions of labor analgesia in primiparas has not yet been reported.

The present study explored the association of ABCB1 gene polymorphisms (rs1128503 and rs1045642) with the analgesic effect and adverse reactions of labor analgesia in primiparas.

All opioid drugs can cause side effects in a puerperant [17, 18]. A previous study demonstrated that ABCB1 is involved in the pharmacokinetics and resistance of different drugs, including opioids [14, 19, 20]. Opioid exposure results in overexpressed ABCB1 in the brain [12]. Elevated expression and activity of ABCB1 at BBB may lead to side effects of the central nervous system drugs [21]. Wang and Sadee [22] demonstrated that rs1128503 and rs1045642 alter the stability and expression level of ABCB1 mRNA. Polymorphisms in the ABCB1 gene are correlated with the efficacy, consumption, and toxicity of opioids, such as methadone [23]. ABCB1 gene polymorphisms may be associated with the outcomes of sufentanil in labor analgesia via altering the stability and expression level of ABCB1 mRNA.

The current cohort study recruited 239 primiparas to analyze the association of ABCB1 gene polymorphisms (rs1128503 and rs1045642) with the analgesic effect and adverse reactions of labor analgesia. All primiparas received the same dose of sufentanil. Consequently, rs1128503 CC genotype carriers had significantly lower 1 h- and 2 h-VAS scores compared to the rs1128503 TT genotype, and adverse reactions were discovered more frequently in the rs1128503 TT genotype carriers, while the Apgar score at 1 min was significantly higher in rs1128503 CC genotype carriers. These results demonstrated that rs1128503 CC genotype carriers had better labor analgesic effects and fewer adverse reactions than rs1128503 TT genotype. However, logistic regression analysis indicated that rs1128503 TC + CC genotypes were negatively related to the 2 h-VAS score and nausea, and positively correlated with Apgar score at 1 min. The present results were following the previous findings conducted in a study with post-caesarean analgesia. Zhang et al. [24] showed that Chinese women who adopted post-caesarean fentanyl analgesia with the rs1128503 TT genotype had significantly higher fentanyl dosage than those with CC and CT genotypes. The current results also conformed with other studies focused on cancer patients. Zhao et al. [25] found that Chinese patients with lung cancer (who underwent curative resection) carrying the rs1128503 TT genotype had a significantly higher dose of sufentanil than the CC genotype. On the other hand, cancer patients carrying the rs1128503 TT genotype showed decreased fentanyl consumption than the rs1128503 C allele carriers. However, pharmacokinetics and adverse effects of fentanyl did not differ markedly between rs1128503 genotypes [26]. Based on these findings, we speculated that the rs1128503 TT genotype needed a high drug dosage to achieve the same analgesic effects or exhibited worse analgesic effects when obtaining the same drug dosage. Additionally, the association of rs1128503 polymorphism with analgesic effects and adverse reactions was affected by disease type and opioid drugs.

The 2 h-VAS score was distinctly lower in rs1045642 TT and CT genotype carriers compared to primiparas carrying the CC genotype, respectively, whereas the 0 h- and 1 h- VAS scores, adverse reactions, and Apgar score at 1 min among rs1045642 genotypes did not differ significantly. Logistic regression analysis revealed that the 2 h-VAS score was positively correlated with rs1045642 CT + TT genotypes compared to the rs1045642 CC genotype. Zhao et al. [25] showed that there was no marked diversity in adverse reactions between rs1045642 genotypes in lung cancer patients who underwent radical resection. In addition, rs1045642 genotypes had no obvious impact on sufentanil doses and VAS scores of lung cancer patients. Also, plasma concentration and adverse effects of fentanyl did not differ markedly between rs1045642 genotypes. Fentanyl consumption was slightly lower in Japanese cancer patients who carried the rs1045642 CC genotype; however, the difference was not significant [26]. Gong et al. [27] demonstrated that cancer patients with rs1045642 TT genotype received lower opioid dosage than those with C allele carriers, although the difference was not significant. Together, these results demonstrated that the rs1045642 genotype had no obvious effects on adverse reactions to sufentanil in different diseases. Recent evidence shows increased rates of intrapartum compromise in fetuses of mothers undergoing epidural, particularly when the fetal weight is reduced (i.e., below the 10 centiles) as a proxy of placental dysfunction [28, 29]. These findings suggested that the analgesia effect regulated genetically is interested in the mechanism of intrapartum compromise.

Nevertheless, the current study has some limitations. First, ABCB1 gene rs1128503 and rs1045642 polymorphisms did not alter the amino acids, and the mechanism of these polymorphisms underlying labor analgesia was not explored. Second, this study was conducted on only one population, which might limit the generalizability of the results to other populations. Third, the current study did not explore the effects of rs1128503 and rs1045642 polymorphisms for the dosage of sufentanil during labor analgesia and their association with other drugs. Fourth, other polymorphisms in the ABCB1 gene or other genes involved in drug metabolism were not explored concerning the association of analgesic effects and adverse reactions of sufentanil. Finally, the relationship between ABCB1 gene polymorphisms and other drugs for labor analgesia was not explored. Moreover, although the statistical power was 99.80%, larger sample sizes could enhance the reliability of the findings. Therefore, additional studies across multiple centers, using large sample sizes, and several analgesic drugs should be performed to substantiate the association of ABCB1 gene polymorphisms with labor analgesia.

In conclusion, ABCB1 gene rs1128503 and rs1045642 polymorphisms are significantly correlated with the analgesic effect and adverse reactions of labor analgesia in primiparas. Taken together, the current results open a novel direction to explore the individual dosages of sufentanil during labor analgesia.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

ABCB1, ATP-binding cassette B1; MDR1, multiple drug resistance 1; VAS, visual analog scale; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; HWE, hardy-weinberg equilibrium; BMI, body mass index; BBB, blood-brain barrier; VAS, visual analog scale; AGE, agarose gel electrophoresis; ANOVA, analysis of variance; FHR, fetal heart rate.

WL, TKX, and JYW designed the research study. XHW, XYW, RX, and HFL performed the research and analyzed the data. WL and TKX wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Study information was noticed by the patients and families. They signed the written informed consent. Ethic committee of The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital) (No.20210006) approved this study.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.