Oxytocin-Related Gene Expression Predicts Outcomes in Induced Near-Term Labor

Article

Variations in genes involved in oxytocin receptor (OXTR) signaling appear to influence oxytocin dosing requirements during induced labor, according to findings from a new study. Genetic variants within the OXTR signaling system also correlate with the duration of labor and the risk of cesarean delivery in women undergoing induced near-term labor.

Chad A. Grotegut, MD, MHSc, of the Division of Maternal Fetal Medicine in the Department of Obstetrics and Gynecology at Duke University, presented results from the study at the 37th Annual Pregnancy Meeting of the Society for Maternal Fetal Medicine held January 23 to 28, 2017, in Las Vegas, NV.

Oxytocin is widely used to induce uterine contractions and augment labor. After initially being activated by oxytocin, OXTR is quick to desensitize, leading to a paradoxical decrease in uterine contractility. During induced labor, women predisposed to OXTR desensitization experience a cluster of related issues: the need for higher oxytocin infusion rates, higher total oxytocin doses during labor, or both; a longer duration of labor; and an increased risk for cesarean delivery due to failed induction or dysfunctional labor.

The study was designed to evaluate whether maternal genotype could explain the variations in oxytocin dosing and labor outcomes among women induced near term. In the search for genetic variants, Grotegut focused on 2 prime candidates: single nucleotide polymorphisms (SNPs) within the genes encoding OXTR and G protein-coupled receptor kinase 6, a key regulator of OXTR desensitization.

The analysis includes DNA from 482 women with a singleton gestation who were undergoing induced labor at 36 weeks or later. Each woman underwent genotyping and haplotype tagging for known SNPs within OXTR and GRK6. The primary end point was the association between maternal genotype and maximal oxytocin infusion rate. Secondary outcomes included the total dose of oxytocin received in labor, the duration of induced labor, and the cesarean delivery rate.

Grotegut and colleagues identified multiple interactions between maternal genotype variants and induced labor outcomes (Table). Five SNPs in OXTR were significantly associated with the maximal oxytocin infusion rate, whereas 2 of these SNPs also correlated with total oxytocin dose.

Table. Interactions Between Maternal Genotype and Labor Outcomes

Outcome SNP (Gene) Genotype (n): Mean Value P Value
Maximal oxytocin infusion rate, mU/min rs1042778
(OXTR)
GG (n = 91): 10.9
GT (n = 187): 13.8
TT (n = 140): 14.0
.004
rs11706648
(OXTR)
AA (n = 272): 12.7
AC (n = 132): 14.0
CC (n = 16): 16.4
.021
rs4686301
(OXTR)
CC (n = 297): 12.7
CT (n = 111): 14.3
TT (n = 12): 17.6
.016
rs9810278
(OXTR)
CC (n = 354): 12.9
CT (n = 64): 15.4
TT (n = 2): 11.0
.022
rs237895
(OXTR)
CC (n = 270): 13.8
CT (n = 125): 12.0
TT (n = 24): 12.9
.027
Total oxytocin dose, mU rs1042778
(OXTR)
GG (n = 94): 6852
GT (n = 196): 10,159
TT (n = 143): 10,425
.015
rs4686301
(OXTR)
CC (n = 308): 8961
CT (n = 114): 10,874
TT (n = 13): 11,426
.034
Duration of labor, h rs9810278
(OXTR)
CC (n = 406): 20.2
CT (n = 68): 22.6
TT (n = 2): 14.4
.041
rs2731664
(GRK6)
AA (n = 114): 17.7
AC (n = 223): 20.2
CC (n = 132): 23.5
.001
rs2287694
(GRK6)
CC (n = 0): NA
CT (n = 55): 26.2
TT (n = 421): 19.7
.009
Cesarean delivery rate, % rs2139184
(OXTR)
AA (n = 6/16): 37.5
AC (n = 35/110): 31.8
CC (n = 101/355): 28.4
.023
rs237888
(OXTR)
 CC (n = 10/47): 21.3
CT (n = 46/174): 26.4
TT (n = 87/261): 33.3
.025
rs2545796
(GRK6)
CC (n = 19/54): 35.2
CT (n = 57/203): 28.1
TT (n = 66/224): 29.5
.032

NA = not applicable, SNP = single nucleotide polymorphism.

Three SNPs in OXTR and GRK6 also correlated with the duration of labor, which was defined as the start of induction to delivery. Of note, the rs2731664 SNP in GRK6 was highly significantly correlated with labor duration across multiple statistical analyses. The mean duration of induced labor was 17.7 hours for women with the AA genotype, 20.2 hours for those with the AC genotype, and 23.5 hours for women with the CC genotype (P = .001). 

Maternal genotype also correlated with mode of delivery, with 3 SNPs in OXTR and GRK6 significantly associated with rates of cesarean delivery ranging from 21.3% to 37.5%.

The next step for the research team is to understand the functional significance of the variations in the OTXR–GRK6 system, said Grotegut. “These findings may one day allow for the development of personalized labor management at term,” he explained.

Source: Grotegut CA, Ngan E, Garrett ME, Ashley-Koch AE, Swamy GK. Single nucleotide polymorphisms in the oxytocin receptor and GRK6 are associated with oxytocin dosing requirements and labor outcomes. Presented at: Society for Maternal-Fetal Medicine 37th Annual Pregnancy Meeting; January 23-28, 2017; Las Vegas, NV. Abstract 27.