The effect of maternal and fetal β2-adrenoceptor and nitric oxide synthase genotype on vasopressor requirement and fetal acid-base status during spinal anesthesia for cesarean delivery

Abstract

Background: Previous work demonstrated that maternal haplotypes of the β₂-adrenoceptor gene (ADRB2) influence ephedrine requirements during cesarean delivery. The use of ephedrine versus a pure α-adrenergic agonist such as phenylephrine has been associated with lower umbilical artery (UA) pH, thought to be secondary to increased fetal metabolism. There are no data evaluating the effect of fetal/neonatal genotypes on the metabolic response to maternally administered vasopressors. We hypothesized that neonatal ADRB2 genotype would affect the extent of neonatal acidemia. We also examined the effect of maternal ADRB2 and the endothelial nitric oxide synthase gene (NOS3) on ephedrine and phenylephrine requirements for treatment of maternal hypotension.

Methods: The study was performed on 104 Chinese women scheduled for cesarean delivery under spinal anesthesia who were participating in a double-blind randomized clinical trial evaluating the maternal and neonatal effects of ephedrine versus phenylephrine infusions. Blood samples were drawn from the UA, umbilical vein, and maternal radial artery to measure blood gas values and lactate, ephedrine, and phenylephrine concentrations, and to determine maternal and neonatal genotype at nonsynonymous single nucleotide polymorphisms at codons 16 (rs1042713) and 27 (rs1042714) of ADRB2 and codon 298 (rs1799983) of NOS. Clinical variables (UA pH, UA lactate, and dose of vasopressors) among genotypes were compared, and regression models were created to assess the effect of genotype on vasopressor dose and fetal acid-base status.

Results: Maternal ADRB2 genotype did not affect the ephedrine dose. Neonatal genotype at codon 16 influenced fetal acid-base status. UA pH was higher in Arg16 homozygous neonates (7.31 ± 0.03 in p.16Arg/Arg vs. 7.25 ± 0.11 in p.16 Arg/Gly and p.16 Gly/Gly; P < 0.001, 95%confidence interval (CI) of difference 0.03 ~ 0.09) and UA lactate was lower (2.67 mmol/L ± 0.99 in p.16Arg/Arg vs 4.28 mmol/L ± 2.79 in. p.16 Arg/Gly and p.16 Gly/Gly; P < 0.001, 95% CI of difference -2.40 ~ -0.82). In neonates born to mothers receiving ephedrine, the magnitude of the difference among genotypes was even greater (pH 7.30 ± 0.02 in p.16Arg/Arg vs. 7.19 ± 0.10 in p.16 Arg/Gly and p.16 Gly/Gly; P < 0.001, 95% CI of difference 0.07 ~ 0.14) and UA lactate was lower (3.66 mmol/L ± 1.30 in p.16Arg/Arg vs. 5.79 mmol/L ± 2.88 in p.16 Arg/Gly and p.16 Gly/Gly; P = 0.003, 95% CI of difference -3.48 ~ -0.80). In a multiple linear regression model (R² = 63.6%; P = 0.03), neonatal ADRB2 genotypes (p.16Arg/Arg and p.27Gln/Glu) and lower neonatal birth weight predicted lower UA lactate concentrations. Phenylephrine dose was not affected by maternal ADRB2 or NOS3 genotypes, and neonatal NOS3 genotype did not affect UA pH or UA lactate.

Conclusion: In contrast to previous findings in a North American cohort, maternal ADRB2 genotype did not affect ephedrine requirements during elective cesarean delivery in a Chinese cohort. However, our findings suggest that neonatal ADRB2 p.Arg16 homozygosity confers a protective effect against developing ephedrine-induced fetal acidemia.

Figure 1. Regression between uterine artery (UA) pH and ephedrine dose (mg) according to neonatal ADRB2 genotype at codon 16

The X-axis represents UA pH, Y-axis represents total ephedrine dose (mg) given to the mothers from the time of the spinal injection until delivery of the baby. The line represents the “fit line” for p.16Arg/Gly and p.16Gly/Gly. Using Pearson’s correlation rank, UA pH and ephedrine dose were correlated in p.16Arg/Gly and p.16Gly/Gly neonates (p = 0.002, r = −0.50), but not in p.16Arg/Arg neonates (p = 0.12, r = −0.56). ◆ p.16Arg/Arg (N = 9) (r² = 31.2%, p = 0.12) ○ p.16Arg/Gly and p.16Gly/Gly (N = 35) (r² = 24.9%, p = 0.002) No Arg16 homozygous neonate had UA pH < 7.28.