Preterm labor, labor progression, and delivery

The contribution of genetic variants to preterm labor, and the progression and outcome of term labor, including mode of delivery, have been the focus of several clinical studies.

The phenotype of “preterm birth” is defined as having 5 components: (1) maternal conditions present before delivery, (2) fetal conditions present before delivery, (3) placental pathologic conditions, (4) signs of the initiation of parturition, and (5) the pathway to delivery . Genetic variants could in theory exert effects on any of these five components; therefore, the nature of and contribution of any genetic variant to overall risk or outcome is difficult to quantify.

For the β ₂ −adrenergic receptor gene ( ADRB2 ), in particular two common polymorphisms found in strong linkage disequilibrium, p.16Arg/Gly and p.27Gln/Glu, have been extensively evaluated in a number of anesthesia-related studies with relevant clinical effects described in the context of airway responsiveness and cardiac perioperative outcomes . As β-adrenoceptors exist on the human uterus and mediate uterine smooth muscle relaxation, and because they were a major pharmacologic target for tocolysis in preterm labor or other forms of uterine hypercontractility, this genetic variant was an obvious early candidate gene for studies of genetic effects on preterm labor and delivery.

In a small association study in a North American cohort, homozygosity for Arg16 of ADRB2 was shown to confer protection from preterm delivery . A subsequent case–control study in a Hungarian population also demonstrated a strong protective effect of Arg16 homozygosity, as no woman with spontaneous preterm birth or rupture of membranes was Arg16 homozygous in this cohort of women, 20% of whom showed this genotype . A Turkish study suggested that the Glu27 variant of ADRB2 increases the risk for preterm delivery . Thereafter, in a cohort of Swiss women diagnosed with idiopathic preterm labor between 24 and 34 weeks’ gestation, hexoprenaline, a β ₂ -adrenergic agonist administered for tocolysis, was found to be more effective among women homozygous for Arg16, demonstrating a true pharmacogenetic effect .

In a large prospective study evaluating the impact of ADRB2 genotype/haplotype on preterm labor, a sub-analysis of North American women with term or near-term labor (>34 weeks) confirmed the hypothesis that Arg16 homozygosity of ADRB2 is associated with a slower rate of labor progress compared with women with all other genotypes ; women with Arg16Arg – Gln27Gln (double homozygous) genotype progressed at the slowest rate of active labor (‘slow haplotype’), and women with Gly16Gly – Glu27Glu (double homozygous) genotype progressed with the fastest cervical rate (‘fast haplotype’).

Another study from the same North American group used a previously validated nonlinear mixed effects model (NONMEM) of labor progression to predict labor progression and pain during the first stage of labor in nulliparous women, according to ADRB2 and OPRM1 (μ-opioid receptor gene). Women with ADRB2 Gln27 homozygosity had a slower transition to active phase labor, resulting in prolonged labor, than those with the other genotypes . Genotype was strongly correlated with ethnicity (e.g., no Asian women included in the study was Glu27 homozygous), and labor was indeed slower among Asians. The study was underpowered to detect an effect of OPRM1 (rs1799971, codon 40) on labor pain, but identified cold sensitivity as a pain modality that may predict the intensity of labor pain.

Using the same model to evaluate the progression of labor, ADRB2 , COMT (catechol-O-methyltransferase gene), and OXTR (oxytocin receptor gene) were examined in a Saudi Arabian cohort . One variant of COMT (rs4633) and one of OXTR (rs53576) were associated with increased duration of the latent phase of the first stage of labor in nulliparous women, resulting in longer labors (prolonged approximately 5 h for COMT and 2 h for OXTR ). These findings among Saudi women contrast with results from other studies that found no effect of OXTR single nucleotide polymorphisms (SNPs) on the duration of the first stage of labor or risk of dystocia . In addition, ADRB2 genotype/haplotype was not associated with labor progression once demographic factors were considered . Data combining all the genetic variants (joined allelic combination) for each woman in the cohort were not reported; therefore, assessing the contribution of specific haplotypes on labor progression was not possible.

Taken together, studies evaluating obstetrical outcomes based on ADRB2 genotype suggest that women carrying Arg16 and/or Gln27 are conferred protection from preterm delivery and have a more ‘quiescent’ uterus, resulting in a slower progression and prolonged labor duration. In addition to ethnicity and maternal weight, factors influencing labor progression are multiple, and ADRB2 is only one of the many possible candidate genes that may influence labor progression. Therefore, at the current time, evaluating women’s genetic profiles is unlikely to contribute in a significant manner to clinical decision-making or risk assessment.

At the opposite extreme of the clinical spectrum from preterm labor (the “over-excitable uterus”), a genome-wide scan study in Sweden has identified at least 6 loci that appear to contribute to the risk of women requiring a cesarean delivery for dystocia (the “poorly contractile uterus”) ; further prospective studies will be needed to validate or refute these findings.

Hemodynamics and vasopressor response during spinal anesthesia for cesarean delivery

The response to vasopressor agents (α- and β-adrenergic agonists) to prevent and manage maternal hypotension following neuraxial anesthesia for elective cesarean delivery has been extensively studied . To date, five studies have evaluated the effect of ADRB2 genotype/haplotype on maternal hemodynamic and vasopressor requirement during cesarean delivery under spinal anesthesia . In the first of these studies in a North American cohort, the incidence and severity of maternal hypotension after spinal anesthesia for cesarean delivery and the response to treatment were affected by ADRB2 genotype/haplotype . Women with either Gly16Gly – Gln27Glu or Gly16Gly – Glu27Glu (double homozygous) haplotype were found to require significantly less vasopressor (ephedrine) for the treatment of hypotension during spinal anesthesia. These two “protective” haplotypes associated with less hypotension are relatively common in Caucasians (20%). In contrast, in a smaller Brazilian cohort, Arg16 homozygosity appeared to confer protection from hypotension, and ephedrine requirements were lower in women with that genotype . In a follow-up study by the same authors that included data from the same cohort, the double homozygous Arg16Arg – Gln27Gln haplotype appeared again to reduce the incidence of hypotension and need for ephedrine, although most of the differences in hypotension incidence occurred after delivery (15–30 min after spinal injection) . The influence of spinal anesthesia itself versus blood loss, oxytocin, or other post-delivery factors was unclear.

In a cohort of Asian women , the 2 haplotypes previously found to be associated with lower ephedrine requirements in the North American cohort were under-represented and ADRB2 genotype/haplotype was not found to significantly influence maternal ephedrine requirements .

A follow-up study from the North American group, using a more contemporary vasopressor regimen with a phenylephrine infusion, again evaluated spinal hypotension and phenylephrine dosing during cesarean delivery . As the effect of phenylephrine, an α ₁ -adrenergic agonist, is unlikely to be directly affected by ADRB2 genotype, any differences in phenylephrine requirements based on ADRB2 are likely an effect on blood pressure regulation in response to spinal anesthesia, rather than a specific pharmacogenetic effect on spinal anesthesia-induced hypotension. In the adjusted analysis, Arg16 homozygosity was associated with moderately greater phenylephrine doses than other genotypes.

Taken together, the two studies from the North American group suggest that the pharmacologic effect of ephedrine in the setting of treatment for spinal anesthesia-induced hypotension is altered by the ADRB2 genotype because the dose of phenylephrine needed to maintain blood pressure after spinal anesthesia is less affected than the ephedrine dose by the ADRB2 genotype . In both North American studies, in contrast to the Brazilian cohort Arg16 homozygous patients received more drug (ephedrine or phenylephrine), suggesting that Arg16 homozygosity predisposes to hypotension with spinal anesthesia, and therefore, higher vasopressor requirements. Historically, ephedrine was the drug of choice to treat spinal anesthesia-induced hypotension during pregnancy, although the current clinical practice is to prevent hypotension with phenylephrine, administered either as a bolus or a continuous infusion. Nonetheless, pharmacogenetic effects may explain why two decades of multiple studies trying to define a single optimal strategy (fluid loading, ephedrine, or phenylephrine) to prevent or treat hypotension during spinal anesthesia for cesarean delivery have failed to identify that one regimen that ‘fits all.’

Hemodynamics and vasopressor response during spinal anesthesia for cesarean delivery

The response to vasopressor agents (α- and β-adrenergic agonists) to prevent and manage maternal hypotension following neuraxial anesthesia for elective cesarean delivery has been extensively studied . To date, five studies have evaluated the effect of ADRB2 genotype/haplotype on maternal hemodynamic and vasopressor requirement during cesarean delivery under spinal anesthesia . In the first of these studies in a North American cohort, the incidence and severity of maternal hypotension after spinal anesthesia for cesarean delivery and the response to treatment were affected by ADRB2 genotype/haplotype . Women with either Gly16Gly – Gln27Glu or Gly16Gly – Glu27Glu (double homozygous) haplotype were found to require significantly less vasopressor (ephedrine) for the treatment of hypotension during spinal anesthesia. These two “protective” haplotypes associated with less hypotension are relatively common in Caucasians (20%). In contrast, in a smaller Brazilian cohort, Arg16 homozygosity appeared to confer protection from hypotension, and ephedrine requirements were lower in women with that genotype . In a follow-up study by the same authors that included data from the same cohort, the double homozygous Arg16Arg – Gln27Gln haplotype appeared again to reduce the incidence of hypotension and need for ephedrine, although most of the differences in hypotension incidence occurred after delivery (15–30 min after spinal injection) . The influence of spinal anesthesia itself versus blood loss, oxytocin, or other post-delivery factors was unclear.

In a cohort of Asian women , the 2 haplotypes previously found to be associated with lower ephedrine requirements in the North American cohort were under-represented and ADRB2 genotype/haplotype was not found to significantly influence maternal ephedrine requirements .

A follow-up study from the North American group, using a more contemporary vasopressor regimen with a phenylephrine infusion, again evaluated spinal hypotension and phenylephrine dosing during cesarean delivery . As the effect of phenylephrine, an α ₁ -adrenergic agonist, is unlikely to be directly affected by ADRB2 genotype, any differences in phenylephrine requirements based on ADRB2 are likely an effect on blood pressure regulation in response to spinal anesthesia, rather than a specific pharmacogenetic effect on spinal anesthesia-induced hypotension. In the adjusted analysis, Arg16 homozygosity was associated with moderately greater phenylephrine doses than other genotypes.

Taken together, the two studies from the North American group suggest that the pharmacologic effect of ephedrine in the setting of treatment for spinal anesthesia-induced hypotension is altered by the ADRB2 genotype because the dose of phenylephrine needed to maintain blood pressure after spinal anesthesia is less affected than the ephedrine dose by the ADRB2 genotype . In both North American studies, in contrast to the Brazilian cohort Arg16 homozygous patients received more drug (ephedrine or phenylephrine), suggesting that Arg16 homozygosity predisposes to hypotension with spinal anesthesia, and therefore, higher vasopressor requirements. Historically, ephedrine was the drug of choice to treat spinal anesthesia-induced hypotension during pregnancy, although the current clinical practice is to prevent hypotension with phenylephrine, administered either as a bolus or a continuous infusion. Nonetheless, pharmacogenetic effects may explain why two decades of multiple studies trying to define a single optimal strategy (fluid loading, ephedrine, or phenylephrine) to prevent or treat hypotension during spinal anesthesia for cesarean delivery have failed to identify that one regimen that ‘fits all.’

Labor pain and analgesia

There is an extensive body of literature on the genetics of pain and response to opioids ; however, findings are not particularly congruent across studies. Specifically, genetic associations seem to vary when examining different pain phenotypes. Indeed, studies evaluating genetic influences on experimental pain in healthy volunteers, oral opioid therapy in cancer patients, postoperative opioid consumption or neuraxial labor analgesia effects have reported divergent, sometimes opposite, effects. A likely explanation for these divergent results is that different pain modalities such as the visceral component of labor pain, are inherently distinct from the predominantly somatic component of postsurgical pain, and that different opioids, delivered through different routes, may affect receptors and pathways in different parts of the nervous system, and undergo metabolism by different metabolic pathways with different pharmacogenetic influences.

The gene coding for the μ-opioid receptor, OPRM1 , is one of the most widely studied genes in the context of pain, and obstetric pain in particular . Genetic variants of OPRM1 have been evaluated in numerous clinical acute and chronic pain settings as well as in patients with alcohol and opioid addiction. A OPRM1 single nucleotide polymorphism, in which adenine is substituted by guanine at nucleotide position 118 (resulting in the replacement of asparagine by aspartate at codon 40 of OPMR), is the most well-studied SNP in the setting of pain and opioid analgesia. The frequency of the G118 allele varies according to race/ethnicity, occurring in approximately 30% among non-Hispanic Caucasians , 60%–80% among Asians , and likely lower among Hispanics and African Americans.

The first clinical trial designed to study the effect of genetic influences on labor pain and analgesic response to neuraxial opioids evaluated the A118G genetic variant of OPRM1 in a Swiss cohort of healthy nulliparous women . Women were enrolled in the third trimester, and on the basis of genotyping, they were classified as homozygous A118 or heterozygous/homozygous G118. If enrolled women requested early labor neuraxial analgesia (<6 cm cervical dilation), their response to intrathecal fentanyl , administered as a component of combined-spinal epidural (CSE) analgesia, was assessed. The study included two separate trials to estimate the median effective dose (ED50) of intrathecal fentanyl based on genotype, defined as the dose of fentanyl providing complete analgesia (verbal rating scale score ≤1/10, 0–10 point scale) for 60 min in 50% of women. Using a sequential allocation design, the ED50 for fentanyl was greater (by a factor of 1.5) among A118 homozygotes than in women with the two other genotypes. In a separate trial using a random-dose allocation method, this finding was confirmed with very similar results; the ED50 was 2-fold greater among A118 homozygotes. In addition, cervical dilatation at the time of labor analgesia request was significantly lower among A118 homozygotes, indicating that these women requested analgesia earlier in labor than women carrying at least one G118 allele. Taken together, these findings suggest that A118 homozygotes require a significantly higher dose of intrathecal fentanyl for early labor analgesia. This is an important finding for clinicians, because the spinal dose cannot be titrated; a dose must be chosen before the effects are assessed, and the adverse effect profile of intrathecal fentanyl is dose-dependent (e.g., nausea, pruritus). Therefore, reducing the dose in women with lower dose requirements has the potential to improve clinical outcomes. The higher dose requirement would apply to approximately 30% of Caucasian women and even higher percentage of Asian women.

Following this first study, the investigators sought to determine whether A118G variant of OPRM1 also influences the duration of intrathecal fentanyl analgesia for early labor analgesia . This prospective observational trial was performed in a cohort of North American women. Similar to the previous study, women were classified in one of two groups according to OPRM1 genotyping. The duration of intrathecal fentanyl analgesia was defined as the time elapsed between administration of the intrathecal fentanyl dose and the next parturient request for analgesia (administered through the epidural catheter). There were no significant differences between genetic groups in the duration of intrathecal fentanyl analgesia in early labor. A possible explanation for these negative results is that all women received a high dose of fentanyl (25 μg), and therefore, a subtle genetic influence may have been masked by this large dose.

As a follow-up to the study evaluating the effect of A118G variant of OPRM1 on the response to intrathecal fentanyl for early labor analgesia, the response to epidural sufentanil was evaluated in a cohort of healthy nulliparous Italian women using an up-down sequential allocation study design . Genotyping was performed between 35 and 37 weeks’ gestation, and women were classified as A118 homozygotes or heterozygous/homozygous G118. Similar to the findings with intrathecal fentanyl, the ED50 was significantly greater (by 25%) among A118 homozygotes than in women with the two other genotypes. On the basis of findings from these three studies in healthy nulliparous women delivering with early neuraxial analgesia, it can be reasonably concluded that the A118G variant of OPRM1 influences the potency of neuraxial lipophilic opioids (fentanyl or sufentanil) for labor analgesia, with lower dose requirements in women carrying the G118 allele, but this SNP does not influence the duration of analgesia.

A group of Swedish investigators conducted an observational study to investigate whether the A118G variant of OPRM1 influences the cervical dilation at the time of arrival in the labor and delivery unit, as a surrogate to estimate the progression of painful labor and the requests for different analgesic modalities during labor . Women were categorized as A118 homozygotes (81%), A118G heterozygotes (18%), and G118 homozygotes (2%). There was no association of cervical dilation on arrival at the delivery unit or use of any type of analgesia (epidural or second-line analgesia) during labor with A118G genotype. These authors concluded that this genotype is unlikely to be of major importance in predicting pain-related behaviors during labor.

The guanosine triphosphate cyclohydrolase gene ( GCH1 ) shows up to 15 SNPs and has been associated with reduced pain sensitivity in a variety of pain settings. Pain behaviors during labor and delivery were assessed in the same cohort of Swedish women , with genotyping of “pain-protective” SNPs of the GCH1 gene . Women were classified as homozygous (2%), heterozygous (27%), and non-carriers (71%) of pain-related SNPs. Homozygous carriers of SNPs associated with ‘pain-protection’ were admitted to the labor and delivery unit in more advanced labor (measured by cervical dilation) than heterozygous carriers and non-carriers. The authors concluded that GCH1 may influence the pain experience during the initial stage of labor. Unfortunately, because the epidural analgesia rate was relatively low (approximately 20%) and epidural analgesia services were not available 24 h per day in the institution where this study was performed, any effect of GHC1 variants, or OPRM1, on the need for or request for analgesia was difficult to assess.

Interestingly, findings in laboring women disagree with other studies examining the influence of A118G genotype of OPRM1 and opioid analgesia on pain . These studies include studies of postoperative intravenous fentanyl consumption , spinal morphine for postcesarean pain , intravenous morphine for postoperative pain , and oral morphine for chronic cancer pain . Potential explanations for such discrepant results are that labor pain is different from that experienced in other clinical settings (e.g., experimental pain, postoperative pain, chronic pain), or perhaps the response to systemic compared with neuraxial opioids is affected differently by the OPRM1 genotype because of differences in receptor mechanism and coupling in different areas of the neurological system, or secondary/linked genetic changes related to neural connections and pain transmission.

The possible effect of polymorphisms of COMT and OPRM1 on analgesia from intravenous fentanyl for labor analgesia was examined in one study . The study did not show any specific effects of either gene on the success of fentanyl analgesia and was underpowered to find effects of combinations of genotypes. While the major finding of this study was that intravenous fentanyl is not effective for labor analgesia, the findings also suggest that one should not expect major differences in intravenous fentanyl analgesia efficacy based on genetics; no particular genetic population seems to benefit significantly more than others from such therapy. Genetic influences, if any, are probably modest in this context.