Polymorphism in the ADRB2 gene explains a small portion of intersubject variability in pain relative to cervical dilation in the first stage of labor.

BACKGROUND: Variability in labor pain has been associated with demographic, clinical, and psychological factors. Polymorphisms of the ß2-adrenergic receptor gene (ADRB2) influence sensitivity to experimental pain in humans and are a risk factor for chronic pain. The authors hypothesized that polymorphisms in ADRB2 may influence labor pain. METHODS: After Institutional Review Board approval and written informed consent, the authors prospectively obtained hourly pain reports from 233 nulliparous parturients during the first stage of labor, of which 199 were included in the current analysis. DNA from blood samples was genotyped at polymorphisms in the genes for the ß2-adrenergic receptor, the µ opioid receptor subtype 1, catechol-O-methyltransferase, fatty acid amide hydrolase, and the oxytocin receptor. Labor pain as a function of cervical dilation was modeled with previously described methods. Patient covariates, ADRB2 genotype, and obstetrical and anesthesia treatment were evaluated as covariates in the model. RESULTS: Labor pain more rapidly became severe in parturients heterozygous or homozygous for the G allele at rs1042714 in the ADRB2 gene. Labor pain increased more rapidly after artificial rupture of membranes, augmentation with oxytocin, and in younger women. Inclusion of covariates explained approximately 10% of the variability between subjects. ADRB2 genotype explained less than 1% of the intersubject variability. CONCLUSION: ADRB2 genotype correlates with labor pain but explained less than 1% of the intersubject variance in the model.

Characterization of the myometrial transcriptome in women with an arrest of dilatation during labor.

OBJECTIVE: The molecular basis of failure to progress in labor is poorly understood. This study was undertaken to characterize the myometrial transcriptome of patients with an arrest of dilatation (AODIL). STUDY DESIGN: Human myometrium was prospectively collected from women in the following groups: (1) spontaneous term labor (TL; n=29) and (2) arrest of dilatation (AODIL; n=14). Gene expression was characterized using Illumina® HumanHT-12 microarrays. A moderated Student's t-test and false discovery rate adjustment were used for analysis. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) of selected genes was performed in an independent sample set. Pathway analysis was performed on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database using Pathway Analysis with Down-weighting of Overlapping Genes (PADOG). The MetaCore knowledge base was also searched for pathway analysis. RESULTS: (1) Forty-two differentially expressed genes were identified in women with an AODIL; (2) gene ontology analysis indicated enrichment of biological processes, which included regulation of angiogenesis, response to hypoxia, inflammatory response, and chemokine-mediated signaling pathway. Enriched molecular functions included transcription repressor activity, heat shock protein (Hsp) 90 binding, and nitric oxide synthase (NOS) activity; (3) MetaCore analysis identified immune response chemokine (C-C motif) ligand 2 (CCL2) signaling, muscle contraction regulation of endothelial nitric oxide synthase (eNOS) activity in endothelial cells, and triiodothyronine and thyroxine signaling as significantly overrepresented (false discovery rate <0.05); (4) qRT-PCR confirmed the overexpression of Nitric oxide synthase 3 (NOS3); hypoxic ischemic factor 1A (HIF1A); Chemokine (C-C motif) ligand 2 (CCL2); angiopoietin-like 4 (ANGPTL4); ADAM metallopeptidase with thrombospondin type 1, motif 9 (ADAMTS9); G protein-coupled receptor 4 (GPR4); metallothionein 1A (MT1A); MT2A; and selectin E (SELE) in an AODIL. CONCLUSION: The myometrium of women with AODIL has a stereotypic transcriptome profile. This disorder has been associated with a pattern of gene expression involved in muscle contraction, an inflammatory response, and hypoxia. This is the first comprehensive and unbiased examination of the molecular basis of an AODIL.

Oxytocin and catechol-O-methyltransferase receptor genotype predict the length of the first stage of labor.

OBJECTIVE: We aimed to identify genetic factors that influence the rate of the first stage of labor. STUDY DESIGN: We prospectively enrolled 233 laboring nulliparous parturients. Demographic, clinical, and genetic data were collected. We evaluated the influence of population and individual variability using a nonlinear mixed effects model. RESULTS: Parturients who were homozygous for "G" at oxytocin receptor gene rs53576 transitioned to active labor later and thus had slower labor. Catechol-O-methyltransferase rs4633 genotype TT was associated with slower latent phase labor. Labor induction with prostaglandin was associated with faster labor, and request for meperidine was associated with slower labor. Birthweight was related inversely to the rate of the active phase. CONCLUSION: There are demographic, clinical, and genetic factors that influence an individual's rate of labor progress. This information could be used in automated form to improve the prediction of the length of the first stage of labor.

Beta-2 adrenoceptor genotype and progress in term and late preterm active labor.

OBJECTIVE: We sought to evaluate whether beta-2 adrenoceptor (ß2AR) genotype at a functional polymorphic site encoding for amino acid residue 16 influences rate of cervical dilatation in term and late preterm active labor. STUDY DESIGN: Subjects who underwent vaginal delivery at ≥34 weeks' gestational age from May 2006 through August 2007 were identified. Each subject had provided venous blood from which DNA was extracted for ß2AR genotyping. Digital cervical examinations with paired examination times were collected from intrapartum records. Rate of cervical dilatation in active labor was determined using linear regression. Rates were compared between genotype groups. RESULTS: Among 401 subjects with satisfactory genotype and intrapartum data, overall rate of active labor was 0.76±0.01 cm/h. When labor was compared by genotype, homozygous Arg/Arg16 subjects progressed at a slower rate (0.64±0.03 cm/h) than all other pooled genotypes (0.8±0.02 cm/h, P<.001). CONCLUSION: Homozygous ß2AR genotype encoding for Arg/Arg16 was associated with slower progress in active labor.

Processes regulating cervical ripening differ from cervical dilation and postpartum repair: insights from gene expression studies.

A greater understanding of the processes that regulate cervical remodeling during pregnancy, parturition, and the postpartum period is required to understand causes of preterm and posterm birth in which abnormal cervical function is the primary culprit. In the current study, gene expression patterns unique to cervical ripening as compared with cervical dilation and/or postpartum repair are identified in a mouse model. Genes differentially regulated from gestation day 15 to late day 18 reveal processes important for cervical ripening. Genes differentially regulated from late day 18 to 2 hours after birth reveal processes that could be important during cervical dilation or the postpartum recovery period. Based on expression patterns, cervical ripening requires a downregulation of collagen assembly genes; increased synthesis of glycosaminoglycans that disrupt the matrix, such as hyaluronan; increased metabolism of progesterone; and changes in epithelial barrier properties. The latter phases of dilation and postpartum recovery are associated with increased assembly of mature collagen, synthesis of matrix proteins that promote a dense connective tissue, activation of inflammatory responses, prostaglandin synthesis, and further changes in epithelial barrier properties and differentiation. Processes/gene expression required for cervical ripening are distinct from those important in latter phases of cervical remodeling and highlight the importance of timing of tissue collection for understanding the molecular mechanisms of cervical ripening.