Genetic and epigenetic regulation of the oxytocin receptor (OXTR) gene in the pathophysiology of postpartum hemorrhage: a current perspective

Authors

Abstract

Postpartum hemorrhage (PPH), most commonly resulting from uterine atony, remains a leading cause of maternal mortality worldwide. Despite routine prophylactic oxytocin administration, PPH may occur unpredictably in women without established risk factors. This review examines the potential role of genetic and epigenetic variations in the oxytocin receptor (OXTR) gene in modulating oxytocin responsiveness and susceptibility to PPH. Emerging evidence suggests that single-nucleotide polymorphisms (SNPs) in the OXTR gene may influence receptor structure and downstream signaling. For example, carriers of the A allele of rs53576 have been reported to require additional uterotonic treatment more frequently than individuals with the homozygous guanine (GG) genotype and may exhibit an increased risk of severe bleeding. Rare variants, such as V281M and E339K, have been proposed to impair receptor localization at the cell membrane, potentially contributing to reduced oxytocin sensitivity. In addition, DNA methylation represents an important regulatory mechanism of OXTR expression. Increased methylation levels, particularly in regulatory regions such as the methylation target 2 region (MT2), may reduce receptor density in the myometrium and attenuate uterine contractility. Epigenetic aging markers (e.g., GrimAge) have also been associated with impaired uterine function, suggesting that biological aging may contribute to interindividual variability in oxytocin response. Overall, variability in OXTR genetic and epigenetic profiles may be associated with differences in oxytocin responsiveness and PPH risk; however, further large-scale and prospective studies are required before any clinical application can be considered.

Keywords

IntroductionPostpartum hemorrhage (PPH), defined as excessive bleeding occurring within the first 24 hours following delivery, is a common complication.¹ The uterine muscles contract after delivery, compressing the blood vessels in the region where the placenta separated from the uterus, and this mechanism controls bleeding. However, severe life-threatening bleeding may occur in cases where the uterine muscles do not contract strongly enough (uterine atony). PPH is conventionally defined as a blood loss of more than 500 ml in vaginal deliveries and 1000 ml in cesarean deliveries, which are the generally accepted standards.^1,2,3
It is a major cause of maternal morbidity and mortality globally. It still is a serious problem in developing countries, but is also showing a rising incidence in developed countries.² It is prevalent in developing countries with a 100> fold higher maternal mortality rate than developed countries. In the UK, it was reported as one of the leading direct causes of maternal deaths from 2013 to 2015.⁴
The incidence of PPH is influenced by several factors, such as the method of measuring blood loss, active management during the third stage of labor (e.g., use of uterotonics, uterine massage, cord traction), and obstetric interventions applied (episiotomy, mode of delivery).^1,5 While insufficient uterine contractions, or uterine atony, is the most common etiological cause of primary PPH cases, placental retention, cervical tears, and rare coagulation disorders can also accompany the condition. Although various risk factors, such as first pregnancy, maternal obesity, macrosomia, multiple pregnancy, and prolonged labor, have been identified in the literature, the most striking aspect of PPH in clinical practice is its unpredictable occurrence without any pre-existing risk factors.^1,6
Under current PPH management, the use of a ‘standard dose’ of oxytocin may sometimes fail due to individual variations and genetic/epigenetic factors. The aim of this review was to examine these genetic/epigenetic factors in the light of the current literature.
Oxytocin-Receptor Interaction: Physiological Significance in Uterine Contraction and PPHOxytocin, a neurohypophyseal peptide, is primarily synthesized in the hypothalamus and released into the systemic circulation; however, it is also produced locally in peripheral tissues such as the uterus, placenta, and amnion.⁷ The oxytocin signaling pathway, central to the labor mechanism, is currently the most fundamental pharmacological tool used in labor induction and PPH prophylaxis.⁸ Oxytocin stimulates the contraction of smooth muscle cells in the myometrium via the oxytocin receptor (OXTR), a typical class I G-protein-coupled receptor that activates the phospholipase C-beta pathway via G(q) proteins.⁷
The pressure exerted by the fetus on the cervix during birth triggers the release of oxytocin via the Ferguson reflex.⁹ This interaction triggers the release of intracellular calcium (Ca²⁺) stores, initiating actin-myosin cross-bridge formation and consequently leading to rhythmic, powerful uterine contractions.⁷ Oxytocin initiates uterine contractions by binding to specific receptors in the myometrium; during this process, high estrogen levels increase receptor sensitivity, while prostaglandin synthesis also supports cervical ripening and contractions.⁹
Physiologically, these contractions not only facilitate the baby's progression through the birth canal but also mechanically close the open blood vessels in the area where the placenta detaches after delivery, acting as a ‘physiological ligature’. Any deficiency in this critical process (uterine atony) leads to uncontrolled excessive bleeding, i.e., PPH.⁷
Genetic and Epigenetic Approach Why Do We Need to Look at the Genetic Background Rather Than Just the Protein Level?The structure of the oxytocin gene was discovered in 1984, and the oxytocin receptor sequence was reported in 1992.^10,11
OXTR is a 7-transmembrane G protein-coupled receptor that can bind to Gαi or Gαq proteins. It activates a number of signaling cascades, such as the mitogen-activated protein kinase (MAPK), protein kinase c (PKC), phospholipase c (PLC), or CaMK pathways. These cascades converge on transcription factors such as CREB or myocyte enhancer factor 2 (MEF-2).¹²
Myometrial OXTR expression, which shows a dynamic increase throughout pregnancy and peaks at the time of delivery, also triggers the release of prostaglandin f2 (PGF2) alpha from the decidua, managing a complex signaling network that initiates labor; however, these levels rapidly decrease in the early postpartum period as the uterus becomes resistant to oxytocin.^7,8
Knowing only about oxytocin levels concerning the pathophysiology of PPH, while it benefits the investigator, but we do not comprehend what made it insufficient or impaired function. This may create a ‘resistance’ or ‘insensitivity’ to oxytocin (with normal protein levels), wherein genetic variations (SNPs) modify the structure of the receptor. Thus, it is important to look into the genetic background of the OXTR gene. Epigenetic controls, especially DNA methylation, can act as a 'switch' that modulates how fast the gene is transcribed back into mRNA, enabling the cell to manufacture needed receptors. Thus, whereas measuring protein levels generates static data, genetic and epigenetic analyses give us the ability to predict an individual’s response (induction of labor or oxytocin supplementation) as well as the risk for atony and assist with tailoring a personalized therapy plan.^13,14
In a large cohort study from Sweden, which included 466,686 births, the reported incidence of PPH following vaginal deliveries was found to be 4.6%. About 18% of the risk for PPH is due to maternal genetic factors (including uterine atony and placental retention), while 11% is attributed to child genetics. But over 50% of the risk is attributed to environmental influences and epigenetic mechanisms (lifestyle, stress, external factors modifying gene expression during pregnancy).¹⁵ A retrospective study that also took place in Israel and evaluated 4406 births (779 in vitro fertilization-intracytoplasmic sperm injection [IVF-ICSI], 120 PGT, and 3507 spontaneous pregnancies) showed a similar risk of postpartum placental complications (PPH, manual removal of the placenta, or need for blood transfusions, etc.) associated with PGT; women who conceived by PGT seemed to have a risk profile comparable to those who were spontaneously pregnant. The higher risk remained even more strongly for standard IVF and microinjection (IVF-ICSI) pregnancies. The logistic multivariate analysis showed that genetic diagnosis itself was not an independent risk factor, and the increased complication rates noted in the IVF-ICSI group were attributable to epigenetic effects on placentation, or genetic background, rather than genetic intervention.¹⁶
According to Deans and Maggert, the best definition of epigenetics is the study of chromosome-based changes in gene expression that can be inherited (from cell to cell or from generation to generation) without any alteration to the DNA sequence.¹⁷
Epigenetic age is calculated based on DNA methylation levels, which undergo regular changes over time in a tissue-specific manner, and is measured using ‘epigenetic clocks’ that estimate biological age via the weighted average of specific cytosine-phosphate-guanine
(CpG) regions. The Horvath (Pan-Tissue) clock, one of the first models developed and proven accurate across numerous different tissue types, has also been validated on endometrial and cervical samples; consequently, it stands out as a particularly powerful tool for investigating functional changes in the myometrium—the muscular layer of the uterus—and age-related risks associated with childbirth.¹⁸ A study published by Erickson and colleagues in 2022 examines the biological aging process underlying the increased incidence of postpartum hemorrhage and uterine muscle (atony) complications associated with advanced maternal age.
The research has demonstrated that epigenetic clocks in the blood (DNA methylation) correlate highly with the level of aging in uterine tissue (myometrium), particularly with the GrimAge clock. This finding suggests that advanced biological age, independent of chronological age, may be associated with an increased risk of PPH through impaired uterine contractile function. In this context, blood-based epigenetic markers may have potential as candidate biomarkers for predicting severe hemorrhage during childbirth; however, further validation is required.¹⁸
The study by Danoff and colleagues links the risk of PPH directly to the epigenetic regulation of OXTR; in particular, it highlights that high DNA methylation in a region known as the methylation target 2 region (MT2) significantly reduces gene expression (receptor levels), and that this may lead to atony by weakening the uterus’s contractile response to oxytocin. This research demonstrates that methylation levels in the MT2 region (particularly the 3’ end), rather than the traditionally studied Exon 3 region, serve as a far more reliable biomarker for predicting the gene’s functionality in both the brain and peripheral tissues. Furthermore, the finding that early-life experiences can exert lasting ‘silencing’ effects on these genetic regions, and that certain genetic variations (SNPs) can exacerbate this epigenetic suppression, provides a biological explanation for why some women fail to respond adequately to standard oxytocin treatment during childbirth, thereby facing a risk of severe bleeding.¹⁴
Treatment and Challenges of PPHThere is strong evidence that the use of oxytocin during childbirth prevents primary PPH. Furthermore, it is suggested that various medical and surgical interventions, including timely blood transfusions, can prevent deaths associated with these hemorrhages.¹⁹
Oxytocin is the first-line drug used to prevent and treat PPH and exerts its effect via oxytocin receptors in uterine muscle cells (myocytes). The use of pharmaceutical (synthetic) oxytocin is routinely recommended and administered to stop bleeding by ensuring continuous contraction of the uterus after the baby is born.^13,20
The current interdisciplinary guideline, prepared using the modified Association of Anesthetists Consensus on Obstetric Hemorrhage (ACCORD) method, mandates early treatment of antepartum anemia (Hb < 10.5–11 g/L); routine uterotonic use, especially in all births; and prophylactic tranexamic acid (TXA) administration in high-risk cesarean sections for the prevention of PPH. It suggests an evidence-based approach integrated for the acute setting, including focused coagulation management (fibrinogen, plasma, erythrocytes) and calcium/temperature control advised by viscoelastic examinations (rotational thromboelastometry [ROTEM]/ thromboelastography [TEG]), with protocolized care through a simulated-trained multidisciplinary team.
As described in the Cochrane Collaboration comprehensive meta-analysis published in 2018, uterotonic drugs significantly prevent postpartum hemorrhage (PPH), most notably oxytocin compared with placebo. In clinical practice, OT has emerged as the modality of choice considering its significant reduction in risk for both suprathreshold and severe bleeding, low maternal side effects, and low-cost nature.⁸ This study emphasizes the effectiveness, safety, and economic benefits of oxytocin as a key tool for intervention in third stage labor, constituting important support to other studies which were carried out before it.²¹
In fact, clinical observations indicate that sensitivity to oxytocin varies widely among women and that this variation is again based on individual differences in OXTR expression levels.⁸
According to a recent review, the lack of an ideal animal model that fully reflects the complex vascular structure and hormonal receptor control of the human uterus makes it difficult to validate new treatments (hemostatic materials, mechanical devices) at the preclinical stage in PPH research.²²
Uterine atony, responsible for 80% of PPH cases worldwide, is a life-threatening clinical condition that can develop suddenly in half of cases without any pre-existing risk factors. The underlying cause of uterine atony is mutations in genes encoding OXTR and contraction-related proteins (CAPs), which impair the uterus's response to hypoxia and drug therapy. While preventive measures and medication are prioritized in treatment management, genetic predisposition is a key factor determining the severity of the disease and resistance to treatment.²³
According to a systematic review, prolonged oxytocin exposure during labor is thought to desensitize uterine receptors, impair contractile abilities, and increase the risk of PPH after a cesarean section. Current studies indicate the necessity for elevated doses of oxytocin postpartum to avert atony in these women; however, controlled clinical evidence remains inadequate. A methodological gap exists in this area, as most research focuses solely on postpartum prophylactic treatment without distinguishing between prenatal and postnatal oxytocin use.²⁴
Elucidating the molecular and genomic mechanisms of this complex regulation, shaped by hormonal stimulation, mechanistic stress, and inflammatory responses, particularly at the OXTR gene promoter level, is critical in predicting the risk of PPH and the response to treatment.^7,8 The molecular mechanisms underlying OXTR signaling and epigenetic regulation are summarized in Supplementary Figure 1.
Structure and Function of the OXTR GeneThis gene (OXTR) is located on the human chromosome 3,¹⁸ and 19.2 kilobases in length. This gene encodes a protein with 389 amino acids long, comprising three introns and four exons, has been reported to be expressed in reproductive organs and both the prefrontal cortex²⁵ as well as the amygdala, hypothalamus, and olfactory bulb.²⁶ OXTR sites have also been identified in the hippocampus, periaqueductal gray, striatum, nucleus accumbens, ventral tegmental area, lateral septum, and medial preoptic area.²⁷
Of note, DNA methylation uniquely regulates the expression of the OXTR gene in a region named MT2,²⁸ and there is evidence that DNA methylation within this CpG region associates with reduced OXTR expression in the brain.¹⁴
Genotype-Phenotype Relationship The Potential Effects of Specific Variants on Oxytocin Sensitivity or PPH RiskAlthough the rs2254298 single-nucleotide polymorphism of the OXTR gene has been reported in the literature as being associated with psychiatric disorders, published studies on PPH are limited.^29,30,31
Erickson et al. reported that the rs53576 variant in the OXTR gene may be associated with variability in postpartum blood loss. According to the research results, carriers of the ‘A’ allele (AA and AG genotypes) experienced significantly more blood loss and had a 79% higher risk of requiring secondary treatment compared to those with the homozygous guanine (GG) genotype. In particular, among individuals with the AA genotype, the rate of bleeding exceeding 1000 mL was reported to be as high as 55.6%, suggesting a potential contribution of genetic background to interindividual variability in the response to exogenous oxytocin. Furthermore, this study argues that OXTR methylation levels in the blood correlate positively with levels in the myometrium, and that high methylation is associated with a greater need for oxytocin and a higher risk of PPH.¹³
Danoff et al. reported that in carriers of the rs53576 "A" allele, the relationship between DNA hydroxymethylation and gene expression is disrupted, leading to oxytocin resistance.¹⁴
Malik et al.'s in vitro study³² examined the variability in clinical response to oxytocin administered at birth, focusing on 11 common variations in the oxytocin receptor gene. They found that variants V45L, P108A, L206V, V281M, and E339K significantly disrupted cellular signal transduction, receptor trafficking, and desensitization processes. Specifically, variants V281M and E339K inhibited receptor localization on the cell membrane, while variants V45L and P108A disrupted the receptor desensitization mechanism by inhibiting the binding of beta-arrestin, which causes receptor deactivation. Consequently, the researchers emphasize that these genetic differences alter the delicate balance between receptor activation and desensitization, directly affecting the required oxytocin dosage and treatment response for patients.²⁹
Ethical ApprovalThis study did not require ethical approval as it is a narrative review based on previously published literature and did not involve human participants, patient data, or animal subjects.
Reporting GuidelinesThis narrative review was prepared in accordance with the SANRA guidelines and relevant best practices for narrative reviews.

Limitations

This review has several limitations. The available evidence on OXTR genetic and epigenetic variations in relation to postpartum hemorrhage is limited, heterogeneous, and largely based on small observational studies, restricting causal interpretation. The functional effects of many reported variants and methylation patterns remain unclear, and findings are not always consistent across populations. In addition, the use of peripheral blood methylation as a surrogate for myometrial tissue may not fully reflect local receptor regulation. Therefore, further large-scale and well-designed studies are needed to confirm these findings and clarify their clinical relevance.

Conclusion

While traditional approaches to PPH management have largely followed a “one-size-fits-all” strategy (e.g., uniform oxytocin administration), this review highlights the heterogeneity of OXTR genetic and epigenetic characteristics. Future studies should further investigate whether OXTR methylation patterns are associated with postpartum hemorrhage risk and whether they may have potential utility in risk stratification; however, their clinical applica-bility requires validation in large-scale prospective studies. In the future, rapid epigenetic screening during the antenatal period (e.g., assessment of OXTR methylation in blood) may help to better characterize interindividual variability in oxytocin responsiveness and may contribute to explaining differences in treatment response. However, further evidence is re-quired before any clinical implications, including the consideration of alternative uterotonic strategies, can be drawn.

Declarations

Abbreviations

ACCORD: Association of Anesthetists Consensus on Obstetric Hemorrhage
Ca²⁺: calcium ion
CAPs: contraction-associated proteins
CpG: cytosine-phosphate-guanine
DNA: deoxyribonucleic acid
GG: homozygous guanine genotype
Gαi: g alpha i protein
Gαq: g alpha q protein
IVF: in vitro fertilization
IVF-ICSI: in vitro fertilization-intracytoplasmic sperm injection
MAPK: mitogen-activated protein kinase
MEF-2: myocyte enhancer factor 2
mRNA: messenger ribonucleic acid
MT2: methylation target 2 region
OXTR: oxytocin receptor
PGF2: prostaglandin f2
PKC: protein kinase c
PLC: phospholipase c
PPH: postpartum haemorrhage
ROTEM: rotational thromboelastometry
SANRA: scale for the assessment of narrative review articles
SNPs: single nucleotide polymorphisms
TEG: thromboelastography
TXA: tranexamic acid

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About This Article

Received:

March 27, 2026

Accepted:

April 24, 2026

Published Online:

April 24, 2026