A role for the liver in parturition and preterm birth

Abstract

Neither the mechanisms of parturition nor the pathogenesis of preterm birth are well understood. Poor nutritional status has been suspected as a major causal factor, since vitamin A concentrations are low in preterm infants. However, even large enteral doses of vitamin A from birth fail to increase plasma concentrations of vitamin A or improve outcomes in preterm and/or extremely low birthweight infants. These findings suggest an underlying impairment in the secretion of vitamin A from the liver, where about 80% of the vitamin is stored. Vitamin A accumulates in the liver and breast during pregnancy in preparation for lactation. While essential in low concentration for multiple biological functions, vitamin A in higher concentration can be pro-oxidant, mutagenic, teratogenic and cytotoxic, acting as a highly surface-active, membrane-seeking and destabilizing compound. Regarding the mechanism of parturition, it is conjectured that by nine months of gestation the hepatic accumulation of vitamin A (retinol) from the liver is such that mobilization and secretion are impaired to the point where stored vitamin A compounds in the form of retinyl esters and retinoic acid begin to spill or leak into the circulation, resulting in amniotic membrane destabilization and the initiation of parturition. If, however, the accumulation and spillage of stored retinoids reaches a critical threshold prior to nine months, e.g., due to cholestatic liver disease, which is common in mothers of preterm infants, the increased retinyl esters and/or retinoic acid rupture the fetal membranes, inducing preterm birth and its complications, including retinopathy, necrotizing enterocolitis and bronchopulmonary dysplasia. Subject to testing, the model suggests that measures taken prior to and during pregnancy to improve liver function could reduce the risk of adverse birth outcomes, including preterm birth.

Selected maternal, fetal and placental trace element and heavy metal and maternal vitamin levels in preterm deliveries with or without preterm premature rupture of membranes

“…However, retinol is implicated through the mechanism of parturition, and until 9 months of gestation it is supposed to accumulate in the liver with an impairment in mobilization and secretion until a point when stored vitamin A compounds begin to spill or leak into the circulation in the form of retinyl esters and retinoic acid and result in destabilization of amniotic membrane and initiate parturition. However, if a critical threshold is reached for the accumulation and spillage of stored retinoids prior to 9 months, for example, due to cholestatic liver disease, which is common in mothers of preterm infants, the increased retinyl esters and/or retinoic acid rupture the fetal membranes and induce preterm birth and its complications . These observations in accordance with our findings point to the need to reevaluate the role of vitamin A in preterm births resulting from PPROM in particular.…”

“…In our study, the level of retinol was significantly higher in the sera of mothers giving birth preterm as a result of PPROM, compared to that in the sera of mothers with spontaneous preterm births presenting with intact membranes. Although vitamin A (retinol) is essential for various biological functions in low concentrations, it can be a pro‐oxidant and highly surface‐active, membrane‐seeking and destabilizing compound in higher concentrations . In the study by Ilhan et al ., vitamin A levels were statistically similar in women with singleton pregnancies diagnosed with PPROM between 24 and 34 weeks of gestation and gestational age‐matched pregnant women who delivered at term .…”

“…Although vitamin A is essential in low concentration for multiple biological functions, it can be teratogenic, mutagenic, pro‐oxidant and cytotoxic in higher concentrations and may act as a highly surface‐active, membrane‐seeking and destabilizing compound . Early disturbances in liver function and retinoid metabolism have also been implicated in preterm birth, and other adverse birth outcomes by the exposure of a fetus to excess retinoid concentrations have been reported …”

Screening for Preterm Birth: Potential for a Metabolomics Biomarker Panel

“…Total serum bile acids have previously been correlated with preterm birth [26]. Mawson suggests that preterm birth and related adverse birth outcomes occur due to liver dysfunction [27]. “With regard to the mechanism of preterm birth, it is proposed that cholestatic liver dysfunction and associated increases in circulating concentrations of retinyl esters and/or retinoic acids rupture the fetal membranes, inducing preterm birth and the characteristic features of the preterm infant, including retinopathy, necrotising enterocolitis and bronchopulmonary dysplasia.”…”

Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism

“…The strength and consistency of the findings (e.g., in terms of links between diagnoses and medication use) suggest the possibility that some aspect of the current vaccination schedule, especially in the wake of preterm birth, which is known to be associated with maternal liver dysfunction [171,172], could be contributing to increases in autism and related chronic diseases in children. Follow-up studies are urged to confirm or refute these findings.…”