Effect of reproductive ageing on pregnant mouse uterus and cervix.

Rima Patel,Evangelia Mourmoura,Paul T Seed,Lucilla Poston,Luc Demaison,James D Moffatt,Rachel M Tribe

doi:10.1113/jp273350

Abstract

Key points Older pregnant women have a greater risk of operative delivery, still birth and post‐term induction.This suggests that maternal age can influence the timing of birth and processes of parturition.We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour.Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function.Uterine ageing and labour dysfunction should be investigated further in older primigravid women. Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth and post‐term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3‐month‐old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin‐43 mRNA expression were reduced in the myometrium from 8‐month‐old vs. 3‐month‐old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age‐induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8‐month‐old mice provide a useful model of reproductive ageing. The present study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women.

Highlights

Over recent decades, the average age of primigravid mothers in developed countries has increased progressively, with women over the age of 35 years comprising a significant proportion of the pregnant population (Office for National Statistics for England and Wales, 2013) (Matthews & Hamilton, 2014)
Other studies have suggested that myometrial tissue responds less effectively to uterotonic agents such as oxytocin or prostaglandins with increasing maternal age (Greenberg et al 2007; Arrowsmith et al 2012), which is supported by the observation that women of older age have a greater probability of requiring oxytocin-augmentation for the induction of labour (Adashek et al 1993; Main et al 2000)
The present study confirms that both gestation and parturition are prolonged in a primiparous mouse model of maternal ageing, and there is deterioration in reproductive capacity as reflected by a decline in litter size

Summary

Introduction

The average age of primigravid mothers in developed countries has increased progressively, with women (including multiparous women) over the age of 35 years comprising a significant proportion of the pregnant population (Office for National Statistics for England and Wales, 2013) (Matthews & Hamilton, 2014). Such trends are accompanied by a simultaneous rise in the incidence of pregnancy complications such as post-term induction, failure to progress in labour, and postpartum haemorrhage (Ecker et al 2001; Roos et al 2010; Yogev et al 2010). Other studies have suggested that myometrial tissue responds less effectively to uterotonic agents such as oxytocin or prostaglandins with increasing maternal age (Greenberg et al 2007; Arrowsmith et al 2012), which is supported by the observation that women of older age have a greater probability of requiring oxytocin-augmentation for the induction of labour (Adashek et al 1993; Main et al 2000)

Methods

Results

Discussion

Conclusion