Studies - RU486 / Chemical Abortion / Maternal Mortality

Repeated Mifepristone Abortion Affects Subsequent Pregnancy Outcomes in BALB/c Mice (2012)

This 2012 MOUSE study from China shows that chemical abortion mifepristone (RU-486) adversely affects the female reproductive system.

Overall, mice that experienced 2 previous medical/chemical abortions had spontaneous abortions (‘miscarriages’) in subsequent pregnancies; repeated medical/chemical abortion affected the expression of metabolic genes in the livers of living offspring; abortion decreased sperm motility in the first generation male offspring; and finally, medical/chemical abortion caused reduced reproductive capacity, caused placental dysfunction, and reduced the expression of protein-making genes needed in pregnancy metabolism.

It should be noted that no spontaneous abortions (miscarriages) were observed in the control groups of mice.

 

http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0048384&representation=PDF

Abstract
Aim:
In this study, we aimed to establish a mouse model of repeated medical termination of pregnancy in order to
determine subsequent outcomes.

Methods:
A model of mifepristone (RU 486)-induced medical abortion was established in BALB/c mice to facilitate the investigation of the impact of medical abortion on subsequent pregnancies, including litter sizes and newborn birth weights.

Pregnant mice were sacrificed to…

– examine midterm pregnancy status, investigate the frequency of fetal resorption,
– measure placental function gene expression by real-time PCR and immunohistochemistry.

Offspring liver mRNA was harvested for real-time PCR to determine gene expression and assess the effects of abortion on offspring development.

Results:
Mice subjected to 2 previous medical abortions experienced spontaneous abortions in subsequent pregnancies.

Medical abortion caused reduced reproductive capacity and affected placental dysfunction, with reduced expression of tissue factor (TF) and genes encoding proteins involved in metabolic functions relevant to pregnancy, such as 11b-hydroxysteroid dehydrogenase 1/2 (11b-HSD1/2) and glucocorticoid receptor (GR).

Reduced expression was also observed for platelet endothelial cell adhesion molecule-1 (CD31) and vascular endothelial growth factor (VEGF).

Repeated Medical Abortion affected the expression of Metabolic Genes in the livers of offspring.

In offspring from subsequent pregnancies, genes involved in lipid metabolism, which may enhance key lipid transcription factors, such as PPARA and PPARG, as well as GR/11b-HSD1, were downregulated in the liver.

In addition, abortion decreased Sperm Motility in F1 Generation males.

Spontaneous abortion frequencies in mice that had undergone 1 or 2 medical abortions were 62.5% (5/8) and 70.3% (19/27) in the T_G2P1 and T_G3P1 mice, respectively.

No spontaneous abortions were observed in the control groups (Table 1)…

Discussion

BALB/c mice that experienced repeated early medical abortions exhibited spontaneous abortion and pregnancy loss during subsequent pregnancies.

In addition, the litter sizes and birth weights of newborns from subsequent pregnancies were also adversely affected.

Moreover, several changes were observed in the expression of genes involved in metabolic functions relevant to midgestation-stage placental function.

The higher frequency of spontaneous abortions in mice that have undergone repeated medical/chemical abortions than in those that had experienced only a single medical/chemical abortion suggests that the risk of spontaneous abortion increases with the increasing number of medical abortions.  [‘dose response’ effect]

During midgestation, repeated medical/chemical abortion significantly increased fetal resorption.

Similarly, studies in humans showed that abortion is associated with significantly increased occurrence of low birth weight and preterm birth, a risk that increases with the number of induced pregnancy terminations [17–18].

Moreover, in subsequent pregnancies, induced abortion is associated with an increased risk of first-trimester miscarriage in subsequent pregnancies [19–20].

Specifically, mifepristone-induced abortion increases the risk of vaginal bleeding during the early gestation period, as compared with women who have not experienced abortion [21].

All of these clinical phenomena were mimicked in the present mouse model.

…Upon placenta and fetal injury, the TF gene is upregulated in women with recurrent miscarriages and intrauterine growth restriction [25–27]. In our mouse model, TF was highly expressed in T_G3P1_E13.5 mice, indicating insufficient placental function after experiencing repeated abortion … In our repeated abortion model, expression of both 11b-HSD1/2 and GR decreased significantly, indicating the dysfunction of placental nutrient exchange

our model is appropriate for further exploration of human reproductive diseases induced by repeated medical abortions.

Taken together, our findings established an inbred model system for investigating the impact of repeated first-trimester mifepristone-induced abortions, which led to subsequent pregnancy loss, affected the expression of placental function-related genes, and impaired development of the F1 generation.

These findings suggest that an adverse fetal environment develops after repeated abortions.

Additionally, repeated medical/chemical abortions may affect endometrial function, which could then impair proper placentation during subsequent pregnancies, when epigenetic regulation may be important; these hypotheses require further investigation.

The present mouse model will allow us to elucidate
the mechanisms involved in repeated medical abortions and will provide health benefits for women and their children.

Conclusion:
Repeated medical abortion impaired the reproductive function of female mice, significantly affecting the outcomes of subsequent pregnancies.

The impact of repeated abortions on the offspring of subsequent pregnancies was also noteworthy and deserves further exploration. Thus, this model provides a useful means to study the mechanisms underlying the above phenomena, which will ultimately benefit the health of women and their children.

17. Shah PS, Zao J (2009) Induced termination of pregnancy and low birthweight and preterm birth: a systematic review and meta-analyses. BJOG 116: 1425–1442.
18. Junli G, Weiyue Z (2010) Influence of artificial abortion on preterm labor in a subsequent pregnancy. Chinese Journal of Obstetrics & Gynecology and Pediatrics (Electronic Edition): 447–451.
19. Sun Y, Che Y, Gao E, Olsen J, Zhou W (2003) Induced abortion and risk of subsequent miscarriage. Int J Epidemiol 32: 449–454.
20. Zhou W, Olsen J (2003) Are complications after an induced abortion associated with reproductive failures in a subsequent pregnancy? Acta Obstet Gynecol Scand 82: 177–181.
21. Liang H, Gao ES, Chen AM, Luo L, Cheng YM, et al. (2011) Mifepristone-induced abortion and vaginal bleeding in subsequent pregnancy. Contraception 84: 609–614

Citation:

http://www.plosone.org/article/fetchObject.action?uri=info:doi/10.1371/journal.pone.0048384&representation=PDF

Lv F, Xu X, Zhang S, Wang L, Wang N, et al. (2012) Repeated Abortion Affects Subsequent Pregnancy Outcomes in BALB/c Mice. PLoS ONE 7(10): e48384. doi:10.1371/journal.pone.0048384 October 2012, volume 7, Issue 10
Editor:
Gayle E. Woloschak, Northwestern University Feinberg School of Medicine, United States of America
Published
October 31, 2012
Copyright:
2012 Lv et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding:
This work was supported by the National Nature Science Foundation of China (number 30901608) and Central Public-interest Scientific Institution Basal Research Fund (Grant number 2009GJSSJKA02). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Competing Interests:
The authors have declared that no competing interests exist

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