Literature Review for MothersBabies

Literature Review for MothersBabies

Pregnancy is a period of complex, simultaneous physiological changes enabling the development of a healthy baby, including hormonal, metabolic, immunomodulatory, and cardiovascular adaptations. Unfortunately, pathophysiological pregnancy states are also becoming more common. Globally, 10% of women suffer from hypertension in pregnancy [1], and 1 in 7 pregnancies are affected by some form of glucose intolerance [2]. Mothers are older and more overweight prior to pregnancy, with disorders such as diabetes and hypertension, both pre-existing and developing during pregnancy, leading to poorer maternal and fetal outcomes [3, 4].

The human microbiome, the population of microbes occupying various body sites, is known to impact on human health through effects on metabolism, immunity, and hormones [5]. Given the major physiological changes during pregnancy, it would be expected that there will also be significant adaptations of the microbiome.

Pregnancy leads to changes in various anatomical niches and the majority of evidence to date has studied these components individually and in small numbers.

 

Changes in the Gut Microbiota

Several alterations in the gut microbiota have been associated with pregnancy progression. The gut microbiota is greatly altered: the β-diversity of species increases and the relative abundance of different species changes e.g. increased proportions of Proteobacteria and Actinobacteria [6]. Animal studies suggest physiological alterations in maternal intestinal microbiota facilitate energy extraction from the diet throughout pregnancy, so that extra energy can be stored as fat tissue with no significant increase in dietary caloric intake [6]. Most of these changes are seen in late pregnancy.

Koren et al (2012) found that in the gut microbiome of 15 women with GDM the change in species diversity during pregnancy was not different to controls, nor did their overall gut microbiota differ in composition, although women with GDM showed reduced microbial richness at the end of the first trimester [6]. However, more recent research demonstrated that the gut microbiota of women with gestational diabetes was altered at multiple levels, including phylum and genus levels, when compared to normoglycaemic pregnant women [7]. Interestingly these changes were still present at analysis performed on the same cohort eight months postpartum [7]. Raising the probability that a maternal baseline microbiome signature defined and potentially modified preconception could be beneficial.

 

Changes in the Oral Microbiota

The oral microbiome shows an overall increase in bacteria, including potentially pathogenic species such as P. gingivalis and A. actinomycetemcomitans [9]. This is of particular interest as prior studies have linked periodontal disease in pregnancy to adverse outcomes [10].

Although not yet specifically studied during pregnancy, extremely relevant to pregnancy and hypertensive disorders of pregnancy are animal and non-pregnant human data suggesting associations between changes in oral and gut microbiota and hypertension [18].

 

Changes in the Vaginal Microbiota

The vaginal microbiome undergoes an increase in Lactobacillus species (normally the dominant vaginal microbe outside of pregnancy), a significant decrease in overall microbiota diversity and increased stability[8]. Most microbiome pregnancy studies have centred on the vaginal microbiome, with some showing a lack of change in diversity being associated with preterm birth [10].

In contrast to the increasing body of literature about the microbiome changing over the course of pregnancy DiGiulio demonstrated that the microbiome remained remarkably stable in the above mentioned body sites throughout the course of pregnancy and in the year following birth [11].

 

The Microbiome of the Placenta

The placenta, previously thought to be sterile prior to labour, also has a microbiome, with a similar composition to that of the oral microbiome [12] – which may be relevant given the periodontal disease/adverse pregnancy outcome links. There are differences in the microbiomes of women with complicated versus uncomplicated pregnancies. In a study of the placental microbiome of 42 women, Aagard et al (2014) found that taxa such as Burkholderia were more common in women delivering preterm [12].

Colonisation of the Newborn:

Although previously thought to be sterile, the newborn has evidence of a gut microbiota at birth, with meconium samples having bacterial populations [13]. There is a paucity of data on vertical transmission of microbiota from mothers to infants.

Mode of delivery affects composition of the neonatal and infant microbiomes, with Caesarean-born infants having a gut microbiota similar to the maternal skin and oral microbiome, while vaginally-born infants have a gut microbiota similar to the maternal vaginal microbiome [14, 15]. These differences are less after 4 months, and almost disappear by 12 months, [16] with breastfeeding having more impact on microbiota at 4 and 12 months.

Breast milk oligosaccharides impact the infant gut microbiota, and breast milk composition (leptin, adiponectin, insulin) affects infant gut epithelial integrity and inflammation, [17, 18] suggesting mechanisms by which breastfeeding status and infant microbiome may affect infant health.

 

What will MothersBabies offer the research world?

Microbiome studies in pregnancy to date have been inadequate: most have focussed on a single microbiome site in the mother and/or infant, or a single time period. Additionally, most studies do not have the microbiome in pregnancy as their primary focus but as an “add-on” to an intervention or cohort study performed for other reasons. The effects on the microbiome of potentially confounding physiological variables (e.g. body composition, blood pressure) and maternal characteristics have also been overlooked.

The paucity of good quality large prospective longitudinal studies related to changes and development of the microbiome from preconception, pregnancy, birth and postpartum states means that a great deal of questions about the role the microbiome plays in pregnancy and early neonatal development remain unanswered.

We therefore propose a comprehensive, longitudinal study of the microbiome in this critical period of the mother and child’s lives starting with preconception microbiome analysis.

We seek to examine whether changes in the composition of the maternal microbiome correlate with the development of abnormal pregnancy physiology and disease processes to a degree that is clinically meaningful and plan for tailored intervention trial based on the ground breaking research that we will discover with the backing of MothersBabies.

References

1. Duley, L., The global impact of pre-eclampsia and eclampsia. Seminars in Perinatology, 2009. 33(3): p. 130-7.

2. Guariguata, L., et al., Global estimates of the prevalence of hyperglycaemia in pregnancy. Diabetes research and clinical practice, 2014. 103(2): p. 176-85.

3. AIHW, et al., Maternal deaths in Australia 2008-2012. Maternal deaths series no. 5., Australian Institute of Health and Welfare, Editor. 2015, Australian Institute of Health and Welfare: Canberra. p. i-97.

4. AIHW, et al., Perinatal deaths in Australia, 1993-2012, Australian Institute of Health and Welfare, Editor. 2016, AIHW: Canberra. p. i-129.

5. Cho, I. and M. Blaser, The human microbiome: at the interface of health and disease. Nature Reviews Genetics, 2012. 13(4): p. 260-70.

6. Koren, O., et al., Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell, 2012. 150(3): p. 470-80.

7. Crusell, M,. et al., Gestational diabetes is associated with change in the gut microbiota composition in third trimester of pregnancy and postpartum. Microbiome, 2018 6(89)

8. Aagaard, K., et al., A metagenomic approach to characterization of the vaginal microbiome signature in pregnancy. PloS one, 2012. 7(6): p. e36466.

9. Fujiwara, N., et al., Significant increase of oral bacteria in the early pregnancy period in Japanese women. Journal of Investigative and Clinical Dentistry, 2017. 8(1): p. e12189.

10. Ide, M. and P. Papapanou, Epidemiology of association between maternal periodontal disease and adverse pregnancy outcomes–systematic review. Journal of Clinical Periodontology, 2013. 40(s14): p. s181-194.

11. DiGuilio, D,. et al,. Temporal and spatial variation of the human microbiota during pregnancy. PNAS, 2015. 112(35) p. 11060-11065.

12. Aagaard, K., et al., The placenta harbors a unique microbiome. Science Translational Medicine, 2014. 6(237): p. 237ra65.

13. Hansen, R., et al., First-pass meconium samples from healthy term vaginally-delivered neonates: an analysis of the microbiota. PLoS ONE, 2015. 10(7): p. e0133320.

14. Nuriel-Ohayon, M., H. Neuman, and O. Koren, Microbial changes during pregnancy, birth and infancy. Frontiers in Microbiology, 2016. 7.

15. Nagpal, R., et al., Sensitive Auantitative Analysis of the Meconium Bacterial Microbiota in Healthy Term Infants Born Vaginally or by Cesarean Section. Frontiers in Microbiology, 2016. 7.

16. Bäckhed, F., et al., Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host and Microbe, 2015. 17(5): p. 690-703.

17. Zivkovic, A.M., et al., Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proceedings of the National Academy of Sciences, 2011. 108(Supplement 1): p. 4653-4658.

18. Victora, C.G., et al., Breastfeeding in the 21st century: epidemiology, mechanisms, and lifelong effect. The Lancet, 2016. 387(10017): p. 475-490.

19. Raizada, M., et al., Report of the National Heart, Lung and Blood Institute Working Group on the Role of Microbiota in Blood Pressure Regulation – current status and future directions. Hypertension, 2017. 70(3): p. 479-485.