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Balistreri. Vessel Plus 2018;2:25 I http://dx.doi.org/10.20517/2574-1209.2018.35 Page 7 of 10

Microbiome interventions
Altered human microbiome, and particularly gut microbiome, is recognized to be significantly associated
[35]
with the onset of various inflammatory diseases (i.e., age-related diseases) . In addition, today, it is also
linked with spontaneous preterm birth and other adverse pregnancy outcomes [Table 1]. Accordingly,
it is suggesting that the administration of probiotics and/or prebiotics can ameliorate several immune
and inflammatory parameters. This is demonstrating that manipulation of gut microbiome may result in
[35]
beneficial effects . In addition, a change in food intake and its quality are also proposed to be beneficial (see
the next paragraph).

Mediterranean diet
The diet, and particularly the Mediterranean diet, represents a very advantageous intervention for the health
of people, and some recent studies also confirm such relevance in both pregnancy and new-borns [35,36] .
Accordingly, a recent investigation has evaluated the effects of adherence to a Mediterranean diet in 997
mother-child pairs from Project Viva in Massachusetts, USA, and 569 pairs from the Rhea study in Crete,
Greece. This large study has demonstrated that greater adherence to Mediterranean diet during pregnancy
[37]
may protect against cardio/pulmonary damage in offspring . Similar data have been obtained in a study
performed in 728 pregnant women who assumed a Mediterranean diet, and enrolled from TIMOUN
[38]
Mother-Child Cohort Study conducted in Guadeloupe (French West Indies) between 2004 and 2007 .
In addition, some studies suggest that the women who prepare for pregnancy, and particularly adolescent
pregnancies, should benefit of an appropriate nutrition and diet for decreasing adverse maternal and new-
[39]
born outcomes . Although early life may be imperative for baby development, meticulous studies are
essential to show the advantages to obtain using prenatal or postnatal diet’s supplementation.

Melatonin and metformin
Useful results might derive by other approaches. Recently, it has been reported that the administration of
antioxidants and anti-remodeling agents associated with the vasodilator therapies could have beneficial
effects in new-borns [40-46] . From this point of view, melatonin (N-acetyl-5-methoxytryptamine, an
indoleamine molecule), appears to be an effective agent for PHN, markedly improving pulmonary vascular
function. However, the date until now obtained derive only from animal studies. Consequently, future
studies should be performed for: (1) optimizing doses and/or therapeutic windows to improve the functional
and anti-remodeling effects in animal models, as preclinical studies ; and (2) extending these investigations
to human pregnant women and new-borns [40-46] .

Another promising treatment might be the metformin, one drug normally used in diabetes therapy,
[47]
even if its effects in pregnancy have been experimented only in the treatment of gestational diabetes .
Consequently, more studies are needed to provide more evidence for the future use of metformin.

CONCLUSIONS AND PERSPECTIVES
Growing evidence from epidemiological, clinical and experimental studies has clearly revealed a close
relationship between adverse in utero environment and the augmented risk of diverse diseases, such as PH
[8]
in later life . Fetal stressors, such as hypoxia, high-altitude, malnutrition, and fetal exposure to nicotine,
alcohol, cocaine and glucocorticoids can directly or indirectly act at cellular and molecular levels, by
altering the cardio/pulmonary development and resulting in programming of heightened cardio/pulmonary
[8]
vulnerability to diverse pathologies, such as PH . The underlying mechanisms and pathways are not
completely identified. However, crucial is the role of epigenetic mechanisms in fetal origin [9,48] . Predictably,
pharmacological manipulations of epigenetic mechanisms present a promising interventional strategy.
Indeed, several experimental studies in animals have offered exciting results, by using DNA methylation
inhibitors and other agents, such as plant-derived isoflavone genistein, leptin, folate, fish oil, omega-3 and