Historically, AF was thought to simply represent a mechanical cushion in which the foetus could develop. Nowadays multiple studies have highlighted the complexity not only in terms of function but also in the composition of the AF [10,11,12,13,14,15,16,17,18,19,20,21].
During foetal life, from the eleventh week of gestation, the baby starts swallowing AF in an amount of about 200–250 ml/kg/day; even if it is true that by breathing and swallowing the amniotic fluid the baby practices using the muscles to be ready for breastfeeding, AF ingestion hides more important effects [22].
After all, the particular composition of the AF highlights how the cushioning function and oral muscle training cannot be the only ones.
AF was found to contain a series of hormones and growth factors such as epidermal growth factor (EGF), transforming growth factor alpha (TGF-α), transforming growth factor beta 1 (TGF-β1), insulin-like growth factor 1 (IGF-1), erythropoietin (EPO) and granulocyte colony-stimulating factor (G-CSF). These factors play a relevant role not only in enhancing bowel trophism, but also in the immunological defence linked to the presence of various broad-spectrum antimicrobial agents such as antibodies, α-defensine, lactoferrin, lysozyme and secretory leukocyte protease inhibitor [22].
Moreover, AF contains carbohydrates, proteins, lipids and electrolytes which diffuse freely from the placenta to the foetal circulation through the skin before the production of keratin begins and which are then swallowed after this ability is acquired.
Ligation of the oesophagus in foetal rabbits to prevent swallowing followed by the infusion of various solutions into the gut distally to the ligature has been performed to demonstrate the nutritive value of foetal swallowing. Animals infused with lactated Ringer’s solution had poor gut development whereas those infused with bovine AF showed normal gut maturation [23].
Lopez de Torre et al. demonstrated growth impairment in chick embryos in which intestinal atresia was surgically reproduced [24].
In birds, the only mean of embryo’s nutrition is AF due to the absence of the placenta. Considering that embryogenesis recalls phylogenesis, it is plausible to suppose that the AF maintained nutritional and bowel trophism function throughout the evolution of the species until the human species appeared.
Studies like the aforementioned are not applicable to human foetus for ethical reasons. Therefore, we investigated the effects of atresias on various levels of the digestive system, as they can be seen as a faithful representation of the bowel ligations previously discussed.
Our results showed that OAs and DAs have a mean BW percentile statistically inferior to the control group. Contrarily, no statistically relevant differences were found between the mean percentile of the other atresias with the control group (Fig. 1A).
Moreover, the incidence of SGA newborns decreases the more distal the level of the atresia, having the lowest percentage in the control group and high percentages in OAs and DAs (Fig. 2).
Considering such results, we can indirectly infer that AF plays a role in the nutritional support of the foetus.
The fact that only OA and DA seem to be significantly affected by AF deprivation in terms of foetus growth could suggest mainly the stomach and marginally the duodenum as the principal sites of absorption of the AF.
Indeed, the mean BW percentiles between JAs and IAs are not statistically different when compared with the control group hence confirming that it is sufficient for the AF to pass the oesophagus and to arrive to the stomach and duodenum to carry out its nutritional function.
Based on these explanations, we are not surprised that OAs and DAs together account for more than 60% of the total SGA newborns enrolled in the present study, the control group included.
The effects of AF as gestation progresses are depicted in Fig. 1B–F. If we consider the trend of the relation between BW and GA at birth, we can observe how it assumes a positive trend with a more rapid increase the lower the level of the atresia. The control group exhibits the steepest increase. In fact, such results could be predicted: the foetus counts on the placenta as the main important vehicle of nutritional agents. Therefore, unless a placental disease is present, we expect that a foetus affected by DT atresia can continue to gain weight. The deceleration in the increase of the positive trend in the DT atresias, when compared with the control group, suggests the existence of another factor taking part in the foetus growth, which fails in this category of patients: it is presumably the absorption of the AF, strengthening once more our theory.
DAs represent the only exception, presumably due to statistical bias resulting from the limited number of patients enrolled in the study.
Concerning the relation between BW percentiles, standardized by the match with GA and birth GA, expressed in Fig. 1B–F too, we observe how the trends in the control group and the distal atresias (JA and IA) are slightly positive or null. From a statistic viewpoint, inference can be made that the GA is not sufficient to explain the variability of the birth percentiles. The explanation might be that, in normal conditions, the foetus weight increases under the influence of a variety of individual biological elements that intervene constantly and independently from the gestational age. OAs and DAs behave differently: the slope of the trendline decreases, drastically in the case of OAs, revealing that in these groups of newborns, an unknown factor determined a growth impairment that worsens as the pregnancy progresses. Such evidence is not only another indirect clue of the effect of AF on foetus growth but also represents further evidence of the stomach as a probable major site of absorption of the fluid and suggests that AF’s nutritional function becomes more important as gestation proceeds.
The data suggested by our work certainly harbour important clinical implications.
The first is that our data stresses the attention on how patients with proximal DT atresias are extremely fragile: their low percentile at birth requires a major grade of care from physicians due to their growth restriction. Moreover, surgeons and anaesthesiologists are well conscious of how low weight and poor nutritional state could have a negative impact in terms of perioperative and postoperative complications.
Furthermore, in case of prenatal findings of bowel dilation in a SGA foetus, the obstetrician must suspect a DT atresia.
In addition, in the case of newborn suspected of neonatal bowel obstruction, the birth percentile can help the surgeon not only in considering the possibility of a DT atresia but coupled with the imaging, it is also possible to predict the defect site in the DT before intraoperative findings are available.
We are aware of the limitations of this study. First is the limited number of patients: to further confirm our ideas, multicentre studies are paramount.
A further limitation is the purely speculative nature of the present study; nevertheless, as previously discussed, our conclusions are reported in similar studies with animal foetuses [23, 24].
