Role of liver hemodynamics in fetal development in twin pregnancies

Abstract

In recent years there has been an increased in twin births, mainly due to the readily access to assisted reproduction and increased maternal age. The rise in twin births have a deep impact to all health systems as multiple pregnancies carries an increased risk of maternal and fetal complication. Although twins can be classified as mono or dizygotic in relation to their embryo origin, it is their classification according to the chorionicity that plays a more significant role in daily clinical practice. Based on this criterion, twins can either be mono or dichorionic. Both are at increased risk of complications, but monochorionic twins carries an even higher risk of adverse outcomes. Monochorionic twins are monozygotic, therefore genetically similar. They can be in in separated amniotic sac if the twinning process occurs between 3 to 8 days after fertilization or have a single amniotic sac if the splitting occurs between 9 to 12 days; in this manuscript we will focus in the first type, also called monochorionic diamniotic (MCDA) twins. The single placental mass of monochorionic twins enables a shared feto-placenta circulation, meaning that co-twins share their blood through a complex network of vascular anastomosis. These vascular connections can be bidirectional or unidirectional and their arrangement seems crucial to a less complicated pregnancy. Nevertheless, this organisation is extremely fragile and unfortunately, often unbalanced. In about 10% of MCDA pregnancies, the circulation favours one twin over the other, giving rise to a disease called twin-to-twin transfusion syndrome. Despite not existing a typical TTTS vascular tree, this condition involves the existence of unidirectional anastomosis, usually arterio-venous, that are not compensated by bidirectional anastomosis. The presence of unidirectional connections allows for a transference of significant blood volume, leaving both fetuses affected. One fetus becomes the donor and suffers with hypovolemia while the other turns into a recipient that experience the effects of hypervolemia. In about 15% of the monochorionic diamniotic twins the placental mass is unequally shared and, if the difference is significant, it will lead to a selective fetal growth restriction. This is an intriguing disease, mainly because the literature failed for a long time to agree upon a definition to this condition. Only recently a panel of international experts reached an agreement and define an objective diagnostic criteria, consequently, even less is known about sFGR compared to TTTS. Contrary to what happens in TTTS, in selective growth restriction the vascular anastomosis may be beneficial if favours the affected fetus. Apart from the placenta characteristics of the main complications in MCDA, very little is known about the pathophysiology and natural history of TTTS and sFGR, leading to numerous unanswered questions. It's reasonable to assume that in events as serious as those, the affected fetuses experience significant burden. These disorders likely affect multiple systems and will require an array of compensatory mechanisms to sustain the fetus during the course of the disease and following successful treatment. One of the systems that can be involved is the Hepatic Arterial Buffer Response (HABR). The Hepatic Arterial Buffer Response is an important liver defence mechanism that focus on preserve hepatic perfusion. Adenosine works as a vasodilator of the hepatic artery (HA) and is produced at constant rate near the final branches of this vessel. Its concentration depends on a washout effect derived from the circulating blood in the space of Mall. If there is a reduction in hepatic blood flow, the concentration of adenosine increases producing vasodilation of HA therefore improving hepatic prefusion. It has been described that in some fetal diseases such mechanism could be active yet, in the context of complicated MCDA it is unknow. It is possible that in TTTS donors, that deals with hypovolemia, HABR could be activated. Similarly, in sFGR, the affected fetus could experience reduction in hepatic perfusion leading to the activation of this liver defence mechanism even though, through a different pathway. Our main goal in this project was to find out if the HABR is active in MCDA twins affected by TTTS and sFGR. To answer this question, three prospective studies were developed with a population of 247 monochorionic twin pregnancies. In the first study we created a ratio between the hepatic artery peak systolic velocities of both co-twins, called HAV-ratio. A ratio between co-twins accentuates subtle variations in HA peak systolic velocities (PSV). This is particularly relevant if the underlying hypothesis posits divergent effects between the co-twins or no effect in one. Such approach highlights the relationship between small variations rendering it particularly advantageous for initial studies. We demonstrated that HAV-ratio is significantly lower in MCDA pregnancies with TTTS when compared to normal MCDA (p<0.001, 95% CI 0.443, 0.643). In TTTS the mean HAV-ratio is 0.47 (±0.035) while in normal pregnancies it is 1.014 (±0.021). The second study was built up on the first and analysed the HA PSV of each affected fetus independently and compared to normal fetuses. Additionally, we analysed the variation in HA PSV in donors before and after fetoscopic laser ablation of vascular anastomosis (FLAVA). We found a significant difference in HA PSV z-scores (HAV-Z) between donor and normal fetuses (β=2.429, 95 % CI 1.887, 2.971; p<0.001). In donors this measurement was 2.4 z-scores higher compared to normal fetuses. This measurement reduces significantly after FLAVA (β=−1.829, 95 % CI −2.593, −1.064; p<0.001). The observed data supports the hypothesis of the activation of hepatic arterial buffer as a direct adaptive response to TTTS in donor twins. The third study focus on the activation of HABR in sFGR. To assess this effect, we used the HAV-ratio between pregnancies affected by sFGR and normal twins and found a significant difference between these two groups. For normal pregnancies the mean HAV-ratio was 1.01 (±0.20) while for sFGR was 0.77 (±0.25). Our findings demonstrate that, in pregnancies affected with selective fetal growth restriction, HAV-ratio is significantly lower than in normal MCDA pregnancies, nevertheless the effect appears less intense than in TTTS. This observation appoints to the activation of HABR in the restricted fetus. This project results in the description of a novel physiologic adaptation in monochorionic twins complicated by either TTTS or sFGR. Improving our knowledge of the pathophysiological processes involved in any medical condition will invariably steer to better understanding of the disease and, in time, will push us to a better care providing safer, more reliable and specific treatments that will improve outcomes of such complicated disorders.