**15. Further investigations**

*Induced Abortion and Spontaneous Early Pregnancy Loss - Focus on Management*

Placental biopsy in cases with abruption shows vasculopathy compatible with stenosis, necrosis, thrombosis, and atherosclerosis in the spinal arteries. Homocysteine in blood vessels acts by removing the methyl groups necessary for the DNA composition of multiplying cells. In many studies, hyperhomocysteinemia has been linked to placental abruption. In an after-analysis, folic acid deficiency was found to increase placental abruption frequency by 25.9% (95% CI-736.3) and hyperhomocysteinemia by 5.3% (95% CI 1.8–15.9). The presence of C677T of MTHFR polymorphism increases placental angiopathy risk by 2.45% (95% CI 1.00–6.02). In placental angiopathy cases, endothelium proteins are released in the blood, such as the von Willebrand factor (vWF), the activator of plasma tissue tPA (tissue plasma activator), the inhibitor of this activator PAI-1 (plasma activator inhibitor-1), fibronectin, and thrombomodulin that act as malfunction indicators. Women with hyperhomocysteinemia appeared to have a disproportionate tPA/PAI-1 ratio and a high vWF, while women with a placental abruption history had a high vWF and thrombomodulin. Thrombomodulin levels were in proportion with homocysteine levels. Administering antioxidant vitamins (folic acid, pyridoxine, and hydroxocobalamin) reduced the tPA/PAI-1 ratio but did not affect vWF, while the sole administration of folic acid reduced vWF levels. Combining hyperhomocysteinemia with thrombophilia, increases placental abrup-

Finally, angiopathy resulting from hyperhomocysteinemia may be at least theoretically involved in placental abruption, therefore it may be useful for cases with abruption in the future to be checked for thrombophilia and hyperhomocyste-

Hyperhomocysteinemia may be associated with increased endometrial death by different mechanisms such as congenital disorders and pre-eclampsia, but its significance as an independent factor is in question. In a small group of patients, it was found to coexist with 11% frequency, while in a different group it was no more apparent than the rest of the population. The findings for its role in slowing intrauterine growth are contradictory. In another group of patients, hyperhomocysteinemia levels were as high as 38% and in a different group that was checked after methionine loading in women with a history of slowing intrauterine growth, hyperhomocysteinemia levels reached 19.2%. On the contrary, in a recursive review of the course of pregnancy in women who were CBS mutation carriers, newborns

Treatment with vitamin B6, B12, and folic acid on its own or combined with other vitamins has been evaluated on small groups of patients with coronary artery disease and obstetrical complications and has been found to induce homocysteine levels and incidents by 30–50% in these groups. In other studies, vitamin C and E were given as antioxidant factors. The significance of adding aspirin or heparin in these groups still remains questionable, even though we can conclude that normalizing homocysteine levels should be enough, in order to achieve the therapeutic response. From the above-mentioned factors, we can estimate that even if there is no unanimity, it is within reason to check homocysteine levels in cases with a

inemia and receive antioxidant vitamin treatment [95–100].

did not appear to have lower birth weight [95–100].

**14. Hyperhomocysteinemia treatment**

**13.5 Other cases of hyperhomocysteinemia effects during pregnancy**

**13.4 Hyperhomocysteinemia and placental abruption**

tion risk by 3.4 [95–100].

**76**

We and other researchers have been searching for such predictive blood biomarkers of miscarriage. Macrophage inhibitory cytokine 1 (MIC-1), which is During the first trimester of gestation macrophage inhibitory cytokine 1 (MIC-1), which is presented in the syncytiotrophoblast and deciduas increases in serum and it is proposed to play an immunomodulatory role in the progression of the pregnancy. Pregnancy is considered as an ideal condition to study the regulation mechanisms of vascular growth under physiologic circumstances. Fetal vasculogenesis, angiogenesis, and vascular adaptation of the uterine circulation are one of a kind [101–104]. There is strong evidence bracing a close relationship between embryonic development and the state of vascularization of the chorionic villi. Normal chorionic villous vascularization is crucial for the normal development of pregnancy. However, it is not well known whether abnormal changes in utero-placental vascular development predispose to abortions [101–104]. The development of a normal functioning placental vascular network requires an important degree of coordination between various angiogenic and angiostatic factors and is exquisitely dependent on signals exchanged between these factors. Abnormalities in the development of placental vasculature may generate a number of gestational pathologies including miscarriages, intrauterine fetal death (IUFD), intrauterine growth restriction (IUGR), placental abruption, and preeclampsia. The importance of angiogenesis and angiogenetic factors in pregnancy is well known, and it has been proved that **chemokines and their receptors** are implicated in pregnancy and abortion, while cytokines and chemokines have a crucial part in controlling immune cells; these molecules are synthesized at the maternal-fetal interface where they have been implicated to play critical roles in the establishment and maintenance of pregnancy. In addition, they take part in other biological processes, such as cellular lymphoid organogenesis, and expression of adhesion molecules. The role of chemokines in angiogenesis during pregnancy has been experimentally demonstrated in cultures of leukocyte-free first trimester gestational decidual cells and in spontaneous miscarriage in mice, but the angiogenetic and angiostatic role of chemokines in the placental growth and decidua has not been well demonstrated [101–104]. These preliminary results propose a disturbance of the chemokine-associated angiogenetic network with a significant number of spontaneous abortions during the 1st trimester of gestation.

### **16. Conclusion**

Miscarriage is the most usual complication of pregnancy. There are currently no definite predictive tests and treatments that can prevent spontaneous miscarriage. While 50% of miscarriages are associated with fetal chromosomal faults, most of the remaining cases are likely to be euploid fetuses that have failed due to implantation problems. Numerous investigators have previously figured that developing an accurate predictive test for miscarriage may open the window for identifying euploid pregnancies that are still viable but intended to miscarry. It follows therefore that possibly, emerging therapeutics could be targeted at such high risk euploid pregnancies so that some of them may continue to viability,

#### *Induced Abortion and Spontaneous Early Pregnancy Loss - Focus on Management*

(i.e., rescuing some from miscarriage). The treatment of miscarriages and especially RPL has a wide variety and should be targeted at the reason. It could be complicated to recommend general therapeutic management especially if they are unproven, invasive, and expensive, because most couples with unexplained recurrent miscarriages have a good outcome. Further investigation of the factors that regulate the possible transcriptional repression of angiogenic chemokines and/or the overexpression of the angiostatic chemokines could cooperate in early prediction and prevention of spontaneous abortions. We assume that an accurate investigation of chemokine networks possibly taking part in the angiogenetic mechanisms of pregnancy would assist in the design of more accurate and possibly individualized angiogenesis-associated strategies for improving the early prediction and prevention of spontaneous abortion.
