**12.6 Combination of multiple mild thrombophilic factors**

### *12.6.1 Plasminogen activator inhibitor (PAI)*

Increased activity of PAI: genetic factors, metabolic disorders of insulin resistance syndrome, hypertension, smoking, etc.

PAI-1: the major physiological inhibitor of plasminogen activation plays a central role in fibrinolysis.

PAI-2: trophoblast and macrophages. Increased PAI activity has been linked to recurrent miscarriages.

4G polymorphism of PAI-1 gene is associated with high levels of PAI-1 and reduced fibrinolytic activity.

Homozygous for 4G has been complicated with preeclampsia, prematurity, IUGR, and placental ablation.

#### **12.7 Combining multiple subtle thrombophilic factors**

*12.7.1 Factor XII deficiency (Hagemann)*


#### **12.8 Increase of homocysteine and thrombophilia**

As mentioned before, decreased MTHFR activity and hyperhomocysteinemia are only obvious as long as there is folic acid deficiency. Substitution with folic acid prevents any phenotypic expression of C677T polymorphism.

Prediction for women with polymorphism who are going to have a spontaneous abortion [77–84]:

**Treatment:** the administration of 0.5–2 mg folic acid reduces homocysteine levels to normal [77–84].

**Homocysteine:** homocysteine is an amino acid formed as an intermediate of metabolism of methionine. Elevated blood levels of homocysteine (hyperhomocysteinemia) consist an important cardiovascular risk factor, which in recent years have significance similar to hypercholesterolemia [85–90].

The detection of women with congenital hyperthyroidism that have much more frequent complications in gestation has led to an investigation of the association between homocysteine and pregnancy complications associated with placental

**73**

*Abortions in First Trimester Pregnancy, Management, Treatment*

sensitive to disturbances in homocysteine metabolism [85–90].

reveals deficiencies related to the transfer of the sulfur group.

pregnancy, there are no measurements [85–90].

cause hypercholesterolemia [85–90].

• Antiphospholipid antibodies

course of pregnancy [85–90].

**12.9 Laboratory criteria**

between them.

vascular lesions such as placental abruption, preeclampsia, abortions, fetal death, and restriction of intrauterine fetal growth. Hyperhomocysteinemia is also associated with spinal tube deficits due to folic acid insufficiency. The result that women with hyperhomocysteinemia of relative cause show complications much more frequently has led to the investigation of obstetric complications with homocysteine, which are relevant with vascular placental failure such as placental abruption, pre-eclampsia, recurrent miscarriages, stillbirth, and intrauterine growth

Methionine consist of an important amino-acid that participates in cell growth and division by providing methyl groups in the biosynthesis of t-RNA, DNA, and proteins. Methionine constitutes a necessary amino acid that plays a crucial role in cellular increase and division by providing methyl groups to t-RNA, DNA, and protein biosynthesis. Homocysteine is synthesized after a methyl group transposition from methionine. The 50% could be catalyzed with a sulfureted group transposition into cystathionine. The remaining 50% of homocysteine may be reformed to methionine by removing a methyl group from two sources: (1) the metabolism of tetrahydrofolic acid (THF) and (2) the catabolism of betaine. Three enzymes take part in these metabolic pathways: methionine synthetase (MS), cysteine synthetase (CBS), and methyl-tetrahydrofolic acid reductase (MTHFR). Vitamin B6 (pyridoxine) consists of a coenzyme in the CBS and MTHFR function, while B12 is a coenzyme in the MS function. The adequacy of folic acid is necessary for both functions. The vascular endothelium may only produce CBS and MTHFR, rendering it more

Homocysteine levels >15–16 μmol/l in nonpregnant women and >6–8 μmol/l in the third trimester of pregnancy are considered abnormal. In pregnancy, homocysteine levels decrease progressively and reach a minimum in the second trimester, while increasing slightly in the third trimester. Causes of fluctuations are estrogen, blood dilution, and increased metabolism of homocysteine in the liver, as well as its removal to the fetus. Mild disturbances in homocysteine metabolism can be detected if its levels are measured 6 hours after methionine administration. In this case, levels >51 μmol/l are considered pathologically out of pregnancy, but for

Generally, the increase in basal levels of homocysteine represents deficits in remethylation, whereas the increase in homocysteine after methionine loading

Hyperhomocysteinemia may be related to mutations in genes controlling the production of CBS and MHTFR and environmental factors such as B6, B12, and folic acid deficiency. Drugs that interfere with the metabolism or absorption of these vitamins, decreased homocysteine excretion in chronic renal failure, and other causes (hypothyroidism, hepatic failure, malignant anemia, and cancer)

It is worth highlighting cases with genetic mutations of the enzymes that cause hyperomyeloidemia, because they are common and appear to play a role in the

**Antibodies vs. cardiolipins:** anti-cardiolipins lgG or lgM, in medium or high levels in 2 or more cases, with a time distance of at least 6 weeks between them.

**Lupusanticoagulant:** in two or more cases with a time distance of at least weeks

*DOI: http://dx.doi.org/10.5772/intechopen.86194*

restriction [85–90].

#### *Abortions in First Trimester Pregnancy, Management, Treatment DOI: http://dx.doi.org/10.5772/intechopen.86194*

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

Increased activity of PAI: genetic factors, metabolic disorders of insulin resis-

PAI-1: the major physiological inhibitor of plasminogen activation plays a central

PAI-2: trophoblast and macrophages. Increased PAI activity has been linked to

4G polymorphism of PAI-1 gene is associated with high levels of PAI-1 and

Homozygous for 4G has been complicated with preeclampsia, prematurity,

**12.6 Combination of multiple mild thrombophilic factors**

**12.7 Combining multiple subtle thrombophilic factors**

*12.6.1 Plasminogen activator inhibitor (PAI)*

tance syndrome, hypertension, smoking, etc.

role in fibrinolysis.

• heparin

abortion [77–84]:

levels to normal [77–84].

• LMWH vs. heparin

• one injection per day

recurrent miscarriages.

reduced fibrinolytic activity.

IUGR, and placental ablation.

*12.7.1 Factor XII deficiency (Hagemann)*

• anti-Xa follow-up is not necessary

• reduced risk of thrombocytopenia

• safe for the fetus as it does not pass the placenta

**12.8 Increase of homocysteine and thrombophilia**

• more likely outcome in obstetric complications [77–84]

prevents any phenotypic expression of C677T polymorphism.

have significance similar to hypercholesterolemia [85–90].

As mentioned before, decreased MTHFR activity and hyperhomocysteinemia are only obvious as long as there is folic acid deficiency. Substitution with folic acid

Prediction for women with polymorphism who are going to have a spontaneous

**Treatment:** the administration of 0.5–2 mg folic acid reduces homocysteine

**Homocysteine:** homocysteine is an amino acid formed as an intermediate of metabolism of methionine. Elevated blood levels of homocysteine (hyperhomocysteinemia) consist an important cardiovascular risk factor, which in recent years

The detection of women with congenital hyperthyroidism that have much more frequent complications in gestation has led to an investigation of the association between homocysteine and pregnancy complications associated with placental

• decreased risk of osteoporosis

• low molecular weight heparin (LMWH)

**72**

vascular lesions such as placental abruption, preeclampsia, abortions, fetal death, and restriction of intrauterine fetal growth. Hyperhomocysteinemia is also associated with spinal tube deficits due to folic acid insufficiency. The result that women with hyperhomocysteinemia of relative cause show complications much more frequently has led to the investigation of obstetric complications with homocysteine, which are relevant with vascular placental failure such as placental abruption, pre-eclampsia, recurrent miscarriages, stillbirth, and intrauterine growth restriction [85–90].

Methionine consist of an important amino-acid that participates in cell growth and division by providing methyl groups in the biosynthesis of t-RNA, DNA, and proteins. Methionine constitutes a necessary amino acid that plays a crucial role in cellular increase and division by providing methyl groups to t-RNA, DNA, and protein biosynthesis. Homocysteine is synthesized after a methyl group transposition from methionine. The 50% could be catalyzed with a sulfureted group transposition into cystathionine. The remaining 50% of homocysteine may be reformed to methionine by removing a methyl group from two sources: (1) the metabolism of tetrahydrofolic acid (THF) and (2) the catabolism of betaine. Three enzymes take part in these metabolic pathways: methionine synthetase (MS), cysteine synthetase (CBS), and methyl-tetrahydrofolic acid reductase (MTHFR). Vitamin B6 (pyridoxine) consists of a coenzyme in the CBS and MTHFR function, while B12 is a coenzyme in the MS function. The adequacy of folic acid is necessary for both functions. The vascular endothelium may only produce CBS and MTHFR, rendering it more sensitive to disturbances in homocysteine metabolism [85–90].

Homocysteine levels >15–16 μmol/l in nonpregnant women and >6–8 μmol/l in the third trimester of pregnancy are considered abnormal. In pregnancy, homocysteine levels decrease progressively and reach a minimum in the second trimester, while increasing slightly in the third trimester. Causes of fluctuations are estrogen, blood dilution, and increased metabolism of homocysteine in the liver, as well as its removal to the fetus. Mild disturbances in homocysteine metabolism can be detected if its levels are measured 6 hours after methionine administration. In this case, levels >51 μmol/l are considered pathologically out of pregnancy, but for pregnancy, there are no measurements [85–90].

Generally, the increase in basal levels of homocysteine represents deficits in remethylation, whereas the increase in homocysteine after methionine loading reveals deficiencies related to the transfer of the sulfur group.

Hyperhomocysteinemia may be related to mutations in genes controlling the production of CBS and MHTFR and environmental factors such as B6, B12, and folic acid deficiency. Drugs that interfere with the metabolism or absorption of these vitamins, decreased homocysteine excretion in chronic renal failure, and other causes (hypothyroidism, hepatic failure, malignant anemia, and cancer) cause hypercholesterolemia [85–90].

It is worth highlighting cases with genetic mutations of the enzymes that cause hyperomyeloidemia, because they are common and appear to play a role in the course of pregnancy [85–90].

#### **12.9 Laboratory criteria**

**Antibodies vs. cardiolipins:** anti-cardiolipins lgG or lgM, in medium or high levels in 2 or more cases, with a time distance of at least 6 weeks between them.

**Lupusanticoagulant:** in two or more cases with a time distance of at least weeks between them.

• Antiphospholipid antibodies


## **13. Pregnancy and hyperhomocysteinemia**

The existence of high homocysteine levels in the blood has a harmful effect on the placenta and decidua and is associated with the appearance of recurrent abortion and placental abruption. Hyperhomocysteinemia has been found to cause more complications such as pre-eclampsia, stillbirth, and deceleration of intrauterine growth [85–90].

#### **13.1 Hyperhomocysteinemia and spinal tube deficiency**

Hyperhomocysteinemia and spinal tube deficiency (NTD) are associated with insufficient MS and MFTHR function, leading to homocysteine accumulation. Reduced methionine methylation and methyl group (necessary for myelin creation) deficiency are responsible for the above complications and not homocysteine effects [10]. Low folic acid levels or reduced intake in cases with increased need (heat sensitive MTHFR) are responsible for spinal tube deficiencies, but also homocysteine level increase. Hyperhomocysteinemia has also been associated with congenital abnormalities on the face and body. Administering 500 mg folic acid for 4 weeks prior to conception or even at the first stage of pregnancy has been found to reduce homocysteine levels by 22% [90–95].

The gene C677T and MTHFR frequency combined with the dietary habits of a population are the reason for variety in NTD appearance in different populations. In Holland, homozygous C677T of MTHFR polymorphism carriers is at 10–16% NTD risk compared to 5% of witnesses. A1298C, a second type of polymorphism, was discovered with just as high risk NTD levels in case of homozygosity [90–95].

#### **13.2 Hyperhomocysteinemia and pre-eclampsia**

Several researchers compared patient groups with witnesses, found an increased hyperhomocysteinemia frequency, as well as increased C677T of MTHFR mutation

**75**

may prevent them [95–100].

*Abortions in First Trimester Pregnancy, Management, Treatment*

hyperhomocysteinemia risk of 20.6% (95% CI 3.6–121.6) [90–95].

High homocysteine levels have proven to be embryo toxic in guinea pigs through the vascular decidua and villi network destruction. Steegers-Theunissen and Co. found that between 8th and 12th week of pregnancy, there are high methionine levels and low homocysteine levels in the extra-embryonic cavity and amniotic fluid compared to the mother, suggesting that homocysteine accumulation may be toxic. Increased miscarriages in the first trimester are not linked to angiopathy, but to methyl group deficiency and defective DNA composition. Wouters and Co. were the first to notice the high hyper-homocysteinemia frequency in the 14% of cases with recurrent abortion with no prior normal pregnancies and in 33% of those with a history of normal pregnancy. Another study in 100 patients with a history of consecutive spontaneous abortions found homocysteinaemia in 12% of them, C677T of MTHFR mutation in 20%, and decreased folic acid levels in 15% of patients. Supplementation of high levels (15 mg) of folic acid and vitamin B6 (750 mg) to 28 patients with recurrent abortion cases improved homocysteine levels and the 17 pregnancies that followed had a successful outcome. In an afteranalysis, homocysteine presence with or without methionine loading showed an increased hyper-homocysteinaemia risk by 4.2 and 2.7%, respectively. In another study where MTHFR genotypes were sought after in embryonic tissues and newborns, all genotype associations were found in embryonic tissue, while in newborns, there were no combinations of three or more mutant alleles. This reveals that embryos with a lot of mutations may be miscarried. As a result, it is proved that there is a correlation between homocysteine metabolic disorder and habitual abortions, but it is not clear whether administering vitamins before conception

**13.3 Hyperhomocysteinemia and recurrent abortions**

frequency in women with pre-eclampsia. So, they were led to the conclusion that it may also constitute a genetic factor in pre-eclampsia manifestation [90–95].

In large woman study groups where homocysteine levels were evaluated in the second trimester of gestation either prospectively or recursively, it was found that the relevant pre-eclampsia risk in women with hyperhomocysteinemia was between 1.32 and 3.2%, while in primigravida, it reached 9.7% and in those who were obese, it reached 6.9%. Certainly, patient choice (with heavy, premature pre-eclampsia) has a lot to do with the various levels of pre-eclampsia in incidence of appearance of hyperhomocysteinemia in the bibliography. In a prospective study of 1049 pregnant women, at their 16th week of gestation, homocysteine levels did not appear to be different amongst patients with an uncomplicated course of gestation and those with pre-eclampsia. It is undetermined whether homocysteine levels should be evaluated in all women with a history of serious pre-eclampsia in a previous pregnancy. Repeated studies in women with angiopathy and high homocysteine levels have proved that pre-eclampsia was seven times more frequent in their pregnancies when compared to those with normal homocysteine levels. Homocysteine does not appear to activate the endothelium as there was not found a comparison between fibronectin and homocysteine during the episode of pre-eclampsia. A study revealed that administration of folic acid and vitamins in women with a history of heavy early course pre-eclampsia decreases its frequency and severity in the subsequent pregnancy, but because these studies were quite small and not random, other greater ones are in progress. At the moment, no specific genotype has been associated with more severe or premature types of the disease. Therefore, homozygosity in C677T had an applicable pre-eclampsia risk of 2.6% (95% CI 1.4–5.1) and a

*DOI: http://dx.doi.org/10.5772/intechopen.86194*

#### *Abortions in First Trimester Pregnancy, Management, Treatment DOI: http://dx.doi.org/10.5772/intechopen.86194*

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

• Medicine (chlorpromazine and hydralazine)

• Chronic infections (syphilis and hepatitis C)

• Annexin-V: a protein with strong, anticoagulant action.

The existence of high homocysteine levels in the blood has a harmful effect on the placenta and decidua and is associated with the appearance of recurrent abortion and placental abruption. Hyperhomocysteinemia has been found to cause more complications such as pre-eclampsia, stillbirth, and deceleration of intrauterine growth [85–90].

Hyperhomocysteinemia and spinal tube deficiency (NTD) are associated with insufficient MS and MFTHR function, leading to homocysteine accumulation. Reduced methionine methylation and methyl group (necessary for myelin creation) deficiency are responsible for the above complications and not homocysteine effects [10]. Low folic acid levels or reduced intake in cases with increased need (heat sensitive MTHFR) are responsible for spinal tube deficiencies, but also homocysteine level increase. Hyperhomocysteinemia has also been associated with congenital abnormalities on the face and body. Administering 500 mg folic acid for 4 weeks prior to conception or even at the first stage of pregnancy has been found to reduce

The gene C677T and MTHFR frequency combined with the dietary habits

Several researchers compared patient groups with witnesses, found an increased hyperhomocysteinemia frequency, as well as increased C677T of MTHFR mutation

of a population are the reason for variety in NTD appearance in different populations. In Holland, homozygous C677T of MTHFR polymorphism carriers is at 10–16% NTD risk compared to 5% of witnesses. A1298C, a second type of polymorphism, was discovered with just as high risk NTD levels in case of

• Multiple placental micro-thrombosis [85–90].

**13.1 Hyperhomocysteinemia and spinal tube deficiency**

**13. Pregnancy and hyperhomocysteinemia**

homocysteine levels by 22% [90–95].

**13.2 Hyperhomocysteinemia and pre-eclampsia**

homozygosity [90–95].

• Acute infections

• No thrombotic effects

• Recurrent abortions

• Endometrial death

• Pre-eclampsia

• B2 glycoprotein 1

• IUGR

• Antiphospholipid syndrome

**74**

frequency in women with pre-eclampsia. So, they were led to the conclusion that it may also constitute a genetic factor in pre-eclampsia manifestation [90–95].

In large woman study groups where homocysteine levels were evaluated in the second trimester of gestation either prospectively or recursively, it was found that the relevant pre-eclampsia risk in women with hyperhomocysteinemia was between 1.32 and 3.2%, while in primigravida, it reached 9.7% and in those who were obese, it reached 6.9%. Certainly, patient choice (with heavy, premature pre-eclampsia) has a lot to do with the various levels of pre-eclampsia in incidence of appearance of hyperhomocysteinemia in the bibliography. In a prospective study of 1049 pregnant women, at their 16th week of gestation, homocysteine levels did not appear to be different amongst patients with an uncomplicated course of gestation and those with pre-eclampsia. It is undetermined whether homocysteine levels should be evaluated in all women with a history of serious pre-eclampsia in a previous pregnancy. Repeated studies in women with angiopathy and high homocysteine levels have proved that pre-eclampsia was seven times more frequent in their pregnancies when compared to those with normal homocysteine levels. Homocysteine does not appear to activate the endothelium as there was not found a comparison between fibronectin and homocysteine during the episode of pre-eclampsia. A study revealed that administration of folic acid and vitamins in women with a history of heavy early course pre-eclampsia decreases its frequency and severity in the subsequent pregnancy, but because these studies were quite small and not random, other greater ones are in progress. At the moment, no specific genotype has been associated with more severe or premature types of the disease. Therefore, homozygosity in C677T had an applicable pre-eclampsia risk of 2.6% (95% CI 1.4–5.1) and a hyperhomocysteinemia risk of 20.6% (95% CI 3.6–121.6) [90–95].

#### **13.3 Hyperhomocysteinemia and recurrent abortions**

High homocysteine levels have proven to be embryo toxic in guinea pigs through the vascular decidua and villi network destruction. Steegers-Theunissen and Co. found that between 8th and 12th week of pregnancy, there are high methionine levels and low homocysteine levels in the extra-embryonic cavity and amniotic fluid compared to the mother, suggesting that homocysteine accumulation may be toxic. Increased miscarriages in the first trimester are not linked to angiopathy, but to methyl group deficiency and defective DNA composition. Wouters and Co. were the first to notice the high hyper-homocysteinemia frequency in the 14% of cases with recurrent abortion with no prior normal pregnancies and in 33% of those with a history of normal pregnancy. Another study in 100 patients with a history of consecutive spontaneous abortions found homocysteinaemia in 12% of them, C677T of MTHFR mutation in 20%, and decreased folic acid levels in 15% of patients. Supplementation of high levels (15 mg) of folic acid and vitamin B6 (750 mg) to 28 patients with recurrent abortion cases improved homocysteine levels and the 17 pregnancies that followed had a successful outcome. In an afteranalysis, homocysteine presence with or without methionine loading showed an increased hyper-homocysteinaemia risk by 4.2 and 2.7%, respectively. In another study where MTHFR genotypes were sought after in embryonic tissues and newborns, all genotype associations were found in embryonic tissue, while in newborns, there were no combinations of three or more mutant alleles. This reveals that embryos with a lot of mutations may be miscarried. As a result, it is proved that there is a correlation between homocysteine metabolic disorder and habitual abortions, but it is not clear whether administering vitamins before conception may prevent them [95–100].

#### **13.4 Hyperhomocysteinemia and placental abruption**

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 abruption risk by 3.4 [95–100].

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

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

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

#### **14. Hyperhomocysteinemia treatment**

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

**77**

trimester of gestation.

**16. Conclusion**

*Abortions in First Trimester Pregnancy, Management, Treatment*

results from administering vitamins in these cases [95–100].

history of NTD, pre-eclampsia, recurrent abortions, and perhaps in cases with placental abruption and endometrial death. It is valuable to look further into the

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

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,

*DOI: http://dx.doi.org/10.5772/intechopen.86194*

**15. Further investigations**

history of NTD, pre-eclampsia, recurrent abortions, and perhaps in cases with placental abruption and endometrial death. It is valuable to look further into the results from administering vitamins in these cases [95–100].
