Managementul gravidei cu trombofilie ereditară și dobândită

Background

Thrombophilia in pregnancy refers to a condition where a woman has an increased tendency to form abnormal blood clots^(1,2). This can be concerning during pregnancy, as clotting disorders may lead to complications like miscarriage, deep vein thrombosis (DVT), pulmonary embolism, preeclampsia, placental abruption, or even stillbirth^(3,4). Thrombophilia may be inherited or acquired, and it can impact both the mother and the baby. Thrombophilia is now considered a multicausal disease, with an interplay of acquired and genetic risk factors.

Thrombophilia in pregnancy increases the risk of various complications for both the mother and the fetus, due to the tendency to develop abnormal blood clots. Some of the major risks associated with thrombophilia during pregnancy include^(9-12):

1. Miscarriage (pregnancy loss)

First-trimester miscarriage: thrombophilia increases the risk of early pregnancy loss, particularly in women with antiphospholipid syndrome (APS) or inherited clotting disorders.

Recurrent miscarriage: women with inherited thrombophilia, especially those with APS, may be at a higher risk for multiple miscarriages.

2. Preterm birth

Thrombophilia can increase the likelihood of premature birth (before 37 weeks) due to clot-related issues, particularly if the placenta is affected by insufficient blood flow.

3. Preeclampsia

Preeclampsia, a condition characterized by high blood pressure and damage to organs like the kidneys or liver, is more common in pregnant women with thrombophi­lia. It can be life-threatening for both the mother and baby if not managed appropriately.

4. Placental abruption

Thrombophilia can lead to blood clot formation in the placenta, which can cause it to detach prematurely from the uterus. Placental abruption increases the risk of heavy bleeding, reduced oxygen and nutrients to the fetus, and it can result in preterm delivery or fetal death.

5. Intrauterine growth restriction (IUGR)

Blood clots in the placenta may limit the supply of oxygen and nutrients to the fetus, leading to IUGR, where the fetus’s growth is slowed, potentially causing complications like low birth weight.

6. Deep vein thrombosis (DVT)

Pregnant women with thrombophilia have an increased risk of developing DVT, where a clot forms in the deep veins (often in the legs). If the clot breaks loose, it can travel to the lungs and cause a pulmonary embolism⁽¹³⁾.

7. Pulmonary embolism (PE)

A pulmonary embolism occurs when a blood clot travels from the legs or other parts of the body to the lungs, blocking blood flow. PE is life-threatening and can be a direct risk to the mother’s health during pregnancy if thrombophilia is not managed^(13,14).

8. Stillbirth

Women with thrombophilia are at a higher risk of stillbirth due to complications with placental blood flow, which can lead to a lack of oxygen and nutrients for the baby.

9. Postpartum hemorrhage

Thrombophilia may also increase the risk of bleeding complications after delivery, such as postpartum hemorrhage. This can be due to abnormal clotting during labor or delivery.

10. Caesarean delivery

In some cases, thrombophilia can lead to complications like clotting in the placenta or uterus, which may result in the need for a caesarean section to ensure the safety of both mother and fetus.

Managing thrombophilia in pregnancy typically involves measures to prevent clot formation, such as: low-dose aspirin to prevent blood clots; heparin or low-molecular-weight heparin (LMWH) to reduce the clotting risk, especially in high-risk cases. Also, close monitoring with regular ultrasounds, blood tests and fetal assessments to detect complications early are necessary^(9-11).

For women with thrombophilia, early detection and proactive management are critical to minimizing the risks and ensuring a safer pregnancy outcome⁽¹⁵⁾.

Objective

Our aim was to study the relationship between the presence of risk factors and the occurrence of thrombotic events, to determine the most efficient diagnostic algorithm for these conditions and, last but not least, to determine the most appropriate therapeutic approach individualized for each case, by conducting a retrospective analytical study on 1507 cases admitted to the Obstetrics and Gynecology Clinic of the University Emergency Hospital Bucharest, Romania, over a period of seven years, between 2017 and 2023.

Regarding the research objectives, we aimed to determine a demographic profile of patients with thrombophilic mutations by identifying the prevalence and characteristics of these mutations, to demonstrate the causal relationship between them and thrombotic events during pregnancy, to stratify high-risk pregnancies according to the types of thrombophilic mutations, and to develop an algorithm for testing and diagnosing hereditary and acquired thrombophilias. We also tried to create a profile of patients with thrombophilic mutations and hypertensive complications associated with pregnancy, especially fetal complications such as intrauterine growth restriction, these profiles being of great help in establishing an appropriate therapeutic approach. The ultimate goal is to increase the quality of medical services following the standardization of thrombophilia identification tests according to age, personal history, associated pathology, or other risk factors present in pregnant patients.

Study design

We included in the study pregnant patients admitted to the Obstetrics and Gynecology Clinic of the University Emergency Hospital Bucharest between January 2017 and December 2023, patients diagnosed with intrauterine pregnancy, regardless of gestational age. We conducted a descriptive and retrospective case-control study, including two categories of patients, a group that presented changes in the values of the collected analyses, with two subcategories depending on the presence or absence of complications during pregnancy, and a control group, also divided into two subcategories depending on the presence or absence of complications during pregnancy.

The initial batch was divided into two groups, depending on the analyzed period, the first consisting of 1025 patients hospitalized between January 2017 and December 2018, and the second consisting of 482 patients hospitalized between January 2019 and December 2023. We made this division in order to be able to perform the genetic analysis of thrombophilic factor mutations only in the first time interval. We mention that, through the program RO 19.10 – “Improving health services in high-risk pregnancy, premature birth and hematological diseases”, carried out within the Obstetrics and Gynecology Department of the University Emergency Hospital Bucharest, the patients benefited from free screening and diagnostic testing for hereditary and acquired thrombophilia.

For the processing and statistical analysis of the collected data, we used SPSS version 21.

Results

Several variables were monitored in the study. Thus, a first variable studied was the age of the patients.  From the batch of 1025 patients, the age of the patients included in the study was between 18 and 43 years old. The subgroup over 36 years old prevailed, this group being also representative by the increase in the overall risk associated with pregnancy, especially in primiparous women. Pregnancy-related complications – more precisely hypertensive, thrombotic complications, respectively fetuses with intrauterine growth restriction – were found to have a higher frequency.

The second variable analyzed in this study was the gestational age, divided into three subgroups, as follows: patients who were selected in the first trimester, representing 45% of the total, in the second trimester (27.4%) and in the third trimester (27.1%).

The third variable analyzed in the study group was hyperhomocysteinemia, and the normal value of the labora­tory used in the study was 11.1 micromoles/L. Fifty patients were identified with values higher than 11.1 micromoles/L, which represented 4.87% of the total, a percentage lower than the average in the specialized literature. We continue with a graphical representation (Figure 4).

Another variable, the fourth, included in the study was the prothrombin gene. The presence of the mutation was found in 54 patients, representing 5.26%, a slightly increased percentage compared to the data in the specialized literature. In 12 cases, an association with the factor V Leiden mutation was found, and in these situations, in three cases, high blood pressure in pregnancy and intrauterine growth restriction appeared.

The factor V Leiden mutation was identified in 130 patients in the study group, the percentage being similar to the data in the specialized literature, associating thrombotic phenomena and pregnancy complications two to three times more often compared to the control group.

The H1299R mutation of factor V was identified in 240 patients, representing 23.41% of the heterozygous form, a less thrombogenic form.

The study monitored the occurrence of various complications considered specific to hereditary thrombophilia accompanying pregnancy, and it found that hypertensive complications (blood pressure greater than 140/90 mmHg) were encountered in 235 patients in the study group, representing 22.82%.

Regarding the occurrence of hypertensive complications according to gestational age, we observed a higher frequency of their occurrence in the second trimester than in the third trimester. Another complication encountered in pregnancies with hereditary thrombophilia is intrauterine growth restriction, found in 86 patients, representing 8.39%.

We also monitored the length that the newborns had at birth. Thus, a number of 40, representing a percentage of 10% of the total, had a length less than 45 cm. The majority (281 cases) measured between 46 and 50 cm, while 76 cases (representing 19.14%) had a length greater than 50 cm.

Regarding the weight that the newborns had at birth, a number of 96, representing a percentage of 24.24% of the total, had a weight of less than 2500 g, the majority (a number of 289 cases) weighed between 2500 and 3500 g, while 12 cases, representing 3.03%, weighed more than 3500 g.

Conclusions

The incidence of thrombophilic mutations was increased in the patients included in the study compared to the data in the specialized literature. We found an incidence of protein S deficiency higher than that reported in the specialized literature, more precisely a percentage of 37% of patients in the first trimester of pregnancy, 4.4% of patients in the second trimester, and 4.5% of patients in the third trimester. We also recorded an incidence of 4.15% of protein C deficiency.

Hypertensive pathology in pregnancy showed a strong correlation with coagulation status, more precisely with protein S deficiency or the presence of lupus anticoagulant, but also with age over 35 years old.

Thromboembolic complications were correlated with coagulation status, the risk of developing them increasing nine-fold in patients with protein S values below 25%.

The risk of premature birth was correlated with coagulation status, increasing by 1.20 times in patients with a protein S deficiency, 1.90 times in pregnant women with intrauterine growth restriction, and 1.8 times in cases with lupus anticoagulant present.

Intrauterine growth restriction was also correlated with coagulation status, the incidence of this complication being higher than the average reported in the specialized literature, and an association was found between its occurrence and protein S deficiency, antithrombin III deficiency, but also with the presence of lupus anticoagulant.

Currently, routine screening for thrombophilic defects is not recommended in women without previous pregnancy complications. However, prevention of placenta-mediated complications, such as recurrent miscarriage, early- and late-onset fetal growth restriction and stillbirth, remains a major and topical health issue.   

Corresponding author: Diana Voicu E-mail: voicu_diana06@yahoo.com

Conflict of interest: none declared.

Financial support: none declared.

This work is permanently accessible online free of charge and published under the CC-BY licence.