1.Introduction
The blood coagulation process is related to the coagulation system, fibrinolytic system and platelet aggregation. Anticoagulants produce anticoagulant effects by interfering with certain parts of the coagulation system. The choice of anticoagulants during pregnancy can be based on the 5 categories of grading criteria (A, B, C, D, X) for the risk of drugs to pregnancy issued by the FDA, with increasing risk, as detailed in Lecture 3, and the drug with the least effect on the fetus is selected.
2. Indications for the use of anticoagulation therapy during pregnancy
The indications for the use of anticoagulation therapy in pregnancy can be briefly divided into two categories: non-obstetric factors and obstetric factors.
2.1 Indications for non-obstetric factors
These include.
(1) Those with a history of thromboembolism;
(2) After repair or replacement of heart valve disease;
(3) Mitral valve lesions with atrial fibrillation;
(4) Hereditary antithrombin III deficiency;
(5) Hereditary protein C deficiency.
The recurrence rate of thromboembolic disease in pregnant women during pregnancy is 5-10%, so anticoagulation therapy during pregnancy is necessary, especially for those who had the disease shortly before pregnancy, and anticoagulation therapy should be started in the middle of pregnancy. Pregnant women in the middle and late stages of pregnancy are in a hypercoagulable state, and patients with combined heart disease tend to rest in the prone position, which is more likely to promote the formation of blood clots. Therefore, patients with combined heart disease in pregnancy, especially when complicated with atrial fibrillation, need to pay more attention to anticoagulation therapy.
2.2 Indications for obstetrical factors
It is mainly for DIC induced by obstetric factors such as stillbirth syndrome, severe gestational hypertension syndrome, early placental abruption, amniotic fluid embolism, or infected abortion sepsis, prenatal and postpartum hemorrhagic shock, etc.
3.Application of anticoagulants
3.1 Heparin
FDA classified as Class C. Heparin is a mucopolysaccharide sulfate with a molecular weight of about 20,000. Heparin is synthesized in mast cells and is particularly abundant in the lungs. Heparin dosage is mostly expressed in units of U. The United States Pharmacopoeia provides that the minimum effective amount of dried heparin extracted from lung tissue is 120u/mg. 1mg of dried heparin produced in China is equivalent to the potency of 125u. The anticoagulant effect of heparin occurs a few minutes after intravenous injection, and its half-life is 1 hour and 2 hours.
The anticoagulant effect of heparin is mainly to strengthen and activate the plasma antithrombin III (ATIII), which is a normal component of the body’s plasma, and it can bind to the activation center of coagulation factors II, IX, Ⅺ, Ⅻ, etc., so as to inactivate these coagulation factors.
Heparin has a large molecular weight and generally cannot pass through the placenta, so it has no adverse effects on the fetus. There have been no reports of fetal malformations due to heparin application. However, some data suggest that heparin may indirectly cause calcium deficiency in the embryo and fetus due to the effect of calcium chelation. It has also been reported in the literature that osteoporosis can occur in pregnant women with long-term heparin application, but this usually occurs in patients with heparin doses over 20,000 u/d and a course of treatment longer than 4 months, so pregnant women with long-term heparin application should pay attention to calcium and vitamin D supplementation.
Although the toxicity of heparin is low, the dosage is difficult to control. Overdose can cause spontaneous bleeding, including mucosal, wound, joint and cerebral bleeding, so regular monitoring and regulation should be performed. Complications associated with long-term heparin application include: (1) aseptic abscess; (2) bleeding from joints and organs; (3) thrombocytopenia; and (4) osteoporosis and hair loss. Heparin should be used with special caution when the following conditions exist: (1) DIC due to placental abruption; (2) severe hyperemesis with mean arterial pressure exceeding 18.7 kpa ()140 mmHg; (3) late DIC; (4) pregnant women about to deliver; (5) surgical incisions or wounds that have not yet healed; (6) those with pre-existing severe bleeding (including pulmonary hemoptysis, ulcerative bleeding, cerebral hemorrhage, etc.); (7) pre-existing bone marrow hematopoietic dysfunction; (8) (8) Poor platelet production.
Heparin overdose can be counteracted by fisetin. Fish essence protein contains a large number of arginine residues, which bind with heparin through ionic bonding and make heparin inactive. Each 1mg of fisetin can neutralize 1mg of heparin. Since heparin is metabolized rapidly, the dosage should be reduced by half if fish protein is needed half an hour after the drug is administered. Heparin cannot be excreted by breast milk and has no effect on the breast baby.
3.2 Low-molecular heparin
Low molecular heparin is made from non-polarized heparin by analysis, chemical modification or enzymatic degradation, with an average molecular weight of 4000-5000, including: enoxaparin sodium FDA classified as class B, dalteparin sodium (dipeptide heparin sodium, farnesamine, FDA classified as class B), ticlopidine (rapid coagulation avoidance, FDA classified as class B). High-molecule heparin has strong antithrombin activity and high binding force with platelets, so the anticoagulant effect is significant. Low-molecule heparin has strong anti-factor Xa activity and high binding force with endothelial cells, so the anti-thrombotic effect is obvious.
Although enoxaparin sodium is a low-molecular heparin, its actual molecular weight is still large, with an average of 4500, so it is difficult to pass through the placenta, and most of the literature reports that this product has no teratogenic effect on the fetus. There are 61 cases of women suffering from various thromboembolic diseases, in their 69 pregnancies, all of them applied enoxaparin sodium in the first 3 months of pregnancy, and no malformation occurred in their fetuses. It is not clear whether long-term application of low-molecular heparin causes osteoporosis, and it has been reported in the literature that the former is less likely to cause osteoporosis when compared with the application of unseparated heparin. It is not known whether low-molecular heparin enters into breast milk, but because of the large molecular weight of this product, it rarely enters into breast milk, and this product has no active effect in the gastrointestinal tract, so it will not cause adverse effects on the breast.
3.3 Coumarins
This class of drugs is represented by double coumarin, which produces slow and long-lasting in vivo anticoagulant effect after oral administration and is ineffective in vitro. Similar drugs include double coumarin ethyl ester (new double coumarin), warfarin and vinblastine coumarin (new anticoagulation). Their basic structures are similar and their anticoagulant principles are the same, and they are all classified as Class X by the FDA. Since their chemical structures are very similar to vitamin K, they may prevent the utilization of vitamin K by competitive antagonism with it, thus blocking the synthesis of prothrombinogen and coagulation factors III, IX, in the liver.
Coumarins are able to pass through the placenta and their application during pregnancy can cause fetal malformations and hemorrhage. Early gestation, especially at 6 weeks and 12 weeks of gestation, can lead to the development of fetal warfarin syndrome (FWS), which is characterized by nasal hypoplasia and punctate epiphysis, in addition to defects of the central nervous system and the eye. Some scholars have collected literature data summarizing 263 cases of pregnant women who used coumarins in early pregnancy and delivered 167 normal infants, 41 cases of spontaneous abortion, 17 cases of stillbirth or neonatal death, 27 cases of FES, and 11 cases of central nervous system or other malformations. The incidence of fetal abortions and abnormalities was as high as 37%.
Of the 208 pregnant women who were exposed to the drug in midterm pregnancy, 175 delivered normal babies (87%). Coumarins are rarely introduced into breast milk and have no effect on the breastfed child, and the American Academy of Pediatrics believes that lactating women taking coumarins can continue to lactate.
3.4 Indandione derivatives
Indandiones are oral long-acting anticoagulants with effects similar to those of coumarins, such as anisodinones and benzindenones, which are classified as Class X by the FDA. Benzindanedione can produce serious toxic side effects (such as granulocyte deficiency, jaundice, nephropathy), and some even cause death, so it is rarely used, anisodindione also has potential risks. Therefore, only for those who can not tolerate coumarin drugs.
These drugs can pass through the placenta and are likely to have adverse effects on the fetus, and there is a lack of information on fetal safety, so they are prohibited during pregnancy. Because these drugs can be introduced into the breast and cause extensive scrotal hematomas in male infants, the American Academy of Pediatrics believes that lactating mothers should be prohibited from breastfeeding with this drug.
In conclusion, the application of anticoagulant therapy during pregnancy should be well indicated. Heparin is safer for both mother and child and should be preferred, but heparin is not effective when taken orally, so in cases where long-term prophylactic anticoagulant use is needed during pregnancy, heparin can be used in early pregnancy and near the full term of pregnancy, and coumarin anticoagulants should be taken between 14 and 36 weeks of pregnancy, and the possible adverse effects and teratogenic effects on the fetus should be clearly explained to the family.
3.5 Aspirin
Also known as acetylsalicylic acid, classified as Class C by the FDA. Aspirin is used in obstetrics not only for the prevention of thromboembolic disease but also for the prevention of hyperemesis gravidarum and for the treatment of antiphospholipid syndrome. It is a non-steroidal anti-inflammatory drug with inhibitory effect on prostaglandin synthase in platelets. It is completely and rapidly absorbed orally. The onset of action is rapid after administration, with peak plasma concentrations reaching 2 hours.
Aspirin inhibits platelet aggregation mainly through two links: firstly, it reduces the synthesis and release of thromboxane A2, which is the main substance that induces platelet aggregation; secondly, it acetylates platelet membrane glycoprotein and inhibits platelet function.
The prevention of thrombosis during pregnancy requires only 25-100 mg of oral aspirin daily. Some recent studies have reported that small doses of aspirin (50-80 mg/d) are significantly effective in preventing the development of hyperemesis and in preventing intrauterine growth retardation in the fetus. The therapeutic effect of low-dose aspirin on miscarriage and intrauterine stillbirth caused by antiphospholipid syndrome has been reported in the literature.
Aspirin can pass through the placenta and the drug concentration in fetal blood can exceed that in maternal blood when aspirin is used by pregnant women. Whether aspirin is teratogenic to the fetus has been controversial. Currently, it is believed that it is not teratogenic to the fetus if applied in small doses. According to the National Perinatal Collaborative Program, no teratogenic effects on the fetus were found in 14,864 cases of aspirin applied in early pregnancy and 32,164 cases of aspirin applied in all stages of pregnancy.
However, long-term and high-dose use of this product can cause coagulation dysfunction in mother and infant, increase the morbidity and mortality rate of perinatal infants, and even lead to fetal malformation. Especially when used before and after delivery, aspirin may cause intracranial hemorrhage in newborns, so it must be used with clinical caution.
Aspirin can be introduced into breast milk in small amounts, and the American Academy of Pediatrics believes that nursing women can continue to breastfeed with this product, but must be alert to possible adverse effects on the infant.
3.6 Dipyridamole
Also known as pansentin and dipyridamole, classified as Class B by the FDA. In addition to inhibition of platelet aggregation, bimatoprost has a vasodilating effect and is used clinically in patients with angina pectoris. It can be used to prevent thrombosis in pregnant women who undergo heart valvuloplasty or prosthetic valves. The incidence of hyperemesis, fetal and neonatal morbidity and mortality rates are lower than those of aspirin. So far, there is no report of fetal malformation caused by the application of this product. Dipyridamole is rarely introduced into breast milk, and lactating mothers can continue to breastfeed with this product.
3.7 Indomethacin
Also known as anti-inflammatory pain, FDA classified as Class B. Although indomethacin has an inhibitory effect on platelet aggregation, it is less commonly used clinically to prevent thromboembolic disease and is mainly used in obstetric clinics to treat preterm labor and excessive amniotic fluid.
It has been reported in the literature that prolonged and high-dose application of this product, or its use after 34 weeks of gestation and after the fetus exceeds 2000 g, can lead to premature closure of fetal ductus arteriosus, primary pulmonary hypertension in the newborn, and impaired fetal renal function.
Therefore, for safety reasons, short-term use of this product is currently considered only before 32 weeks of gestation and when other drugs are not appropriate. In addition, animal studies have shown that the use of indomethacin in pregnant rats can lead to fused ribs, spinal abnormalities and other bone deformities in fetuses. Indomethacin can be introduced into breast milk, and there have been reports of convulsions in nursing mothers who continued to breastfeed after taking large amounts (200 mg/d) of this product. The American Academy of Pediatrics believes that nursing women may continue to breastfeed when regular doses of this product are administered, but should be aware of possible adverse effects on the infant.
3.8 Streptokinase
FDA classified as Class C. The molecular weight of this product is 47,000, so it is extremely unlikely to pass through the placenta and will not have a fibrinolytic effect on the fetus.
Theoretically, the application of thrombolytic therapy before 12 weeks of gestation can interfere with placental implantation, but this has not been confirmed in clinical practice. Some scholars have collected 166 cases of pregnant women with various thromboembolic diseases who applied streptokinase from 9 weeks to 38 weeks of gestation from the literature, and no teratogenic effect on the fetus was found, nor did it cause placental abruption or antepartum hemorrhage. Therefore, it is safe to be used in pregnant women with indications for thrombolytic therapy.
Because of the large molecular weight of streptokinase, it is very unlikely to be introduced into breast milk, and lactating mothers can continue to breastfeed with this product.
3.9 Urokinase
FDA classified as Class B. The molecular weight of this product exceeds 30,000, so it can rarely pass through the placenta. There have been several case reports of pregnant women with pulmonary embolism who were treated with urokinase and delivered full-term healthy infants. To date, fewer than 200 cases of thrombolytic therapy in pregnancy have been reported, with streptokinase being used in the majority of these cases. It is not known whether urokinase is introduced into breast milk, but the molecular weight of this product is large, so it is very unlikely to be introduced into breast milk, and it is estimated that the effect of this product on the fetus is not significant when it is applied to lactating mothers. Although the effect of thrombolytic drugs on the fetus is not significant, the use of this product before or within 1 week after delivery may cause severe uterine bleeding, and there is a risk of placental abruption if the product is used before 18 weeks of gestation.