Antenatal Anticoagulant Therapy and Neonatal Hemorrhagic Syndrome. Case Report

Neonatal hemorrhagic syndrome, which affects several principal organs during the early neonatal period, denotes a deficiency of vitamin K and coagulation factors. This article presents the case of a patient who gave birth at term, had congenital heart disease and required several prior surgical interventions including corrected transposition of the great vessels via ventricular septal defect (VSD) repair, atrial septal defect (in childhood) and tricuspid valve replacement (6 years ago), mitral regurgitation (MR), grade I pulmonary regurgitation (PR), grade II mitral and tricuspid valve regurgitation, and grade II heart failure based on the New York Health Association (NYHA) classification. Throughout the pregnancy, the patient received large doses of anticoagulant, specifically acenocumarolum, until the moment she gave birth. The vaginal delivery was spontaneous, contrary to the recommendations given to the pregnant woman in a secondary healthcare institution. At birth, the newborn was in satisfactory condition, with 8/9 on the Apgar score. However, the newborn’s condition wors-ened over time, suspected of having neonatal hemorrhagic syndrome caused by medications received by the mother. Forty-eight hours after birth, the newborn died. Anticoagulant therapy cannot be regarded as 100 percent risk-free during pregnancy due to the potential for hemodynamic disorders to develop in both the mother and the unborn child. Considering the high incidence of perinatal mortality in such cases (10-30%), it is advised that a multidisciplinary team work together to inform the mother about potential complications, collaboratively determine the length of treatment with vitamin K antagonists (VKAs), develop a plan for monitoring the pregnancy, and determine which institution the mother and newborn would benefit from receiving qualified medical assistance.


INTRODUCTION
Vitamin K deficiency bleeding can occur in newborns early and later following birth. Early forms usually appear in the first 24 hours of life; anticoagulants and maternal malnutrition (vitamin K deficiency) are direct risk factors. Scientific literature lists carbamazepine, phenobarbital, phenylhydantoin, rifampicin, cephalosporins, and VKAs (coumarins, warfarin) as medications that interfere with vitamin K metabolism in newborns when administered 15 days before birth. The clinical case presented in this article demonstrates circumstances in the development of neonatal hemorrhagic syndrome because of bleeding caused by vitamin K deficiency. Vitamin K deficiency bleeding usu-ally occurs after 24 hours after birth but may present as late as the first week of life. Vitamin K deficiency bleeding is observed in infants who have not received prophylactic vitamin K at birth, with an incidence ranging from 0.25 to 1.7 cases per 100 births. [1] After regimens for prophylaxis were introduced, vitamin K deficiency bleeding has fallen from 4.4-7.2 cases per 100,000 births to 1.4-6.4 cases per 100,000 births in reports from Asia and Europe. In India and China, mandatory vitamin K prophylaxis is required, considering the high burden of neonatal deaths, to reduce the long-term morbidity and mortality related to vitamin K deficiency bleeding. [2][3][4] Neonatal hemorrhagic syndrome, which affects several principal organs during the early neonatal period, denotes a deficiency of vitamin K and some coagulation factors. A Cochrane systematic review entitled "Vitamin K supplementation during pregnancy for improving outcomes" synthesizes existing evidence related to this problem. Vitamin K deficiency can be a serious risk for the pregnant woman and the newborn. Bleeding is caused by reduced levels of prothrombin, an important element of the blood that is dependent on vitamin K, which disrupts the blood clotting process and can lead to excessive maternal or neonatal bleeding. [5,6] Exposure of women to vitamin K anticoagulants during pregnancy may affect the fetus in utero by the formation of coumarin embryopathy (CE). [7] Approximately 6% of newborns exposed to the consumption of coumarin during pregnancy develop CE, and skeletal abnormalities (midfacial hypoplasia, epiphyseal calcifications) are recorded in 80% of these children. Central nervous system malformations (e.g., midline structural defects) have been detected in 45% of children diagnosed with CE. Signs of intracranial hemorrhage have been observed in 10% of newborns. Since coumarins cross the placenta, affecting fetal coagulation, they increase the risk of intracranial hemorrhage before birth. [8] Moreover, the immaturity of the fetal liver is a major cause of slow metabolism of warfarin and a low level of coagulation factor in the fetus, thus the anticoagulant effect in the fetus is significantly stronger than in the mother. In addition, there is an increased risk of bleeding in newborns during birth, sometimes with a possible fatal outcome. [9] This hypothesis is also supported by Shearer [10] , who mentions that insufficient vitamin K levels can lead to intracranial hemorrhage shortly after birth. Babies are born with lower levels of vitamin K and do not receive adequate amounts of breast milk due to the lower rate of placental transfer. [7] The medication taken by the mother affects the metabolism of vitamin K and can oftentimes increase the incidence of disease in infants. A mortality rate of 20% has been estimated in neonates with severe bleeding disorders, including intracranial hemorrhage (50%) and neurological impairment. [5] Hetzel suggests that the administration of vitamin K antagonists should be under strict control during anticoagulant treatment in pregnant women with mechanical heart valves. [7] CASE REPORT Patient A., a 20-year-old primigravida with a history of congenital heart disease (CHD), corrected transposition of the great vessels via VSD repair, ASD (in childhood), tricuspid valve replacement (6 years ago), MR, grade I PR, grade II mitral and tricuspid valve regurgitation, and grade II heart failure based on the NYHA classification, was registered under the surveillance of her primary care physician at 12 weeks of pregnancy. The pregnancy was planned and wanted.
Over the course of the pregnancy, the patient was monitored by her family doctor and consulted by obstetric, cardiology, and heart surgery specialists. Taking into consideration pre-existing heart problems and previous surgical interventions, the  Even though delivery was recommended to take place in a tertiary level maternity hospital following leaking of amniotic fluid and the onset of regular uterine contractions, the patient urgently went to a primary level maternity unit in her place of residence. The following diagnostics were recorded: 39-weeks pregnant, primipara, premature rupture of membranes (PROM), longitudinal position of the fetus, cranial presentation, anterior variety, position II.
The first period (4 hours 30 minutes) and the second (30 minutes) of birth took place physiologically, without signs of fetal suffering, and without the utilization of fetal vacuum extraction and forceps. At birth, the newborn was in a satisfactory condition with 8/9 on the Apgar score, had clean, pale skin and mucous membranes. The neurological status of the newborn was assessed as satisfactory. There were no pathological ocular symptoms. The head was in a dolichocephalic form, and a 3×3 cm cephalohematoma was observed in the occipital region.
The postpartum period was complicated on the second day following birth with the appearance of a hematoma in the region of the external genital organs, as well as hemodynamic disorders. The patient was transferred to a tertiary level healthcare facility, where the following diagnostics were established: day four postpartum, condition following natural childbirth, hematoma in the region of the internal and external genital organs, grade II iron deficiency anemia, CHD, corrected transposition of the great vessels via VSD repair, ASD, tricuspid valve replacement, MR, grade I PR, grade II mitral and tricuspid valve regurgitation, and grade II heart failure based on the NYHA classification. Laboratory readings indicated low prothrombin (36%), but the level of fibrinogen could not be detected. During her stay in the intensive care unit, she was prescribed an anticoagulant treatment and a blood transfusion. On the sixth day following her admission, she was discharged in a satisfactory condition.
Twenty-two hours after birth, the newborn was in an aggravated condition; it suddenly became restless, refused to suck, and had a painful scream and moan. The newborn's skin turned paler, muscle hypertonia was observed, breathing was difficult, and it had SaO 2 of 88%-90%.
Twenty-four hours after birth, the newborn's condition became extremely critical. It was very pale. Regarding its neurologic condition, it had a week reaction to physical examination. The newborn went into a coma and began to convulse. Its head grew in volume with a cranial circumference of 39.4 cm (4.4 cm greater than at birth) and at the level of the occipital bones a fluctuating collection of fluid was observed. SpO 2 was not determined, frequency of heart contractions was 110 per minute, respiratory rate was 38-40 per minute, and capillary recovery time was >3 seconds. A complete blood count (CBC) showed the following: hemoglobin -87 g/L, erythrocytes -2.9×10 12 cells/L, hematocrit -32%, leukocytes (WBC) -28.8×10 3 /microL, metamyelocytes -2%, unsegmented -10%, segmented -50%, eosinophils -0%, lymphocytes -36%, monocytes -2%. The newborn was given vitamin K (2 mg), volume expansion with 0.9% NaCl -10 ml/kg, dopamine -10 mcg/kg/min increased to 15  The cause of death based on the autopsy was determined to be a neonatal hemorrhagic syndrome. Acute bleeding disorders, rectal bleeding and per diapedesis in the epicranial aponeurosis, at the level of the leptomeninges, brain, thymus, lungs, diaphragm, stomach, intestines, and kidneys were observed. Collection of blood occurred at the level of the leptomeninges and diaphragm. The amount of blood accumulated in the right lung was 10 ml and in the stomach -100 ml.

DISCUSSION
The advantages and disadvantages of different anticoagulant regimens should be discussed at length before pregnancy. The mother must understand that the use of VKAs is the most effective regimen for preventing valvular thrombosis and therefore, the safest regimen for her, though these risks for the mother also put the child in danger. At the same time, it is important for the mother to be compliant regardless of the chosen regimen. Subsequently, continuation of VKA administration may be considered in pregnant women after fully informed consent. The pregnant woman in the clinical case received treatment with VKAs throughout her pregnancy. When a higher dose of VKAs is required, the treatment may be discontinued between 6 and 12 weeks and replaced with an adjusted dose of unfractionated heparin (UFH) or low-molecular-weight heparins (LMWH) IV twice daily, with dose adjustment according to maximum anti-factor Xa levels.
One of the important issues is to determine when it is appropriate to stop treatment with anticoagulants. Thus, according to the 2012 American College of Chest Physicians (ACCP) Guidelines, VKAs should be discontinued three weeks before the expected date of birth. [11] The 2014 American College of Cardiology and the American Heart Association (ACC/AHA) guide recommends discontinuing VKAs at 36 weeks pregnancy and initiating UFH IV therapy, which should be stopped approximately 4-8 hours before the expected birth with resumption of treatment 4-6 hours after birth in the absence of bleeding. VKA treatment can be resumed 24 hours after birth. [12] The European Society of Cardiology (ESC) guide "Guidelines for the management of cardiovascular diseases during pregnancy" (2018) proposes dose adjustment depending on INR values and factor Xa. The authors also mention that vaginal birth while the mother is on VKAs is contraindicated due to the risk of fetal intracranial bleeding and hemorrhagic complications in the mother, which can occur regardless of the chosen regimen. The incidence of such complications is lower when administering VKAs during pregnancy than when LMWH or UFH is administered during pregnancy. Patients receiving VKAs are recommended caesarean section when labor begins. [13] The guide recommends stopping VKA treatment at 36 weeks of gestation and replacing it with UFH or LMWH IV until 36 hours before birth. At that point, LMWH should be replaced with UFH IV. [13] The ACCP guide recommends that pregnant women at remarkably high risk of thromboembolism (older generation mitral valves and previous thromboembolism) should continue to take warfarin as close to birth as possible, generally 48 hours before the expected time of birth, when VKA therapy should be replaced by UFH or LMWH. [11] In the case of an unexpected birth before the scheduled date when the patient should receive oral anticoagulant therapy, cesarean section is recommended due to the risk of fetal intracranial hemorrhage. Panduranga et al. recommend stopping the UFH IV 4-6 hours before birth and resuming it 4-6 hours after birth. [15] Montavon et al. consider that UFH or LMWH should be administered 12 hours after cesarean section or 6 hours after vaginal birth in combination with VKAs the next day until therapeutic INR values are reached. [9] Analyzing the characteristics of the presented clinical case, the patient had a history of CHD, namely -corrected transposition of the great vessels, condition following VSD repair, ASD (in childhood), tricuspid valve replacement (6 years ago), which from the beginning warranted the patient's inclusion in the risk group for hemodynamic disorders during pregnancy, as well as during childbirth and postpartum. Pregnancy is a risk for such patients, so it requires supervision at a tertiary level medical facility. Pregnant women with this cardiac disease must be monitored as rigorously as possible due to changes in coagulation and increases in the volume of blood circulating during pregnancy.
At present, there is no national protocol available that clearly outlines the doses of anticoagulants that can be administered during pregnancy, be it that they are recom-mended for pregnant women with a severe heart disease or following heart surgery. Patients that have had cardiac procedures and surgeries requiring anticoagulants in relatively high doses are presented as unique cases, and the doses are recommended on an individual basis depending on the type of procedure, blood parameters, and the general condition of the patient.
During pregnancy, the dose of anticoagulant administered has been correlated with the INR index, in accordance with existing guidelines, which recommend maintaining the mean values of this indicator between 2.5 and 3.5. At the same time, it is known that utilization of coumarins, which cross the placental barrier, may cause neonatal hemorrhagic syndrome, which is probably what occurred in the presented case.
The presence of an advanced heart disease indicates the need for delivery to take place in a tertiary level maternity hospital so that parturition can be appropriately monitored and supervised. Coagulation testing should take place at the moment the patient is admitted to the hospital, availability of blood products should be verified, and a multidisciplinary team should be established in case the patient's condition worsens or she begins to hemorrhage. Likewise, the newborn requires a more rigorous examination in the neonatal period; additional investigations are available at tertiary level facilities and the newborn thus benefits from qualified medical care in terms of diagnosis and treatment.
From an obstetrical point of few, there is no relationship between consequences to the fetus and the obstetrical conduct of delivery. The autopsy report showing the presence of neonatal hemorrhagic syndrome was indicated by acute circulatory bleeding disorders and accumulation of blood in the right lung and stomach. Considering the presence of desquamative interstitial bronchopneumonia, residual aspiration syndrome, and pre-existing heart problems, we consider that the bleeding experienced by the newborn was not caused by the labor itself, but by the long-term administration of coumarin anticoagulants (acenocoumarol) to the mother during pregnancy and up until labor. The administration of this medication led to vitamin K deficiency in the pregnant woman and, consequently, in the newborn, causing acute circulatory bleeding disorders and accumulation of blood, which were determined to be the cause of death. Also, administration of vitamin K in the period immediately following childbirth was indispensable. Coagulation disorders in the fetus during the neonatal period were a consequence of the mother's condition, which, during childbirth, was also complicated by coagulation disorders (hypoprothrombinemia), requiring qualified medical assistance, including blood transfusion.
Another case of coumarin embryopathy after in utero (throughout intra uterine life) exposure to acenocoumarol was described in 2018 by Ankur Singh; however, the neonate showed all features of coumarin embryopathy (flat facial profile, depressed nasal bridge, short columella, skeletal stippling, short distal phalanges in hand) and cephalohematoma in addition. The authors conclude that doses causing embryopathy remained unexplored field, and that coumarins act as double edge sword as fetus is unnecessarily exposed to teratogenic effect of drug. [16] In another case report, K. Stefanidis describes an uneventful course of pregnancy and delivery in a pregnant patient with a mechanical heart valve receiving anticoagulation treatment because of mitral valve replacement at the age of 16 due to rheumatic disease. The antithrombotic regimen used was acenocoumarol 2 mg/day throughout the 2nd and 3rd trimesters of pregnancy with replacement of acenocoumarol by enoxaparin sodium 60 mg twice daily (low-molecular-weight heparin -LMWH) in the 1st trimester during weeks 7-12. International normalized ratio (INR) values were kept above 2.5. At 36 weeks of gestation, acenocoumarol was substituted with unfractionated heparin and 2 days later the patient entered spontaneous premature labor and was emergently delivered via cesarean section (INR=1.4). No coumarin embryopathy or neonatal bleeding was revealed and the postoperative course of the mother was uneventful. Possibly, the case was a success due to optimum replacements of coumarins. [17] Vitamin K metabolism can also be disrupted by maternal medication in the 15 days before birth, which requires the administration of antenatal vitamin K (10-20 mg/day orally). If this treatment has been omitted, the intramuscular (IM) administration of 10 mg intrapartum vitamin K to the mother is recommended at the beginning of birth. [14] Therefore, immediate postnatal administration of vitamin K is considered optimal for vitamin K deficiency prophylaxis for this group of children. According to the recommendations provided by Mihatsch (2016), all newborns should receive prophylactic vitamin K. The administration of prophylactic vitamin K should be documented. Parental refusal of prophylactic vitamin K after being adequately informed should be documented, particularly considering the risk of late vitamin K deficiency bleeding (VKDB). [16] Healthy newborns should receive either 1 mg vitamin K1 by IM injection at birth or 3 mg vitamin K1 twice orally after birth, at 4-6 days and 4-6 weeks, or 2 mg vitamin K1 orally at birth and a weekly dose of 1 mg orally for 3 months. The success of oral administration depends on compliance with the chosen protocol, which can vary between populations and environments. If the infant vomits or regurgitates within 1 hour of administration, the oral dose may be repeated. The oral route is not suitable for premature infants and newborns who are ill, have cholestasis or impaired intestinal absorption, are unable to take oral vitamin K, or for those whose mothers have taken medicines that interfere with vitamin K metabolism. [18,21] Dose-ranging studies suggest that current recommended doses of vitamin K for premature infants lead to supraphysiological levels. A randomized study showed that administration of 0.2 mg vitamin K IM at birth resulted in adequate serum levels, whereas 0.5 mg IM and 0.2 mg IV resulted in high levels of vitamin kepoxide, demonstrating hepatic overaccumulation. [19] Thus, an initial dose of prophylactic vitamin K1 of 0.2 mg IM should maintain adequate levels of vitamin K in premature infants born before the 32 nd week of pregnancy until at least the fourth week following birth. This should occur without causing hepatic overaccumulation of vitamin K1, which is recycled during the first week of life. [20] Treatment of hemorrhagic syndrome caused by vitamin K deficiency is focused on strict monitoring of coagulation tests: PT, platelets, fibrinogen, APTT. If VKDB is suspected, an IV of 1-2 mg vitamin K should be administered parenterally, slowly, for 10-15 minutes or subcutaneously (in case of lack of venous access) as soon as possible. This will reduce the duration of bleeding in a few hours. After 4-6 hours, it is necessary to repeat the PT. If PT remains prolonged and APTT is normal in a clinically stable child, a repeated dose of 1 mg vitamin K IV should be administered. Coagulation tests should be repeated every 4-6 hours. If PT and APTT remain prolonged, 10-20 ml/kg FFP should be administered for 30-60 minutes. In the presence of major bleeding, 10-20 ml/kg FFP or prothrombin complex concentrates (factors involved in the "extrinsic" and common coagulation pathway: VII-proconvertin; Stuart-Prower factor; V-proaccelerin; II -prothrombin and I-fibrinogen) should be administered. If signs of anemia and/or hypovolemic shock are present (pale skin, increased capillary recovery time, increased frequency of heart contractions, normal or decreased arterial blood pressure) PRBCs -15-20 ml/kg should be administered.
Postpartum vitamin K prophylaxis is critical for reducing VKDB morbidity and mortality in newborns. Based on 2017 World Health Organization (WHO) recommendations, prophylactic vitamin K administration should be characterized by the following: • After birth, all newborns should be given 1 mg of vitamin K IM after the first hour of life (the time when the baby should be in skin-to-skin contact with the mother and breastfeeding should be initiated) (III B). • Newborns that require surgical procedures or experience trauma during birth, premature newborns, and those exposed antenatally to drugs that interfere with vitamin K uptake have a high risk of bleeding and require administration of 1 mg vitamin K IM early after birth (III B). [22] Doses and timing of vitamin K depending on birth weight were reviewed and proposed by the French Society of Neonatology in 2017. [23] • Healthy full-term babies: 1 mg (0.1 ml) IM after the first hour following birth (preferably as soon as possible, up to 3-6 hours after birth) • Premature babies weighing ≥1.5 kg: 1 mg (0.1 ml) IM after the first hour following birth (preferably as soon as possible, up to 3-6 hours after birth), then weekly 1 mg until corrected gestational age of 40 weeks. [19] • Premature babies weighing ≤1.5 kg: 0.5 mg (0.05 ml) IM, preferably IV, slowly, for 10-15 minutes, after the first hour following birth (preferably as soon as possible, up to 3-6 hours after birth), weekly until the baby weighs ≥1.5 kg. Then weekly 1 mg until the corrected gestational age of 40 weeks. [23]