Hemorrhagic Disease of Newborn

Etiology

The etiology for vitamin K deficiency can be grouped as idiopathic or secondary. The etiology of idiopathic causes is not known, but a few of the secondary causes have been explored. Vitamin K deficiency leads to decreased activity of clotting factors, resulting in hemorrhagic disease of the newborn. Adults can synthesize vitamin K in the large intestine through the gut bacteria, but neonates have reduced stores of vitamin K due to insufficient placental transfer and a sterile gut that fails to synthesize the necessary levels of vitamin K. Additionally, breast milk is deficient in vitamin K and poor hepatic storage.[3][4]

Vitamin K deficiency can manifest in babies born to mothers on anti-tubercular drugs (isoniazid, rifampicin), antiepileptics (phenytoin, barbiturates, and carbamazepine), broad-spectrum antibiotics (cephalosporins), or vitamin K antagonists such as warfarin.[2] Infants born with malabsorption diseases such as cystic fibrosis or hepatobiliary diseases such as biliary atresia have also been shown to develop vitamin K deficiency. Mutations in genes encoding for the gamma-glutamyl carboxylase and epoxide reductase have also been reported.[5]

Epidemiology

All infants irrespective of race, sex, color, religion, national origin, etc. are known to be affected by vitamin K deficiency bleeding. However, in a study conducted on 50 newborns, VKDB was found to have an increased incidence amongst male infants, breastfed infants, and those born via spontaneous vaginal delivery.[6]

In early VKDB, the incidence in infants who have not received vitamin K prophylaxis ranges from about 6% to 12%. In classic VKDB, the incidence has gone down from 0.25% to 1.5% in earlier studies to 0.01% to 0.44% in recent studies. This has been achieved due to the inclusion of vitamin K prophylaxis in routine newborn care. In late VKDB, the incidence is 1 in 15,000 to 1 in 20,000 births and is seen predominantly in exclusively breastfed babies or babies with cholestasis or malabsorption (as vitamin K absorption is dependent on bile). The most common presenting symptom of late VKDB is intracranial bleeding, which has a mortality of 20%–50% and associated morbidity.[4]

Pathophysiology

Vitamin K is a fat-soluble vitamin that occurs in 2 forms- vitamin K1 or phylloquinone (present in green leafy vegetables) and vitamin K2 or menaquinone (synthesized by the gram-negative bacteria in the intestines).[7][8] Although vitamin K has many other roles in the body, its major role involves the activation of clotting factors. It does so by gamma-carboxylation of glutamic acid residues of clotting factors 2,7,9 and 10 via post-translational modification.[9]

A deficiency of vitamin K in the body leads to inadequate activation of these clotting factors and hence leads to bleeding in the body, which manifests as hemorrhagic disease of the newborn or, more specifically, known as VKDB.

History and Physical

If VKDB is suspected, it is important to take a proper history. The following points in the history that could lead to a proper diagnosis include:

1. Drugs taken during pregnancy- anticonvulsants, anti-tubercular drugs, warfarin, salicylates, etc.
2. Gestation period- preterm babies are at a higher risk of having VKDB.
3. If breastfed or bottle-fed- as bottle/formula-fed infants are at lower risk due to fortified feedings with essential vitamins and minerals.
4. Place of delivery- generally home-delivered infants do not have access to immediate vitamin K prophylaxis and hence are at a greater risk.

Physical findings in a patient with VKDB are:

1. Cephalhematoma
2. Intracranial bleeding
3. Intrathoracic bleeding, which can cause hemoptysis, and associated respiratory distress
4. Intra-abdominal bleeding- melena or hematemesis
5. Bleeding from the skin- petechiae present over the skin
6. Bleeding from mucous membranes, including the gums, nose, etc.
7. Bleeding after circumcision
8. Bleeding from the umbilical stump after cutting the umbilical cord at birth
9. Bleeding from vaccination sites[10]

Intracranial bleeding is mostly associated with late VKBD and presents with a floppy baby, lethargy, feeding difficulties, bulging fontanelles, decreased respiratory rate, altered consciousness, convulsions, or pallor.[11]

Evaluation

History, physical examination, and laboratory investigations, along with any significant radiological findings, can help to arrive at the diagnosis early and start treatment.

Most commonly advised laboratory tests are:

1. Complete blood count- will have normal platelet levels (1.5-4 lacs/cubic mm)

2. Clotting profile:

• International normalized ratio (INR) greater than or equal to 4
• Prothrombin time (PT) more than 4 times the normal[4]
• Prothrombin time will be increased due to decreased activity of factor 7
• Partial thromboplastin time (PTT) will also be increased due to decreased activity of factors 2,9 and 10
• Clotting time will be increased due to clotting factor deficiency
• Fibrinogen levels will remain normal

3. Protein induced by vitamin K antagonist (PIVKA) estimation- PIVKA are proteins induced in vitamin K absence. These are evaluated by HPLC (high-pressure liquid chromatography), ELISA (enzyme-linked immunosorbent assay), or immuno-electrophoresis. Any amount of PIVKA is abnormal and indicates vitamin K deficiency.[3] It disappears around day 5 of the administration of vitamin K.[12]

4. Chest X-ray or ultrasound to determine if there is bleeding in body cavities- intrathoracic, intra-abdominal

5. Computed tomography (CT) and magnetic resonance imaging (MRI) studies to evaluate for intracranial hemorrhage

Treatment / Management

Treatment of VKDB mainly focuses on prompt administration of vitamin K to the infant and then further investigation for the cause of the disease.

In cases of severe life-threatening bleeding, immediate blood transfusions can be given along with fresh frozen plasma to reduce the bleeding.

Late VKDB can present with intracranial hemorrhage. The most common form being sub-dural hemorrhage may require surgical evacuation or intracranial shunting to relieve increased intracranial pressure and associated symptoms.[13]

Late VKDB can also present with neurological abnormalities despite treatment that will require regular follow-up and continuous monitoring. Physiotherapy can be advised to retain/strengthen neural function. If unable to suck or swallow, babies may require nutritional assistance.

Nonetheless, a single intramuscular (IM) dose of 1 mg of vitamin K is known to improve the coagulation profile within 1 to 7 days.[14](A1)

Infants not protected from VKBD through prophylaxis may have unrecognized liver disease.

Differential Diagnosis

The most common differential for VKDB is trauma- accidental or non-accidental injury. Other differentials include:

• Clotting factor deficiencies such as hemophilia A or hemophilia B. Non-reversal of condition despite administering clotting factors may help to determine the exact cause.
• Disseminated intravascular coagulation (DIC)- running laboratory studies will help to differentiate between DIC and VKDB.
• Thrombocytopenia, especially maternal immune thrombocytopenia as antibodies to platelets, can cross the placenta and decrease infant platelet count manifesting as purpura. However, in VKDB, the platelet count is generally normal.
• For infants presenting with isolated gastrointestinal bleed, intussusception can be a differential.

However, based on laboratory studies, it becomes easier to arrive at the diagnosis and treat the disease accordingly.

Treatment Planning

For early and classic forms of hemorrhagic disease of the newborn, the treatment is with oral vitamin K (2mg dose) repeated at 2-4 weeks and at 6-8 weeks.

For the late form of the disease, oral vitamin K is not as efficacious as parenteral, and hence currently, 0.5-1 mg single IM dose is administered to infants.[2] 

For infants weighing less than 1500 gm, 0.5 mg IM single dose is given.

For infants weighing more than 1500 gm, 1 mg IM single dose is given.[12]

All breastfed babies with diarrhea and malabsorption require an additional post-natal dose of vitamin K to prevent late vitamin K deficiency bleeding.[3]

In the case of life-threatening hemorrhages, 10-20 ml/kg of fresh frozen plasma should also be administered.

More than 20% of blood loss and features of shock require immediate blood transfusions.[3]

Toxicity and Adverse Effect Management

There is no known toxicity or side effects associated with vitamin K1. Vitamin K1 is a naturally occurring, fat-soluble form of vitamin K. Before the introduction of vitamin K1, vitamin K3 was used. Vitamin K3 is a synthetic, water-soluble derivative of menadione. In higher doses, it has been associated with kernicterus, hemolytic anemia, and hyperbilirubinemias.[3]

Vitamin K was earlier thought to be associated with an increased risk of childhood cancers. However, studies have shown no such association.[15]

Due to having a safe profile, vitamin K1 is widely accepted as routine prophylaxis in most countries.[1]

Prognosis

Vitamin K prophylaxis at birth has proven to significantly improve the prognosis by decreasing mortality. Patients presenting with intracranial hemorrhage might have associated morbidity in the form of neurological damage. However, vitamin K has reduced the incidence of hemorrhagic disease of the newborn, and its usage should be continued as effective prophylaxis.[14]

Complications

The most important complication of hemorrhagic disease of the newborn is bleeding, which can often be fatal in infants. It is one of the most important causes of intracranial hemorrhage in the first year of life.[16]

Morbidity is generally seen with late vitamin K deficiency bleeding, and it manifests as neurological defects such as hydrocephalus, encephalopathy, cerebral atrophy, seizures, and severe developmental delay.[4]