PHYTONADIONE

Fetal Risk Summary

Phytonadione is a synthetic, fat-soluble substance identical to vitamin K1, the natural vitamin found in a variety of foods (1). It is used for the prevention and treatment of hypoprothrombinemia caused by to vitamin K deficiency (1). Animal reproduction studies have not been conducted with phytonadione.

In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 5 newborns had been exposed to phytonadione during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Four (80.0%) major birth defects were observed (none expected), including 2/0 cardiovascular defects and 1/0 spina bifida. No anomalies were observed in four other defect categories (oral clefts, polydactyly, limb reduction defects, and hypospadias) for which specific data were available.

The use of phytonadione (vitamin K1) during pregnancy and in the newborn has been the subject of several large reviews (2,3,4 and 5). Administration of vitamin K during pregnancy is usually not required because of the abundance of natural sources in food and the synthesis of the vitamin by the normal intestinal flora. Vitamin K1 is indicated for maternal hypoprothrombinemia and for the prevention of hemorrhagic disease of the newborn (HDN) induced by maternal drugs, such as anticonvulsants, warfarin, rifampin, and isoniazid (2,3,4 and 5).

The placental transfer of vitamin K1 is poor (6,7). A 1982 study found no detectable vitamin K (<0.10 ng/mL) in the cord blood of nine term infants, although adequate levels (mean 0.20 ng/mL) were present in eight of the nine mothers (6). Vitamin K1, 1 mg IV, was then given to six additional mothers shortly before delivery (11–47 minutes) resulting in plasma vitamin K1 values of 45–93 ng/mL. Vitamin K1 was detected in only four of the six cord blood samples (ranging from 0.10 to 0.14 ng/mL), and its appearance did not seem to be time dependent. In a 1990 study, women were administered one or two doses of vitamin K1 10 mg IM at 4-day intervals, and if not delivered, followed by daily oral 20-mg doses until the end of the 34th week or delivery (7). Treated subjects had significantly higher vitamin K1 maternal and cord plasma levels than controls (11.592 vs. 0.102 ng/mL and 0.024 vs. 0.010 ng/mL, respectively). Although the median plasma vitamin K1 levels in the mothers treated only with IM doses were similar to those treated with IM and oral doses, cord plasma levels in the latter group were significantly higher (0.42 vs. 0.017 ng/mL). No correlation was found between cord plasma levels of vitamin K1 and gestational age or duration of therapy (7).

Vitamin K1 is nontoxic in doses less than 20 mg (3). In a double-blind trial, 933 women at term were given 20 mg of either K1 or K2, the naturally occurring vitamins (8). No toxicity from either vitamin was found, including any association with low birth weight, asphyxia, neonatal jaundice, or perinatal mortality.

Oral vitamin K1 has been suggested during the last 2 weeks of pregnancy for women taking anticonvulsants to prevent hypoprothrombinemia and hemorrhage in their newborns, but the effectiveness of this therapy has not been proven (2,3). In a group of mothers receiving phenindione, an oral anticoagulant, 10–30 mg of vitamin K1 was given either IV or intraamniotically 2–4 days before delivery (9). In a separate group, 2.5–3.0 mg of vitamin K1 was injected IM into the fetuses at the same interval before delivery. Only in this latter group were coagulation factors significantly improved.

In summary, phytonadione (vitamin K1) is the treatment of choice for maternal hypoprothrombinemia and for the prevention of HDN. Maternal supplements are not needed except for those patients deemed at risk for vitamin K deficiency. A recommended dietary intake from food of vitamin K1 during pregnancy of 45 µg (100 nmol) has been proposed (10).

Breast Feeding Summary

Levels of phytonadione (vitamin K1) in breast milk are naturally low with most samples having less than 20 ng/mL and many less than 5 ng/mL (2,3). In 20 lactating women, colostrum and mature milk concentrations were 2.3 and 2.1 ng/mL, less than half that found in cow's milk (11). Administration of a single 20-mg oral dose of phytonadione to one mother produced a concentration of 140 ng/mL at 12 hours, with levels at 48 hours still about double normal values (11). In another study, 40 mg orally of vitamin K1 or K3 (menadione) were given to mothers within 2 hours after delivery (12). Effects from either vitamin on the prothrombin time of the breast-fed newborns were nil to slight during the first 3 days.

Natural levels of vitamin K1 or K2 in milk will not provide adequate supplies of the vitamin for the breast-fed infant (2,3). The vitamin K1–dependent coagulation factors II, VII, IX, and X, are dependent on gestational age (2). In the newborn, these factors are approximately 30%–60% of normal and do not reach adult levels until about 6 weeks (2). Although not all newborns are vitamin K1 deficient, many are, because of poor placental transfer of the vitamin. Exclusive breast feeding will not prevent further decline of these already low stores and the possible development of deficiency in 48–72 hours (2,3). In addition, the intestinal flora of breast-fed infants may produce less vitamin K than the flora of formula-fed infants (2). The potential consequence of this deficiency is hemorrhagic disease of the newborn.

The American Academy of Pediatrics has suggested that HDN be defined as “a hemorrhagic disorder of the first days of life caused by a deficiency of vitamin K and characterized by deficiency of prothrombin and proconvertin (stable factor, factor VII), and probably of other factors” (13). The hemorrhage is frequently life threatening with intracranial bleeds common. A 1985 review (2) identified three types of HDN: Early HDN (onset 0–24 hours) Classic HDN (onset 2–5 days) Late HDN (onset 1–12 months) The maternal ingestion of certain drugs, such as anticonvulsants, warfarin, or antituberculous agents, is one of the known causes of early and classic HDN, whereas breast feeding has been shown to be a cause of classic and late HDN (2). The administration of phytonadione to the newborn prevents HDN by preventing further decline of factors II, VII, IX, and X (2).

The use of prophylactic vitamin K1 in all newborns is common in the United States but is controversial in other countries (2). The Committee on Nutrition, American Academy of Pediatrics, recommended in 1961 and again in 1980 that all newborns receive 0.5–1.0 mg of parenteral vitamin K1 (13,14). The Committee recommended that administration to the mother prenatally should not be substituted for newborn prophylaxis (13). The bleeding risk in breast-fed infants who did not receive prophylactic vitamin K1 is 15–20 times greater than in infants fed cow's milk, given vitamin K1, or both (2). In spite of this evidence, new cases of HDN are still reported (3,15). In a recent report, 10 breast-fed infants with intracranial hemorrhage as a result of vitamin K deficiency were described (15). Onset of the bleeding was between 27 and 47 days of age with three infants dying and three having permanent brain injury. Milk levels of total vitamin K (K1+K2) varied between 1.36 and 9.17 ng/mL. None of the infants had been given prophylactic therapy at birth.

In summary, the natural vitamin K content of breast milk is too low to protect the newborn from vitamin K deficiency and resulting hemorrhagic disease. The administration of vitamin K to the mother to increase milk concentrations may be possible but needs further study. All newborns should receive parenteral prophylactic therapy at birth consisting of 0.5–1.0 mg of phytonadione. Larger or repeat doses may be required for infants whose mothers are consuming anticonvulsants or oral anticoagulants (2,13). The American Academy of Pediatrics considers the maternal use of vitamin K1 to be compatible with breast feeding (16).

References

1. American Hospital Formulary Service. Drug Information 1997. Bethesda, MD: American Society of Health-System Pharmacists, 1997:2834–36.
2. Lane PA, Hathaway WE. Vitamin K in infancy. J Pediatr 1985;106:351–9.
3. Payne NR, Hasegawa DK. Vitamin K deficiency in newborns: a case report in a-1-antitrypsin deficiency and a review of factors predisposing to hemorrhage. Pediatrics 1984;73:712–6.
4. Wynn RM. The obstetric significance of factors affecting the metabolism of bilirubin, with particular Reference to the role of vitamin K. Obstet Gynecol Surv 1963;18:333–54.
5. Finkel MJ. Vitamin K1 and the vitamin K analogues. J Clin Pharmacol Ther 1961;2:795–814.
6. Shearer MJ, Rahim S, Barkhan P, Stimmler L. Plasma vitamin K1 in mothers and their newborn babies. Lancet 1982;2:460–3.
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8. Blood Study Group of Gynecologists. Effect of vitamins K2 and K1 on the bleeding volume during parturition and the blood coagulation disturbance of newborns by a double blind controlled study. Igaku no Ayumi 1971;76:818. As cited in Nishimura H, Tanimura T. Clinical Aspects of the Teratogenicity of Drugs. New York, NY: American Elsevier, 1976:253.
9. Larsen JF, Jacobsen B, Holm HH, Pedersen JF, Mantoni M. Intrauterine injection of vitamin K before delivery during anticoagulant therapy of the mother. Acta Obstet Gynecol Scand 1978;57:227–30.
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11. Haroon Y, Shearer MJ, Rahim S, Gunn WG, McEnery G, Barkhan P. The content of phylloquinone (vitamin K1) in human milk, cows' milk and infant formula foods determined by high-performance liquid chromatography. J Nutr 1982;112:1105–17.
12. Dyggve HV, Dam H, Sondergaard E. Influence on the prothrombin time of breast-fed newborn babies of one single dose of vitamin K1 or Synkavit given to the mother within 2 hours after birth. Acta Obstet Gynecol Scand 1956;35:440–4.
13. Committee on Nutrition, American Academy of Pediatrics. Vitamin K compounds and the water-soluble analogues. Pediatrics 1961;28:501–7.
14. Committee on Nutrition, American Academy of Pediatrics. Vitamin and mineral supplement needs in normal children in the United States. Pediatrics 1980;66:1015–21.
15. Motohara K, Matsukura M, Matsuda I, Iribe K, Ikeda T, Kondo Y, Yonekubo A, Yamamoto Y, Tsuchiya F. Severe vitamin K deficiency in breast-fed infants. J Pediatr 1984;105:943–5.
16. Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 1994;93:137–50.