Description of the condition
Vitamin K deficiency can present a serious health risk to pregnant women and their babies that may lead to haemorrhage, especially in newborns. Haemorrhaging occurs due to reduced levels of prothrombin - an important element of the blood dependent on vitamin K for coagulation - that slows down the blood-clotting process and may result in excessive maternal or neonatal bleeding (Shils 2006). Vitamin K deficiency is extremely rare among the general adult population, although it may occur when vitamin absorption is impaired due to an underlying pathology (Food and Nutrition Board 2001; WHO/FAO 2004). It is largely unknown what type of crucial role vitamin K plays during pregnancy (UMMC 2011). However, as nutritional requirements generally increase in pregnancy, the risks of clinically relevant deficiencies also escalate, especially among pregnant women with poor nutritional status (Guelinckx 2009).
Ingestion of certain therapeutic drugs such as carbamazepine and heparin anticonvulsants may also impede vitamin K metabolism in pregnant women and give rise to vitamin K deficiency (Davidson 1986; Shils 2006). Women's exposure to vitamin K anticoagulants during pregnancy may affect the fetus in utero, resulting in coumarin embryopathy (CE) (Hetzel 2006). Approximately 6% of newborns exposed to maternal coumarin intake during pregnancy develop CE, with skeletal anomalies (e.g. midfacial hypoplasia and epiphyseal calcifications) found in 80% of these babies. Central nervous malformations (e.g. midline structural defects) were detected in 45% of babies diagnosed with CE; and signs of intracranial haemorrhage were observed in 10% (Van Driel 2002). Moreover, since coumarins cross into the placenta, they later affect fetal coagulation which increases the risk of intracranial haemorrhage before birth (Van Driel 2002). Women's consumption of therapeutic drugs during pregnancy may be associated with maxillonasal hypoplasia in newborns in the first trimester, which can lead to problems with facial and orthodontic development (Howe 1994). Van Driel 2002 and colleagues observed that of the pregnant women who were administered with coumarins, a vitamin K anticoagulant or blood-thinning medicine, 22% experienced miscarriage (Van Driel 2002). However, there is insufficient evidence to support a link between vitamin K deficiency and miscarriage.
Women of reproductive age undergoing bariatric surgeries for obesity-related morbidity treatment may also experience adverse pregnancy outcomes associated with various nutritional deficiencies (ACOG 2013). Women are likely to experience frequent nutritional shortages following bariatric surgery, but the risks of severe deficiencies are greater after malabsorption-inducing surgery rather than procedures that are solely restrictive (Guelinckx 2009). Deficiencies of vitamin K, vitamin B12, and some trace minerals have previously been reported in pregnant women who have undergone bariatric surgery (Guelinckx 2009; Shankar 2010).
Vitamin K deficiency bleeding (VKDB) is a bleeding disorder in young infants with inadequate levels of vitamin K that can lead to haemorrhaging inside the infant's skull soon after birth (Shearer 2009). Infants are born with naturally low levels of vitamin K and do not receive adequate amounts from breast milk due to the slower transfer rate through the placenta (Shearer 2009). Premature infants with vitamin K shortages and impaired oral absorption are more susceptible to vitamin K deficiency immediately following birth (Shearer 1992). The onset of early VKDB, for example, occurs among infants from birth or 24 hours immediately prior to delivery (Lane 1985). Maternal drug consumption affecting vitamin K metabolism may typically increase this condition among infants (McNinch 1983; Stevenson 1980). Therefore, coagulation disorders require immediate treatment with vitamin K administration prior to diagnosis. In Western European countries, the incidence of late VKDB in infants without vitamin K prophylaxis was found to be 5/105 births versus 11 and 72/105 births in Japan and Thailand, respectively (Shearer 2009). Immediately following birth, the proportion of VKDB infants who received no vitamin K administration was estimated to be 0.01% to 0.44% (Kazmin 2010). A mortality rate of 20% was also estimated in newborns with severe bleeding disorders, including intracranial haemorrhage (50%), and common persistent neurologic impairment (McNinch 1991; Von Kries 1992).
Several adverse pregnancy outcomes affect babies born to women with epilepsy (WWE). Evidence suggests that anticonvulsant drugs may impede folic acid and phytomenadione (vitamin K) metabolism causing higher risks of neural tube defects and early haemorrhage among newborns (Nulman 1999). It has been recommended that pregnant women who take phenobarbital, carbamazepine or phenytoin should commence maternal phytomenadione supplementation four weeks prior to the delivery due date (Nulman 1999). Although uncommon, the use of vitamin K antagonists during pregnancy can give rise to liver disease in neonates (Hetzel 2006). Hetzel 2006 suggests that vitamin K antagonists should be highly controlled during anti-coagulation in pregnant women with mechanical heart valves.
Description of the intervention
Pregnant women deficient in vitamin K may need to incorporate vitamin K supplements into their prenatal vitamin regimen. In certain disease conditions such as cystic fibrosis, coeliac disease, or Crohn's disease in which sufficient vitamin K absorption is impaired, vitamin K supplementations are essential, especially in the form of a multivitamin that contains vitamin K, which is regarded as more beneficial than vitamin K supplementation alone (UMMC 2011). Pregnant women taking anticonvulsant drugs are recommended to take vitamin K two weeks prior to delivery (UMMC 2011). Vitamin K status in pregnant women who take prothrombin-depressing anticoagulants, such as coumarin, should be carefully assessed (Institute of Medicine 1990). Women without these conditions who experience a normal pregnancy are generally not required to take vitamin K supplements unless, for example, they are diagnosed with malabsorption syndrome or are taking antibiotics such as cephalosporins, which inhibit vitamin K absorption by destroying vitamin K-forming bacteria as well as bacteria that is harmful to the body (UMMC 2011).
Vitamin K formulation and prophylactic administration differ by country (WHO/FAO 2004). For example, in the United States, vitamin K1 or phylloquinone is available as a supplement either separately or as a component of a multivitamin complex in 5 mg tablets (UMMC 2011). Vitamin K is widely sold over the counter as water-soluble chlorophyll tablets, capsules, or liquid (UMMC 2011). Vitamin K is administered parenterally or orally, and various reported doses have been administered to pregnant women: for example, 10 mg of intravenous or intramuscular vitamin K daily for two to seven days (Liu 2006); one 10 mg dose of vitamin K intramuscularly, repeated again after four days followed by 20 mg daily of oral vitamin K (Kazzi 1989); 10 mg of intramuscular vitamin K between four and 96 hours before delivery (Pathak 1990); and 10 mg of vitamin K1 daily is recommended for pregnant women on anticonvulsant therapy from 36 weeks of pregnancy onwards (Cornelissen 1993).
There is insufficient evidence to show that excessive vitamin K ingestion has toxic effects on the human body. As vitamin K passes through the placenta and is found in breast milk, pregnant and lactating women should seek advice from their health practitioner before commencing vitamin K supplements (UMMC 2011). However, oxidative damage, red cell fragility, and methaemoglobin may develop in cases of high doses of water-soluble vitamin K3 (menadione) consumption, and local hypersensitivity reactions, mostly due to vitamin K1 dermal injections, may also occur (Expert Group on Vitamins and Minerals 2003). A daily intake of 1 mg or less is unlikely to have any harmful effects according to guidelines from the United Kingdom (NHS 2011). Also, as toxicity for the oral consumption of vitamin K remains unknown, 10 to 20 mg or more of phylloquinone is recommended to be safe for common clinical administration in the United States (WHO/FAO 2004). Furthermore, patients with chronic fat malabsorption who take such doses have shown no evidence of side effects (WHO/FAO 2004). Synthetic menadione and its derivatives are not recommended, particularly for vitamin supplements in newborns (WHO/FAO 2004). Moreover, due to interactions with certain drugs and the potential for side effects, vitamin K supplements are restricted for pregnant and lactating women, as vitamin K passes through the placenta and is found in breast milk; warfarin consumers; and those with a rare metabolic disease called glucose-6-phosphate dehydrogenase (G6PD) deficiency (UMMC 2011).
How the intervention might work
Antenatal administration of vitamin K supplementation for pregnant women may provide significant benefits for improving both maternal and neonatal outcomes. Vitamin K supplementation may improve the deficiency of factor VII in megaloblastic anaemia of pregnancy with thrombocytopenia (Morris 1963). Adequate supplementation that includes vitamin K and other essential micronutrients has been recommended for pregnant women who have undergone bariatric surgery in order to remedy maternal and fetal complications such as severe anaemia, congenital abnormalities and low birthweight (Guelinckx 2009; Shankar 2010). Furthermore, maternal administration of vitamin K has been suggested to improve prothrombin and partial thromboplastin activities and reduce the incidence and severity of intraventricular haemorrhage (IVH) in infants (Morales 1988; Pomerance 1987) although a Cochrane review (Crowther 2010) shows no impact of vitamin K in preventing IVH. Antenatal vitamin K supplementation may help to reduce the risk of haemorrhagic complications in infants born to WWE who take antiepileptic drugs during pregnancy (Choulika 2004; Kaaja 2002), including a reduction in the occurrence of vitamin K deficiency in such infants (Cornelissen 1993).
Why it is important to do this review
The effects of vitamin K deficiency, especially haemorrhagic complications, other adverse outcomes and the need for vitamin K supplementation, have mostly been reported in relation to neonates. Vitamin K deficiency, remedial supplementation and associated morbidities in women of reproductive age, specifically during pregnancy, have not been well described. Evaluation of the efficacy and safety of different treatment regimens for vitamin K supplementation during pregnancy is therefore crucial to improve maternal and neonatal outcomes. A previous Cochrane review examined the effect of vitamin K supplementation, including women at risk of imminent very preterm birth in the prevention of neonatal periventricular haemorrhage (PVH) and associated adverse outcomes in preterm neonates (Crowther 2010). Therefore, in this protocol and subsequent review, we will include all pregnant women regardless of their pregnancy stage and we will aim to assess the effects of vitamin K supplementation on a set of neonatal and maternal outcomes that were not covered by earlier reviews, specifically by Crowther 2010.