Can vitamin K stop bleeding in early pregnancy

Cochrane Database Syst Rev. 2017 Jun; 2017(6): CD010920.

Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

To assess the effects of vitamin K supplementation administered to pregnant women for improving maternal and neonatal outcomes.

Background

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.

Objectives

To assess the effects of vitamin K supplementation administered to pregnant women for improving maternal and neonatal outcomes.

Methods

Criteria for considering studies for this review

Types of studies

All randomised (individual and cluster) or quasi‐randomised controlled trials assessing the effect of vitamin K supplementation during pregnancy. We will also consider trials presented only as abstracts. We will exclude cross‐over trials.

Types of participants

All pregnant women in any stage of their pregnancy and their infants. We will include trials in which pregnant women are a subset of the participants included in the study, if reported in a way that relevant data can be extracted. This review will exclude studies in which vitamin K was given to women at risk of imminent preterm birth for preventing neonatal PVH, as this is covered in an existing review by Crowther 2010.

Types of interventions

We will assess the effects of vitamin K administered orally, intramuscularly or intravenously to pregnant women during any stage of their pregnancy. This review will exclude studies in which vitamin K was administered to women at risk of imminent preterm birth for the prevention of neonatal PVH, as this has already been evaluated in an existing review by Crowther 2010. The intervention group will be pregnant women who have received prenatal vitamin K supplementation alone or in combination with micronutrients, regardless of the dosages, frequency, duration and timing of delivery. The three comparison groups will consist of pregnant women receiving any dosage of vitamin K supplements versus no vitamin K supplements; micronutrients including vitamin K versus micronutrients without vitamin K; and vitamin K versus a placebo or no treatment.

Types of outcome measures

Primary outcomes

1. Perinatal death.

2. Neonatal bleeding.

3. Maternal bleeding incidence, e.g. during pregnancy, intrapartum haemorrhage and postpartum haemorrhage.

Secondary outcomes

Newborns

1. Stillbirth.

2. Neonatal death.

3. Infant death.

4. Subcategories of neonatal bleeding: a) very early onset (nought to 24 hours after birth), b) classic haemolytic disease of the newborn (24 hours to seven days of life), and c) late haemolytic disease or acquired protein C deficiency (APCD) of the newborn (two to 12 weeks of life).

5. Preterm birth (less than 37 weeks of gestation).

6. Low birthweight.

7. Long‐term neurodevelopment.

8. Congenital malformation.

9. Severe liver disease: a) induced intrahepatic biliary obstruction, b) cholestatic disease.

10. Malabsorption of vitamin K, e.g. gut resection.

11. Biliary atresia (congenital absence or closure of the major bile ducts, the ducts that drain bile from the liver).

12. Other morbid conditions, e.g. low Apgar score at five minutes, vitamin K deficiency.

We will summarise any adverse outcomes reported in the included studies.

Mothers

1. Vitamin K deficiency in pregnant women.

2. Anaemia, e.g. megaloblastic anaemia.

3. Hypoprothrombinemia.

4. Thrombocytopenia.

5. Other morbid conditions, e.g. spontaneous abortion.

We will summarise any adverse outcomes reported in the included studies.

Economic data for the use of healthcare resources

Newborns

Special care/intensive care admission; length of hospitalisations; length of other treatment care after hospital discharge; and length of mechanical ventilation.

Mothers

Antenatal hospital admission; utilisation of intensive care units; use of daycare units; and ventilation and dialysis.

Search methods for identification of studies

Electronic searches

We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group’s Trials Register. 

The Cochrane Pregnancy and Childbirth Group’s Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:

1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

2. weekly searches of MEDLINE;

3. weekly searches of Embase;

4. handsearches of 30 journals and the proceedings of major conferences;

5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

We will apply no date restrictions on the searches. Trials identified through the searching activities described above are each assigned to a review topic (or topics). The Trials Search Co‐ordinator searches the register for each review using the topic list rather than keywords. 

Searching other resources

We will also search reference lists of retrieved trials, included trials and relevant review papers.

We will not apply any language restrictions.

We will contact researchers in the area, if needed.

Data collection and analysis

Selection of studies

Two review authors (S Shahrook (SS), N Hanada (NH), K Sawada (KS), E Ota (EO) and R Mori (RM)) will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult a third person.

Data extraction and management

We will design a form to extract data. For eligible studies, at least two review authors (SS, NH, KS, EO and RM) will extract data using the agreed form. We will resolve discrepancies through discussion or, if required, we will consult a third person. We will enter data into Review Manager software (RevMan 2012) and check for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details.

Assessment of risk of bias in included studies

Two review authors (SS, NH, KS, EO and RM) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion or by involving a third assessor.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

• low risk of bias (any truly random process, e.g. random number table; computer random number generator);

• high risk of bias (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number);

• unclear risk of bias.   

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

• low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

• high risk of bias (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth);

• unclear risk of bias.   

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

• low, high or unclear risk of bias for participants;

• low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

• low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re‐include missing data in the analyses which we undertake.

We will assess methods as:

• low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

• high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

• unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

• low risk of bias (where it is clear that all of the study’s pre‐specified outcomes and all expected outcomes of interest to the review have been reported);

• high risk of bias (where not all of the study’s pre‐specified outcomes have been reported; one or more reported primary outcomes were not pre‐specified; outcomes of interest are reported incompletely and so cannot be used; the study fails to include results of a key outcome that would have been expected to have been reported);

• unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias. We will assess whether each study was free of other problems that could put it at risk of bias:

• low risk of other bias;

• high risk of other bias;

• unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias by undertaking sensitivity analyses ‐ seeSensitivity analysis. 

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals. 

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.  

Unit of analysis issues

Cluster‐randomised trials

We will include cluster‐randomised trials in the analyses along with individually‐randomised trials. To take account of design effect, we will adjust their sample sizes using the methods described in the Cochrane Handbook using an estimate of the intracluster correlation co‐efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster‐randomised trials and individually‐randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs, and if the interaction between the effect of the intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform a sensitivity analysis to investigate the effects of the randomisation unit.

Trials with more than two treatment groups

If trials with more than two intervention groups (multi‐arm studies) are identified, only directly relevant arms will be included. If studies with various relevant arms are identified, groups will be combined to generate a single pair‐wise comparison (Higgins 2011), and the disaggregated data in the corresponding subgroup category will be included. If the control group is shared by two or more study arms, the control group over the number of relevant subgroup categories will be divided to avoid double counting the participants (for dichotomous data, we will divide the events and the total population, and for continuous data, we will assume the same mean and standard deviation but will divide the total population). The details will be described in the ‘Characteristics of included studies’ tables.

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention‐to‐treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta‐analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either a T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. 

Assessment of reporting biases

If there are 10 or more studies in the meta‐analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2012). We will use fixed‐effect meta‐analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random‐effects meta‐analysis to produce an overall summary if an average treatment effect across trials is considered clinically meaningful. The random‐effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials. If the average treatment effect is not clinically meaningful, we will not combine trials.

If we use random‐effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of  T² and I².

We will assess the evidence quality (as very low, low, moderate and high) using the GRADE approach (Guyatt 2008) by investigating the design and implementation of the trials, indirectness of evidence, and several other domains.

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses and sensitivity analyses. We will consider whether an overall summary is meaningful, and if it is, use random‐effects analysis to produce it.

We plan to carry out the following subgroup analyses, where possible.

1. Gestational age: less than 20 weeks versus ≥ 20 weeks.

2. Vitamin K supplementation dosage: above or equal to versus below the US recommended daily dietary intake of 90 µ/d.

3. Route of vitamin K administration: oral versus intramuscular or intravenous.

4. Women with epilepsy versus women without epilepsy.

Subgroup analysis will be restricted to the review's primary outcomes:

• Perinatal death.

• Neonatal bleeding.

• Maternal bleeding incidence, e.g. during pregnancy, intrapartum haemorrhage and postpartum haemorrhage.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2012). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

Sensitivity analyses including only randomised control trials will be performed to assess the risk of bias effects (trials with low or unclear sequence generation and allocation concealment, and either high levels of attrition or inadequate blinding) from the meta‐analysis. If any cluster‐randomised trials are identified and included, sensitivity analysis using a range of ICC values will be carried out. We will carry out sensitivity analysis for primary outcomes only.

Acknowledgements

We are thankful for the support provided by the Cochrane Pregnancy and Childbirth Group during the protocol development process.

As part of the pre‐publication editorial process, this protocol has been commented on by four peers (an editor and three referees who are external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

Thanks also to Ms Emma Barber for her editorial support.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Notes

Withdrawn from publication for reasons stated in the review

What's new

Contributions of authors

S Shahrook drafted the protocol with advice from R Mori. E Ota, K Sawada and N Hanada assisted in drafting the protocol.

Sources of support

Internal sources

• National Center for Child Health and Development, Japan.

External sources

• Ministry of Health, Labour and Welfare, Japan.

  Health Labour Sciences Research Grant (No.13800128)

Declarations of interest

None known.

Notes

This review title has been relinquished and the protocol has now been withdrawn from publication in the Cochrane Library.

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