Vitamin K

If you are not doing something controversial, you are not doing something important.
Michael Skinner
09-04-2018 14:52
  1. Vitamin K injection is one of the procedures almost every child undergoes immediately after birth in most developed countries. Vitamin K plays an important role in the blood clotting process, and it is believed that its deficiency can potentially lead to Vitamin K Deficiency Bleeding (VKDB)

  2. Vitamin K in neonates: facts and myths. 2011, Lippi, Blood Transfus

    Vitamin K was first discovered in the early 1930s by the Danish biochemist Henrik Dam who observed – while studying cholesterol metabolism in chickens – that chicks fed with a diet free of sterols and low in fat tended to develop subcutaneous and intramuscular haemorrhages. Further studies on different foods led to the discovery of an "anti-haemorraghic factor", which was designated vitamin K (with the "K" standing for "Koagulations-Vitamin") given that it was essential for normal haemostasis.
    Vitamin K1 is acquired through the diet and is prevalently present in leafy green vegetables such as spinach, Swiss chard, Brassica (e.g. cabbage, kale, cauliflower, turnip, and Brussels sprout), some fruits such as avocado, banana and kiwi, as well as in some vegetable oils, especially soybean oil. Many bacteria that colonize the human intestine synthesize vitamin K2 or menaquinone, There is, however, ongoing debate on whether bacterial synthesis of vitamin K in the intestine provides a significant supply of this vitamin in humans.
    According to the U.S. Institute of Medicine, the recommended dietary allowance of vitamin K is 120 μg in adult men and 90 μg in adult women, but it is much lower in other countries and Europe, where, for example, a daily average of ~1 μg per kg of body weight is recommended. The Third National Health and Nutrition Examination Survey set the thresholds of adequate vitamin K intake as 2 μg/day for infants in the first 6 months of life. Human breast milk contains between 1 and 4 μg/L of vitamin K1.
    According to the age of onset, there are three types of the desease that had been named "Vitamin K Deficiency Bleeding (VKDB)" in 1999.
    1) Early VKDB presents within 24 hours of birth and is almost exclusively seen in infants of mothers taking drugs which inhibit vitamin K. These drugs include anticonvulsants, antituberculosis drugs, some antibiotics and vitamin K antagonists (coumarin, warfarin). The clinical presentation is often severe with cephalic haematoma and intracranial and intra-abdominal haemorrhages. The incidence of early VKDB in neonates of mothers taking these drugs without vitamin K supplementation varies from 6% to 12%.
    2) Classical VKDB occurs between 24 hours and 7 days of life and is associated with delayed or insufficient feeding. The clinical presentation is often mild, with bruises, gastrointestinal blood loss or bleeding from the umbilicus and puncture sites. Blood loss can, however, be significant, and intracranial haemorrhage, although rare, has been described. Estimates of the frequency vary from 0.25% to 1.5% in older reviews and 0–0.44% in more recent reviews.
    3) Late VKDB is associated with exclusive breast-feeding. It occurs between the ages of 2 and 12 weeks. The clinical presentation is severe, with a mortality rate of 20% and intracranial haemorrhage occurring in 50%. Persistent neurological damage is frequent in survivors. In fully breast-fed infants who did not receive vitamin K at birth, the incidence is between 1/15,000 and 1/20,000. Babies with cholestasis or malabsorption syndromes are at particular risk.
    As in other circumstances in science and medicine, there is an apparent paradox in haemostasis in neonates in that prolonged global coagulation tests do not translate into a particular bleeding phenotype. In fact, it is now clear that the physiology of haemostasis in childhood differs considerably from that in adults. Studies in humans and animals clearly indicate that coagulation factors in neonates are qualitatively similar to those in adults. [1] [2]
    The haemostatic system is not fully mature until 3 to 6 months of age. It is, therefore, essential to acknowledge that the differences observed between adults and infants are probably physiological and do not always reflect an underlying pathological condition.
    Although both intramuscular and oral administration of vitamin K protect against classical VKDB, a single oral dose does not protect all infants against late VKDB.

  3. Vitamin K deficiency bleeding 2009, Shearer, Blood Rev

    There is little accurate national data on the incidence of classical VKDB, even in industrialized countries. In a two-year prospective survey in the British Isles during 1988–1990 the incidence rate was 5.4 per 100,000 births for classical VKDB and it was similar to that for late VKDB.
    The incidence of classical VKDB in Oslo during 1934–1939 was 0.8%. The later important and influential studies in the 1960s by a group in Cincinnati showed that the incidence of moderate or severe bleeding in an urban population was 1.7% among breast-fed infants who had not received VK. This data from Cincinnati would not have been representative of the national incidence of VKDB in the USA since the hospital served a mainly black disadvantaged population.
    Economic deprivation predisposes to classical VKDB, and it might be expected that there would be a greater incidence in underdeveloped countries.
    Late VKDB that presents as intracranial bleeding is often preceded by warning bleeds or bruising that should always be investigated by appropriate laboratory tests.

  4. Efficacy

  5. Vitamin K prophylaxis for the prevention of vitamin K deficiency bleeding: a systematic review. 2016, Sankar, J Perinatol

    A systematic review that evaluates the effect of vitamin K prophylaxis on the incidence of VKDB.
    The median burden in low- and middle-income countries is 80 (72 to 80) and 8.8 in high-income countries (5.8 to 17.8) per 100,000 live births.
    The strategy of routine prophylaxis is not free of any pitfalls. The usual prophylactic dose (1 mg) is ~1000 times more than the daily requirement. Experimental studies have shown increased sister chromatid exchange in lymphocyte suspensions and mutagenic activity at such high concentrations. Also, intramuscular administration can cause local trauma, injury to vessels and nerves, abscesses and muscle hematoma. Not surprisingly, some countries are reluctant about universal prophylaxis and instead practice selective prophylaxis to at-risk neonates only.
    For classical VKDB, the reduction in the incidence of any bleeding following vitamin K prophylaxis was 27%, and of moderate to severe bleeding – 81%. In another study the reduction in the incidence of secondary bleeding after circumcision in neonates who received vitamin K prophylaxis was 82%.
    The authors did not find any randomized or quasi-randomized trials that evaluated the effect of vitamin K prophylaxis on the incidence of late VKDB. Observational studies suggest that the incidence rate of late VKDB following vitamin K prophylaxis was reduced by 98%.
    The Cochrane review found no evidence of a difference between the oral and intramuscular route in effects on biochemical indices of coagulation status. As compared with IM prophylaxis, multiple oral doses are cheaper and do not have the theoretical risk of mutagenicity.
    In the past, synthetic vitamin K3 (that was associated with increased risk of hemolysis and kernicterus) was used for routine prophylaxis. With the introduction of the natural vitamin K1 (phylloquionone) most countries started using it. Vitamin K3 Is still in use for VKDB prophylaxis in some countries, i.e. Russia and Ukraine.

  6. In the developed countries, vitamin K1 has been used for VKDB prophylaxis since the 1960s. For further reading "Vitamin K" will refer to K1.
    Currently vitamin K in form of injection is available by the following vendors:
    AquaMEPHYTON (Merck)
    Konakion MM (Roche)

  7. Oral administration

  8. A new mixed micellar preparation for oral vitamin K, prophylaxis: randomized controlled comparison with an intramuscular procedure in breast fed infants. 1998, Greer, Arch Dis Child

    Through the first 8 weeks of life, three doses of the new oral preparation (Konakion MM) maintain haemostasis and vitamin K status in breast fed infants at least equal to that of the intramuscular preparation.

  9. Quite a few more studies have been conducted comparing efficacy of intramuscular and oral administration of vitamin K. Majority of these studies concluded that efficacy of the oral administration is non-inferior to the intramuscular one: [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15].
    There have been other studies though that claim the oral administration is less effective than intramuscular for late VKDB prophylaxis: [1]

  10. Prevention of vitamin K deficiency bleeding: the efficacy of the different multiple oral dose schedules of vitamin K. 1997, Cornelissen, Eur J Pediatr

    This study compared various VKDB prophylaxis protocols in 4 countries. The authors conclude that 3 oral doses are less effective than an intramuscular injection. However a previous formulation of the Konakion was used (it contained phenol and propylene-glycol among other ingredients).
    In the Netherlands a daily dose of 25 mcg had been used. It was at least as effective as an injection. However in the following studies it was found that there were few cases of VKDB in infants with predisposing liver deceases who received vitamin K orally.
    In Denmark a weekly oral dose of 1 mg for 3 months duration allowed to reduce the incidence rate of late VKDB to zero.
    With oral administration, 29% of the vitamin is being absorbed in the intestines.
    Coagulation status is significantly higher in summer-born infants in comparison to those who were born in spring.

  11. Influence of maternal vitamin level

  12. Vitamin K prophylaxis to prevent neonatal vitamin K deficient intracranial haemorrhage in Shizuoka prefecture. 1996, Nishiguchi, Br J Obstet Gynaecol

    In Japan, the incidence rate of intracranial hemorrhage was 1 in 4,000 babies before using vitamin K. In Germany and the United Kingdom, where vitamin K has been used, the likelihood of hemorrhage was 1 in 30,000. The blood coagulability status in infants was significantly higher when vitamin K2 was given to nursing mothers (15 mg/day from the 14th day after giving birth for two weeks).

  13. Are breast-fed infants vitamin K deficient? 2001, Greer, Adv Exp Med Biol

    Breast milk contains very little vitamin K (~1 µg/l). But if the mother consumes more than 1 mcg/kg/day during pregnancy and lactation, the level of vitamin K increases significantly in milk (up to 80 mcg/l) and in the infant's blood plasma. More: [1]

  14. Vitamin K in preterm breastmilk with maternal supplementation. 1998, Bolisetty, Acta Paediatr

    Six nursing mothers received 2.5 mg/day of vitamin K1 orally for 2 weeks. After the first dose, the average concentration of vitamin K in their breastmilk increased from 3 µg/l to 23 µg/ml, and it stabilized at 64 µg/l after 6 days.

  15. Vitamin K1 content of maternal milk: the influence of the stage of lactation, lipid composition, and vitamin K1 supplements given to the mother. 1987, von Kries, Pediatr Res

    Comparison of fore and hind milk from the mothers revealed higher vitamin K1 concentrations in hindmilk, suggesting that the lipid content influences the vitamin K1 concentration in maternal milk. Samples of maternal milk from nine mothers collected from day 1 to day 36 of lactation showed significantly higher vitamin K1 concentrations in colostral milk than in mature milk.
    Vitamin K supplementation in the mother’s diet (0.5–3 mg) significantly increased the vitamin K concentration in milk.

  16. Newborn jaundice

  17. Effect of Vitamin-K Dosage on Plasma-Bilirubin Levels in Premature Infants. 1956, Bound, Lancet

    In the 1950s, newborns were given large doses of vitamin K2 (up to 90 mg). In this study, it turned out that of premature infants who received 30 mg of vitamin K for three days, 38% had high levels of bilirubin (more than 18 mg/100 ml) on the fifth day, and among those who received 1 mg, only 4% had a high bilirubin level (high bilirubin level is newborn jaundice). In addition: [1] [2] [3] [4]

  18. Overnutrition in Prenatal and Neonatal Life: A Problem? 1965, Cochrane, Can Med Assoc J

    Recent studies have confirmed the toxic effect of excessive amounts of synthetic vitamin K that is administered to newborns and premature infants. It also turned out that the administration of large amounts of vitamin K to the mother shortly before birth leads to an increase in the bilirubin level in the newborn. This substance, which was previously considered harmless, is dangerous if it is given in large quantities to mothers before giving birth, that's why these days much smaller doses are administered. Vitamin K of natural origin does not have such an effect.

  19. Merck and other manufacturers report that possible newborn jaundice is associated with the dose of the vitamin. [1] [2] [3]

  20. The dosage

  21. Vitamin K status of premature infants: implications for current recommendations. 2001, Kumar, Pediatrics

    Premature infants have very high levels of vitamin K two weeks after injection. The authors suggest to reduce the dose for premature newborns.

  22. Vitamin K prophylaxis for premature infants: 1 mg versus 0.5 mg. 2003, Costakos, Am J Perinatol

    In premature infants, vitamin K levels on the second day after injection (0.5–1 mg) were 1900–2600 times higher than normal levels in adults, and on the tenth day, they were 550–600 times higher. The vitamin level in the group that received 0.5 mg did not differ from the group that received 1 mg.

  23. Plasma concentrations after oral or intramuscular vitamin K1 in neonates. 1985, McNinch, Arch Dis Child

    The vitamin K plasma concentration in newborns 12 hours after injection was 9000 times higher than the usual concentration in an adult. It was 2200 times higher 24 hours after injection.
    The plasma concentration of vitamin K 4 hours after oral administration is 300 times higher, and after 24 hours it is 100 times higher than the usual concentration in an adult.
    Cow's milk contains significantly more vitamin K. When 40 years ago, newborns were given 90 ml of cow's milk for the first 48 hours, the incidence rate of VDBK had reduced from 0.8% to almost zero.
    It is reported here that the blood coagulation status in infants depended on the dose of breast milk in the first days of life. For those who received more than 100 ml of milk per day on the 3rd and 4th day, it was significantly higher than those who received less than 100 ml/day in the first 4 days. In addition: [1]
    It is reported here that in infants who were started to feed immediately after birth, the blood coagulation status was significantly higher than in infants who were started to feed 24 hours after birth.

  24. Cancer

  25. Childhood cancer, intramuscular vitamin K, and pethidine given during labor. 1992, Golding, BMJ

    Among those children who received an intramuscular injection of vitamin K, the risk of cancer was 2 times higher. A similar result was obtained in another study by the same authors.
    This essentially means that prevention of 30-60 cases of hemorrhagic disease will lead to 980 additional cases of cancer.
    The fact that human evolution allowed the development of vitamin K deficiency in normal breastfed babies, which leads to a small risk of hemorrhagic disease, have always been perceived as physiologically flawed. The most likely explanation for this phenomenon is that there is some evolutionary advantage that outweighs this risk.
    It is possible that relative vitamin K deficiency in the critical phase of rapid growth may protect vulnerable tissues from mutagenesis.

  26. Case-control studies of relation between childhood cancer and neonatal vitamin K administration. 1998, Passmore, BMJ

    The probability of bleeding among infants not belonging to any risk group is 1 in 10,000. Among those who received the injection, the probability of bleeding is 1 in a million.
    In this study, cancer (mainly leukemia) was associated with an intramuscular injection of vitamin K (OR = 1.44, CI: 1.00–2.08). Children who were diagnosed before the age of 12 months were excluded from the study.
    Several more studies had been conducted that did not find a correlation between injection and increased risk of cancer. In this study, there was no correlation between injection and cancer in general, although a correlation with acute lymphoblastic leukemia before the age of 6 was found (OR=1.79).
    At the moment, it is believed that there is no connection between vitamin K injections and increased cancer incidence rate. However, randomized trials have not been conducted, and a small increase in risk cannot be ruled out.
    The authors believe that injections should only be administered to infants at risk.

  27. Vitamin K and childhood cancer: analysis of individual patient data from six case-control studies. 2002, Roman, Br J Cancer

    The authors analyzed 6 studies on association between vitamin K injections and cancer, and concluded that if the data to be analyzed in a certain way, no association between the risk of leukemia and the injection can be found, but use of revised analysis methods demonstrates a moderate association (OR = 1.21, CI: 1.02-1.44). When just a single study was excluded from the analysis, the statistical significance disappeared (OR = 1.16, CI: 0.97-1.39).
    The authors conclude that although it is impossible to fully negate moderate association, there is no convincing evidence that vitamin K injection is associated with leukemia.

  28. Why we need a clinical trial for vitamin K. 1994, Slattery, BMJ

    The risk of hemorrhagic disease is increased by surgical procedures, asphyxiation during labor, prolonged labor, high levels of protein in the urine of the mother, and breastfeeding.
    Vitamin K is given to newborns, but we still do not know if it has substantial hazards. Although vitamin K has been used for 30 years, the first study of its long-term effects was published only in 1992.
    Because the population exposed to vitamin K is very large even quite small hazards would involve many adverse events. It is therefore important to be able to put reasonably close bounds on the potential damage that vitamin K prophylaxis could cause. Past research has not allowed us to do this but a large randomized controlled clinical trial of vitamin K against no vitamin K, enrolling only infants at low risk of hemorrhagic disease, would do so.

  29. Other ingredients

  30. CDC reports that all newborns suffer from vitamin K deficiency, and that the injection is completely safe. Benzyl alcohol is used as a preservative, which is also completely safe and is used in many medications. True, they write, it was found in the 80s that premature infants can get sick from the benzyl alcohol toxicity, since many drugs contain it as a preservative. But despite the fact that toxicity was found only in premature newborns, the doctors have been trying to minimize the amount of benzyl alcohol in the medications they prescribe to all children. It is clear, they write (though they do not report why) that the amount of benzyl alcohol in the injection is so low that it is safe.

  31. The half-lethal dose of benzyl alcohol for mice is 0.48 g/kg (common ethyl alcohol is 4 times less toxic than benzyl alcohol).
    In total, the injection vial (from Hospira) contains 9mg of benzyl alcohol per 2mg of vitamin K. That is approximately 0.7% of the half-lethal dose for a newborn (3mg/kg).
    Wikipedia reports that:
    1) benzyl alcohol is very toxic to the eyes. Pure benzyl alcohol causes necrosis of the cornea.
    2) benzyl alcohol is toxic for newborns, it causes gasping syndrome. Gasping syndrome is a disease that no longer exists. It was caused by cleaning newborns' skin with benzyl alcohol until the 1980s. Some newborns began to choke and died. The benzyl alcohol dosage sufficient to cause this disease onset is 99 mg/kg.
    The fact that benzyl alcohol is toxic had been known at least since the early 1970s. This did not prevent its unrestricted usage on premature newborns until the early 80s, when it was proved that it is toxic not only for dogs, but also for infants. But even this did not stop its usage in injections which are given on the first day after birth.

  32. Amphastar manufactures vitamin K without benzyl alcohol. Instead, propylene glycol is used as a preservative. Propylene glycol is also used as antifreeze and braking fluid, it can cause renal failure, and is a known neurotoxin.

  33. Amphastar also adds polysorbate 80 to vitamin K. The polysorbate 80 amount in this product is 10mg, which is 200 times more than in Gardasil. (Kanavit, vitamin K used in some Eastern European countries, also contains polysorbate 80.
    Konakion MM does not contain benzyl alcohol, propylene glycol or polysorbate 80.

  34. Hospira reports that intravenous vitamin administration can be lethal. Serious effects and deaths were also observed due to intramuscular injection.

  35. Safety (other)

  36. Anaphylactic shock due to vitamin K in a newborn and review of literature. 2014, Koklu, J Matern Fetal Neonatal Med

    Infants are born with an immature innate immune system. Since their immune systems are weaker than in adults, they are less likely to develop an anaphylactic reaction. A possible mechanism for the formation of anaphylaxis in newborns has not yet been elucidated.
    This paper describes the first case of anaphylactic shock due to vitamin K injection.
    Additional sources: [1]

  37. Nicolau's syndrome is a gangrenous dermatitis, which is caused by various medications. Injection of vitamin K can also occasionally cause it.
    Texier's disease is a pseudo-sclerodermal reaction that occasionally occurs after an injection of vitamin K and lasts for several years.

  38. Sometimes instead of vitamin K, methylergometrine is mistakenly injected into a newborn. Methylergometrine is a psychedelic alkaloid that is used to prevent bleeding after childbirth. It is confused with vitamin K, because their vials are similar. All the babies who received it orally have survived. Among newborns who were injected with it, the mortality rate was 7.5%. [1] [2] [3] [4] [5] [6] [7]

  39. Pain

  40. Until 1999, it was believed that children begin to experience pain upon reaching 12 months of age.

  41. Are There Long-Term Consequences of Pain in Newborn or Very Young Infants? 2004, Page, J Perinat Educ

    For years, health-care practitioners in the United States have cared for infants without viewing pain as one of the significant risks or disadvantages in making treatment decisions. Superficial observations conceded that pain medications had some risks along with their advantages, and that infants seemed to forget pain anyway. If the patient never returns to complain about the pain later, how could it be very important?
    However, studies conducted in the 90s revealed that pain experienced in infancy has long-term consequences. For example, babies who were circumcised without lidocaine ointment suffered from pain during the vaccination more than circumcised with lidocaine, which in turn suffered more than uncircumcised.
    Compared to undisturbed pups, rat pups who had been separated from their mother exhibited suppression of immune system and significantly greater susceptibility to the metastasis of injected tumor cells.
    Endotoxin injection on as few as two occasions in the first week of life has been shown to exacerbate responses to stress much later in the mature animal. Neonatal endotoxin injection in rats has also been shown to result in delayed wound healing in the mature animal, which reflects the animals' inability to mount an inflammatory response.
    Neonatal rats that underwent needle prick (painful) on a paw exhibited increased pain sensitivity in preadolescence, greater anxiety, a significant alcohol preference and social hypervigilance manifesting as prolonged chemosensory memory of a novel juvenile rat.
    In prematurely born babies (which are subject to many more painful medical procedures than those born at term), pain sensitivity was reduced.
    Multiple birth trauma increased the relative risk for adult violent suicide 5-fold in men versus 4% in women. However, the provision of opioids to the mother at the time of delivery lowered the suicide risk by 31% in both sexes.
    The authors conclude that although an individual may not preserve a conscious memory of an early painful event, it is recorded elsewhere in the body, as evidenced by the previously presented long-term outcomes. Multiple procedures in the preterm and low- to extremely low-birth-weight infant, as well as “routine” newborn medical procedures (from heel sticks to circumcision), may alter infant development. The implication is that infant pain should be avoided when possible and, when necessary, assessed and treated at least as diligently as adult pain. Parents, as well as caregivers, need to recognize that pain must be added to the list of risks when deciding whether to provide a treatment or consent to a procedure in an infant. This consideration has not been a part of the traditional decision-making model for most practitioners.

  42. Miscellaneous

  43. Delayed cord clamping in very preterm infants, the incidence of intraventricular hemorrhage and late-onset sepsis: a randomized, controlled trial. 2006, Mercer, Pediatrics

    Delayed cord clamping (even for 30-40 seconds) seems to protect "very low birth weight" infants from intraventricular hemorrhage (IVH) and late-onset sepsis.

  44. Breastmilk, PCBs, dioxins and vitamin K deficiency: discussion paper. 1989, Koppe, J R Soc Med

    Late form of hemorrhagic disease of the newborn is a new disease, which was described in 1985, and is observed only in exclusively breastfed infants. Breast milk in industrialized countries is contaminated with polychlorobiphenyls (PCBs), polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs).
    Xenobiotics were found in the milk of Dutch mothers, but they were absent in the milk of a woman who recently immigrated from Suriname. A woman who immigrated from Suriname 15 years ago also did have xenobiotics in her milk.
    PCBs, PCDDs and PCDFs are known to cause liver enlargement, increased blood clotting time, liver cirrhosis, etc. Clinical symptoms of infants whose mothers were poisoned with these substances included stunted growth, smaller head circumference, hirsutism, etc. Children who have been fed with PCBs-contaminated milk have suffered from (among other things) fatigue, anorexia, abdominal pain, vomiting and eczema. In animals, monkeys had fatty liver, pancreatic atrophy, and gastrointestinal hemorrhage after a high dose. Millions of chickens who die due to contaminated food have subepicardial bleeding. Mice exhibit cleft palate, bleeding and subcutaneous edema.
    The authors measured the level of dioxins in milk of 14 mothers. Mothers of 4 infants who suffered bleeding had a significantly higher dioxin level than ten other mothers. The authors believe that there is probably a causal relationship between PCBs, dioxins and furans in breast milk and late hemorrhagic disease. These xenobiotics are also possibly associated with prolonged jaundice in newborns.
    Additional sources: [1] [2]

  45. Reasons for refusal of newborn vitamin K prophylaxis: implications for management and education. 2016, Hamrick, Hosp Pediatr

    Among the parents who refused vitamin K injection, most were white (78%), over 30 years old (57%), and college graduates (65%). Most refused hepatitis B vaccine (90%) and erythromycin eye ointment (77%). The most common source of information was the Internet. Concerns included synthetic or toxic ingredients, excessive dose, and side effects. Eighty-three percent of parents reported awareness of risks associated with vitamin K refusal, but most did not understand the potential danger of bleeding, especially the likelihood of intracranial hemorrhage and death.
    In the hospital where oral administration of vitamin K was available, the percentage of refusals from the injection was much higher.
    The authors conclude that the information on the Internet on which the parents' decisions are based is often unconfirmed by peer-reviewed scientific sources, and encourages natural childbirth without medical intervention. The most important issue, per the authors, is that the specific problems that are highlighted on Internet sites are not addressed by doctors in their conversations with mothers.

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