Early Vitamin K Deficiency Bleeding in a Neonate Associated with Maternal

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PERINATAL/NEONATAL CASE PRESENTATION Early vitamin K deﬁciency bleeding in a neonate associated with maternal Crohn’s disease

A Ohishi, S Nakashima, T Ogata and S Iijima

We report herein a case of early vitamin K deﬁciency bleeding (VKDB) in a neonate associated with maternal Crohn’s disease. A female neonate was born at 37 weeks’ gestation and weighed 2778 g. She developed broad purpura on her back on day 1. Laboratory data showed anemia, prolonged coagulation time and elevated protein induced by vitamin K absence or antagonist-II. Early VKDB has not been reported in a neonate born from mother with active Crohn’s disease. It is essential to give vitamin K selectively as soon as possible after birth to prevent early VKDB in neonates.

Journal of Perinatology (2014) 34, 636–639; doi:10.1038/jp.2014.64

INTRODUCTION hospital; third: one month of age) (Table 1).8 There were no It is well known that neonatal vitamin K deficiency bleeding particular descriptions on the record of nurse until next morning, (VKDB) can be prevented through the administration of vitamin K. but the neonate could not take oral vitamin K syrup because of Early VKDB is known in association with maternal medications feeling of sickness. such as antiepileptic drugs,1,2 but is not well known in relation to Broad purpura and some petechiae on the neonate’s back were maternal Crohn’s disease. Early VKDB has not been reported in a discovered at the first clinical examination by a pediatrician at neonate born from mother with active Crohn’s disease. On the about 24 h after birth (Figure 1a). The neonate cried vigorously, other hand, in adults, vitamin K deficiency due to Crohn’s disease but her skin was slightly pale. Her blood pressure was 69/36 (mean has been reported in association with osteoporosis,3–5 but is not 46) mm Hg, and her heart rate was 170 beats per minute. Her well known in association with bleeding in neonates. blood examination done before blood transfusion and vitamin K Here, we report a case of early neonatal VKDB that was infusion showed severe anemia and disorder of clotting function associated with maternal Crohn’s disease. In high-risk neonates (Table 2a). Biochemical examination revealed no abnormalities such as infant with prematurity or delivered from complicated (Table 2b). The neonate received an infusion of vitamin K (2 mg) and mother, selective administration of vitamin K parenterally as soon − as possible after birth is very important for preventing early VKDB. transfusion of frozen fresh plasma (15 ml kg 1) and packed red blood cells (15 ml kg − 1) two times after which her clotting function and anemia improved. Laboratory results made improve- CASE ments at 24 h after initiation of treatment in the neonatal A female neonate was born at 37 weeks’ gestation by scheduled intensive care unit (Table 2a). Toward evening, the purpura on cesarean section because of breech presentation. Her mother was her back had enlarged and swollen (Figure 1b). She started enteral feedings on day 3, received phototherapy from days 3 to 10 with 34 years old, gravida 1, para 1. The mother began suffering from − Crohn’s disease at age 17 years, and had undergone massive total bilirubin 17.3 and 21.0 mg dl 1, respectively, and was enterectomy (broad range ileum, ascending colon and sigmoid discharged on day 18. Head and abdominal computed tomo- colon) because of ileo-sigmoid colon fistula and stenosis at age 27 graphy performed on day 11 and head magnetic resonance years. The mother had received mesalazine for Crohn’s disease imaging performed on day 15 revealed no intracranial hemor- and took a low-residue diet, although mild diarrhea had continued rhage, ischemic changes in the brain or abdominal hemorrhage. since enterectomy. IOIBD (International Organization For the Also, absence of clinical presentations such as irritability, convul- Study of Inflammatory Bowel Disease) assessment score6 was 4 sion, bloody stool and abdominal distension, denied the at age 17 years, 0 at the mother’s first pregnancy and 1 at present possibility of intracranial, interperitoneal and gastrointestinal pregnancy. The mother’s first delivery at age 31 was normal. In hemorrhages. present pregnancy, she had received ritodrine because of Close investigation of the blood clotting function and threatened premature delivery since 29 weeks’ gestation. The fibrinolytic function were conducted (Table 2b). Elevated PIVKA present neonate’s birth weight was 2778 g, with Apgar scores of (protein induced by vitamin K absence or antagonist)-II1,9,10 over − 8 and 9 at 1 and 5 min, respectively. The neonate was brought 8000 mAU ml 1, decreasing PIVKA-II with vitamin K administra- to the newborn nursery. tion, and low vitamin K-dependent clotting and fibrinolytic factors A common practice of neonatal vitamin K prophylaxis in Japan indicated a status of vitamin K deficiency. The neonate was given is to give oral vitamin K three times (first: after birth by vitamin K intravenously on day 4 and orally once per week up to establishing oral feeding; second: on discharge from maternity 2 months of age from then on and she did not need to

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. Correspondence: Dr A Ohishi, Department of Pediatrics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan. E-mail: [email protected] Received 19 July 2013; revised 6 March 2014; accepted 6 March 2014 Crohn’s disease and neonatal vitamin K deﬁciency A Ohishi et al 637

Table 1. Recommendations for prophylactic administration of vitamin K for newborn (2011 modiﬁed version)7,8 by the Japan Pediatric Society

I. Recommendation for all full-term neonates without any complications. 1. After birth: give 1 ml of vitamin K2 syrup (2 mg of vitamin K2) once orally, after checking that the infant has established oral feedings several times. 2. One week of age (on discharge from the maternity hospital): give 1 ml of vitamin K2 syrup once orally. 3. One month of age (at the time of routine health checkup): give 1 ml of vitamin K2 syrup once orally. Administrations after 1 month can be omitted if the infant is fed with milk. As an alternative method, vitamin K2 syrup can be given once orally per week until 3 months of age. Mothers should be encouraged to consume a vitamin K-rich diet that includes green and yellow vegetables or natto (fermented soybeans). Infants born at a maternity center and at home with an obstetric nurse should also be given vitamin K.

II. Recommendation for premature infants and infants with complications. 1. Orally administered infants: give vitamin K same as full-term newborn. 2. Infants unable to receive oral administration: give vitamin K2 0.5–1.0 mg through the venous circulation. 3. Mothers receiving drugs with vitamin K inhibitory effects or mothers complicated by malabsorption diseases such as celiac Figure 1. (a) Broad purpura on neonate’s back discovered at – sprue: give vitamin K2 0.5 1.0 mg through the venous approximately 24 h after birth. (b) The purpura on her back had circulation. (Parenteral administration of vitamin K for over enlarged and swollen toward evening. 1 week before delivery also can be considered.) Parenterally fed expectant mothers should be administered vitamin K as needed. maternal medication, such as anticoagulants or anticonvulsants, 1,2 III. Therapeutic administration. which results in vitamin K deficiency in the neonate. 1. With suspicion of vitamin K deficiency bleeding: give vitamin In Japan, since 1988, physicians have followed the recommen- – K2 0.5 1.0 mg through the venous circulation as soon as possible dation that oral vitamin K2 should be given three times after blood sampling. (Intramuscular injection should be avoided.) (Table 1).7,8,12 Consequently, the frequency of late VKDB in Japan 2. Severe cases and extremely low birth weight infants: concurrent has significantly decreased from 18 (1978 to 1980) to 1.9 (1999 to use of fresh frozen plasma and factor IX preparation should be 2004) per 100 000 births.12 Oral vitamin K prophylaxis similar to considered. that in Japan is administered in the France, Germany, Denmark and many other European countries, while using vitamin K1 in countries except Japan.1,12 be supplemented with vitamin K thereafter. There were no risk However, oral administration with this guideline has a limitation factors for vitamin K deficiency other than Crohn’s disease, such as in the prevention of early VKDB because this condition often maternal medication (warfarin or antiepileptic drugs), poor oral occurs before the first oral vitamin K administration. In fact, the feeding, total parenteral nutrition or extreme fattiness. We neonate in the present case developed purpura and petechiae investigated the mother’s clotting function with serum obtained before she was given the first vitamin K dose. We conducted a before the cesarean section at 33 weeks’ gestation (Table 3). These small survey in the newborn nurseries of two obstetric clinics and results indicated that the mother’s clotting function was slightly at our university hospital, which follows the Japanese vitamin K lower than the usual values for pregnant women.11 The mother’s recommendation,7,8 and discovered that full-term neonates with- C-reactive protein at 31 and 34 weeks’ gestation was 1.99 and out any complications (n = 148) were given the first vitamin K at 4.35 mg dl − 1, respectively; this suggested the probable presence approximately 18.2 ± 6.0 h after birth. It would be better to of inflammation or activation of her Crohn’s disease. The describe clear time restriction until administering vitamin K orally hemoglobin of the cord blood at birth was 13.7 g dl − 1, and the in the Japanese guideline. mother’s hemoglobin F was negative, which indicates that there Although there have been some descriptions of neonates with was no fetomaternal transfusion. We possibly thought that early complications or risk factors for early VKDB,1 there are no concrete VKDB was due to severe maternal vitamin K deficiency secondary guidelines for determining which neonates require prompt to vitamin K malabsorption from Crohn’s disease. prophylaxis. There are some methods to note vitamin K deficiency mother and neonate who need vitamin K administration: (1) screening the mother’s clotting function and administering DISCUSSION vitamin K to the neonate immediately after birth parenterally, (2) VKDB in neonates is classified into three types: early, classical and screening the mother’s clotting function and administering vitamin late.1,2 Classical VKDB develops mainly as gastrointestinal hemor- K to the mother at least 1 week before delivery,13 (3) checking the rhage from day 2 to 7, and late VKDB develops as mainly neonate’s PIVKA-II level after birth and administering vitamin K to intracranial hemorrhage from 2 weeks to 6 months. The under- the neonate. Screening the mother’s clotting function can be lying reasons for these hemorrhages are mostly maternal misleading, in that some cases have occurred in which the neonate nutritional and cholestatic conditions. Compared with classical experienced VKDB despite the mother’s normal prenatal clotting and late VKDB, early neonatal VKDB causes mainly internal function.2,14 Investigation of the neonate’s PIVKA-II level is ideal,15,16 hemorrhage within 24 h after birth. The etiology of early VKDB is but requires substantial time to obtain the laboratory results.

Table 2a. Infant’s laboratory data (timeline)

Time after birth 24 h On 2 Days 3 Days 5 Days 8 Days 10 Days 26 Days 68 Days Institutional admission normal value

White blood cell (WBC) count (μl − 1) 10 400 9.4–34.0a Red blood cell (RBC) count (×104 μl − 1) 175 514 ± 0.7b Hemoglobin (Hb) (g dl − 1) 5.8 10.8 19.0 ± 2.2b Hematocrit (hct) (%) 17.9 61 ± 7.4b Platelets (Plt) (×104 μl − 1) 18.0 8.0–35.6a Reticulocytes (%) 9.6 32 ± 14b T-Bil (mg dl − 1) 5.5 8.2 11.6 17.8 21 18.5 0.3 0.3–1.3 D-Bil (mg dl − 1) o0.1 o0.1 o0.1 o0.1 0–0.2 ID-Bil (mg dl − 1) 5.4 8.1 17.7 0.2 0.3–1.2 Prothrombin time (PT) (sec) >200.0 14.3 12.8 11.2 13.0 ± 1.43b Activated partial thromboplastin time 195.0 38.0 44.8 37.3 42.9 ± 5.80b (APTT) (sec) PT-INR Immeasurable 1.21 1.08 0.92 0.80–1.20 Hepaplastin test (%) 86 70–120 Fibrinogen (mg dl − 1) 119 202 206 2.83 ± 0.58b Fibrin degradation products (μgml− 1) o1.0 o1.0 PIVKA-IIc (mAU ml − 1) 117 000 9290 o8000 Abbreviation: PIVKA-II, protein induced by vitamin K absence or antagonist. aPremature infant’s normal value. bNeonatal normal value. cProtein induced by vitamin K absence or antagonist-II (using electrochemiluminescent immunoassay).

Table 2b. Infant’s coagulation status (on admission) Table 3. Mother’s laboratory data (33 weeks gestation)

Institutional Institutional normal normal value value

White blood cell (WBC) count (μl − 1) 10 400 9.4–34.0a Prothrombin time (PT) (sec) 14.2 8.10–11.90a Red blood cell (RBC) count (×104 μl − 1) 175 514 ± 0.7b Activated partial thromboplastin 41.3 23.90–43.34a Hemoglobin (Hb) (g dl − 1) 5.8 19.0 ± 2.2b time (APTT) (sec) Hematocrit (hct) (%) 17.9 61 ± 7.4b PT-INR 1.17 0.80–1.20 Platelets (Plt) (×104 μl − 1) 18.0 8.0–35.6a Fibrinogen (mg dl − 1) 678 235–490a Reticulocytes (%) 9.6 32 ± 14b PIVKA-II (mAU ml − 1) 17 800 o8000 T-Bil (mg dl − 1) 5.5 0.3–1.3 D-Bil (mg dl − 1) o0.1 0–0.2 Abbreviation: PIVKA-II, protein induced by vitamin K absence or antagonist. − a ’ 11 ID-Bil (mg dl 1) 5.4 0.3–1.2 Normal value at 33 weeks gestation. Prothrombin time (PT) (sec) >200.0 13.0 ± 1.43b Activated partial thromboplastin time 195.0 42.9 ± 5.80b (APTT) (sec) We think that the mother’s more severe vitamin K deficiency PT-INR Immeasurable 0.80–1.20 Fibrinogen (mg dl − 1) 119 2.83 ± 0.58b raised by disease activity and diet possibly led the present − ’ fi Fibrin degradation products (μgdl 1) o1.0 o1.0 neonate to VKDB in contrast to the fact that the mother s rst child PIVKA-IIc (mAU ml − 1) 117 000 o8000 did not develop VKDB. Vitamin K deficiency with inflammatory bowel disease is well known in internal medicine and orthopedics Clotting factors fi 3,4,14 XII (%) 19 50–150 because vitamin K and D de ciency lead to osteoporosis. The – degree of vitamin K and D deficiency has been reported to be well XI (%) 27 75 145 3 IX (%) 2 70–130 correlated with inflammatory bowel disease. It has been reported 5 VIII (%) 83 60–150 that 46% patients with Crohn’s disease have vitamin K deficiency. VII (%) o375–140 In the present case, the mother’s Crohn’s disease was possibly X (%) 4 70–130 more active and that her nutrition could have been poorer at V (%) 43 70–135 delivery of this neonate than at the delivery of her first child, II (%) 18 75–135 – because her C-reactive protein was slightly higher (2.41 vs less XIII (%) 67 70 140 than 1 mg dl − 1) and her serum albumin was slightly lower (2.6 to Protein C antigen (%) 11 70–150 2.9 vs 3.1 to 3.3 mg dl − 1).17,18 In addition, her diarrhea was more Protein C activity (%) o10 64–146 severe and she could not take enough meal because of gastric Protein S antigen (%) 53 60–150 – distress and abdominal fullness at the current delivery. On the von Willebrand factor activity (%) 271 60 170 other hand, in order for vitamin K to be absorbed in the gastric Abbreviation: PIVKA-II, protein induced by vitamin K absence or anta- tract, it needs to be ingested simultaneously with bile acid and fat. gonist. The mother’s vitamin K deficiency at her current hospital aPremature infant’s normal value. admission was considered to be influenced by her fat-restricted bNeonatal normal value. diet for Crohn’s disease. We regarded that the mother’s disease c Protein induced by vitamin K absence or antagonist-II (using electro- activity and diet at the time of hospitalization have led to chemiluminescent immunoassay). her vitamin K malabsorption and vitamin K deficiency. As fetal

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