Hubungan Antara Kadar Vitamin D (25(OH)D) Dengan Terjadinya Necrotizing Enterocolitis (NEC) Pada Bayi Kurang Bulan

Pramitasari, Yesi Adisti and dr. Eko Sulistijono (2022) Hubungan Antara Kadar Vitamin D (25(OH)D) Dengan Terjadinya Necrotizing Enterocolitis (NEC) Pada Bayi Kurang Bulan. Magister thesis, Universitas Brawijaya.

Abstract

Necrotizing enterocolitis ( NEC ) merupakan sindrom multifaktorial nekrosis iskemik intestinal akut dan menjadi salah satu penyebab kegawatan gastrointestinal pada neonatus. Insiden NEC adalah 1 per 1000 kelahiran hidup (5%-10%), dan lebih dari 90% terjadi pada pada bayi kurang bulan. NEC terjadi karena invasi bakteri, aktivasi kekebalan, tidak terkontrolnya peradangan dengan produksi oksigen reaktif (ROS) dan nitrogen, vasokonstriksi diikuti oleh iskemia pada perfusi, kegagalan barrier usus dan nekrosis usus. Janin tidak memiliki produksi endogen 25 (OH) D dan sepenuhnya tergantung pada transfer dari ibu. Sementara 25 (OH) D melewati plasenta, kadar 1,25 (OH)2D terbatas pada sirkulasi ibu dan diyakini diproduksi secara de novo di plasenta dan pada janin itu sendiri. Calcitriol atau 1,25(OH)2D, metabolit aktif vitamin D, berinteraksi dengan reseptor spesifik yang disebut reseptor vitamin D (VDR). Reseptor VDR diekpresikan pada sel enterosit, dimana pengaktifannya menginduksi proliferasi, differensiasi dan induksi apoptosis. Konsentrasi metabolit utama vitamin D pada tali pusat secara konsisten lebih rendah daripada konsentrasinya dalam serum ibu. Konsentrasi 25- hydroxyvitamin D dan 24,25-dihidroksivitamin D pada vena tali pusat berkorelasi secara signifikan dengan konsentrasinya yang ditemukan pada sirkulasi maternal, yang menunjukkan bahwa 2 metabolit tersebut berdifusi dengan mudah melintasi sawar plasenta dan konsentrasi vitamin D janin sepenuhnya bergantung pada ibu. Transmisi vitamin D transplasental terutama terjadi pada trimester ketiga kehamilan sehingga bayi prematur beresiko tinggi mengalami defisiensi vitamin D. Defisiensi vitamin D didiagnosis ketika 25 (OH) D <20 ng / mL. Insufisiensi vitamin D didefinisikan sebagai 25 (OH) D 20-30 ng / mL, dan 25(OH)D > 30 ng / mL dianggap normal. Defisiensi vitamin D pada saluran gastrointestinal menyebabkan bacterial clearance kolon menurun, berkurangnya ekspresi tight junctions (TJs) di epitel usus dan peningkatan peradangan yang dimediasi Th1 pada usus. Penelitian ini menggunakan desain penelitian observasional dengan studi kohort. Alokasi subjek penelitian ke dalam kelompok penelitian dilakukan secara consequtive sampling pada subjek yang memenuhi kriteria inklusi dan ekslusi hingga memenuhi syarat besar sampel pada masing-masing kelompok pada bulan Maret – Mei 2020 di ruang rawat inap neonatologi RSUD Saiful Anwar Malang. Adapun kriteria inklusi penelitian ini yaitu : (a) semua bayi kurang bulan yang lahir dan dirawat di bangsal rawat inap RSUD dr. Saiful Anwar Malang (b) bayi kurang bulan dengan usia kehamilan 28-37 minggu (c) bayi dengan pemberian nutrisi ASI eksklusif atau predominan ASI (d) orang tua atau penanggung jawab bersedia mengikutkan anaknya dalam penelitian. Dengan kriteria eksklusi sebagai berikut: (a) pasien menderita kelainan kongenital (congenital anomalies of kidney and urinary tract, penyakit jantung bawaan) (b) orang tua/wali menyatakan tidak bersedia mengikuti penelitian. Kriteria drop out : (a) pasien meninggal saat 24 jam pertama pengamatan (b) orang tua/wali menyatakan tidak bersedia mengikuti penelitian. Prosedur penegakan diagnosis viii Necrotizing enterocolitis (NEC) berdasarkan pada Bell’s modification criteria dan dikonfirmasi oleh ahli neonatologi. Alat untuk mengukur kadar vitamin D serum dengan metode enzyme-linked immunosorbent assay (ELISA) dengan sampel darah dari vena tali pusat diambil dari semua subjek neonatus dalam 24 jam pertama kehidupan. Uji normalitas data dilakukan dengan Uji Kolmogorov- Smirnov karena data terdistribusi normal dan dilakukan uji homogenitas dengan Uji Levene karena data terdistribusi homogen. Kemudian dilakukan Analisis uji regresi logistic univariat dan multivariat. Selanjutnya dilakukan uji Spearman karena data tidak terdistribusi normal. Sampel pada penelitian ini lebih banyak bayi kurang bulan dengan NEC dibangdingkan dengan bayi kurang bulan tanpa NEC. Dengan rata-rata usia kehamilan 33,61 ± 2,08 minggu dengan rerata berat badan lahir 1953,90 ± 409 gram. Pada hasil penelitian ini didapatkan lebih banyak bayi kurang bulan dengan necrotizing enterocolitis (NEC) (27/51) dibandingkan dengan bayi kurang bulan tanpa necrotizing enterocolitis (NEC) (24/51). Rata-rata kadar vitamin D (25(OH)D) secara keseluruhan adalah 13,38  5,44 ng/mL dimana proporsi bayi dengan status defisiensi paling dominan 84,3% (43/51), insufisiensi 15,7% (8/51), dan tidak ada bayi kurang bulan dengan kadar vitamin D yang normal. Didapatkan kadar vitamin D pada bayi kurang bulan dengan NEC lebih rendah (10,18 ± 4,07 ng/mL) daripada bayi kurang bulan tanpa NEC (16,95 ± 4,45 ng/mL). Dimana pada kelompok bayi kurang bulan dengan NEC sebanyak 26 pasien dengan status defisiensi dan 1 pasien dengan status insufisiensi. Pada kelompok tanpa NEC didapatkan dengan 17 pasien dengan status defisiensi dan 7 pasien dengan status insufisiensi. Dari hasil analisis univariat didapatkan bahwa defisiensi vitamin D meningkatkan risiko terjadinya NEC sebesar 10,7 kali. Selain itu demam intrapartum dapat meningkatkan terjadinya NEC sebesar 3,5x dengan nilai p=0,09 (95%CI 0,8-14,9). Tidak diberikan IMP merupakan faktor yang meningkatkan terjadinya NEC sebesar 4x dengan nilai p=0,039 (95%CI 1- 14,9). Perokok pasif dapat meningkatkan kejadian NEC sebesar 2,8x dengan nilai p=0,049 (95%CI 0,9-8,9).Kelahiran very preterm (usia kehamilan <32 minggu) telah meningkatkan terjadinya NEC sebesar 6,2 kali dengan nilai p=0,006 (95%CI 1,7-23,2) dan respiratory distress dapat meningkatkan terjadinya NEC sebesar 20 kali dengan nilai p=0,000 (95%CI 4,5-88,2). Selanjutnya dilakukan uji analisis multivariate, didapatkan defisian vitamin D meningkatkan terjadinya NEC sebesar 19,4 kali dengan nilai p=0,043 (95%CI 0,7-21,7) dan respiratory distress dapat meningkatkan kejadian NEC sebesar 9,4 kali dengan nilai p=0,02 (95%CI 1,2-70). Berdasarkan hasil uji korelasi spearman diperoleh kesimpulan bahwa terdapat hubungan yang signifikan antara kadar vitamin D dengan onset terjadinya NEC (p=0.029). Kadar vitamin D berkorelasi positif dengan onset hari timbulnya NEC, dimana semakin tinggi kadar vitamin D maka timbulnya onset NEC semakin lama dan sebaliknya. Dari hasil uji korelasi juga diperoleh kekuatan korelasi sebesar r=0,487 yang artinya kekuatan korelasi cukup. Berdasarkan hasil tersebut, dapat disimpulkan bahwa didapatkan Kadar vitamin D (25(OH)D) lebih rendah pada bayi kurang bulan dengan necrotizing enterocolitis dibandingkan dengan bayi kurang bulan tanpa necrotizing enterocolitis. Penelitian ini menunjukkan adanya hubungan antara kadar vitamin D(25(OH)D) dengan terjadinya necrotizing enterocolitis pada bayi kurang bulan secara signifikan

English Abstract

ix SUMMARY Yesi Adisti Pramitasari, NIM. 188070901011002. Department of Child Health, Faculty of Medicine Universitas Brawijaya, dr. Saiful Anwar General Hospital, Malang, June 2022. The Correlation Between Levels of Vitamin D (25(OH)D) and Necrotizing Enterocolitis (NEC) in Preterm Infants. Supervisors: Eko Sulistijono, MD, Paed(C) and Brigita Ida RVC, MD, Paed(C). Necrotizing enterocolitis (NEC) is a multifactorial syndrome of acute intestinal ischemic necrosis and is one of the causes of gastrointestinal emergencies in neonates. The incidence of NEC is 1 per 1000 live births (5%- 10%), and more than 90% of NEC occurs in preterm infants. NEC is caused by bacterial invasion that leads to immune activation, uncontrolled inflammation with reactive oxygen (ROS) and nitrogen production, vasoconstriction, followed by perfusion ischemia, and ultimately failure of the intestinal barrier and intestinal necrosis. A fetus does not have endogenous 25(OH)D production and completely depends on transfer from the mother. While 25(OH)D crosses the placenta, the level of 1,25(OH)2D is restricted to the maternal circulation and is believed to be produced de novo in the placenta and in the fetus itself. Calcitriol or 1,25(OH)2D, the active metabolite of vitamin D, interacts with a specific receptor called the vitamin D receptor (VDR). The VDR is expressed on the enterocyte. Its activation induces proliferation, differentiation, and apoptosis. The concentration of the main vitamin D metabolite in the umbilical cord is consistently lower than its concentration in maternal serum. The concentrations of 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D in the umbilical cord vein significantly correlates with its concentration in the maternal circulation, indicating that these 2 metabolites diffuse readily cross the placental barrier and that fetal vitamin D concentrations are entirely dependent on the mother. Transplacental vitamin D transmission mainly occurs in the third trimester of pregnancy so preterm infants are at high risk for vitamin D deficiency. Vitamin D deficiency is diagnosed when 25(OH)D < 20 ng/mL. Vitamin D insufficiency is defined as 25(OH)D of 20-30 ng/ml, and 25(OH)D > 30 ng/mL is considered normal. Vitamin D deficiency in the gastrointestinal tract leads to decreased colonic bacterial clearance, reduced expression of tight junctions (TJs) in the intestinal epithelium, and increased Th1- mediated inflammation in the gut. This study used an observational research design which is a cohort study. The allocation of research subjects into research groups was done by consecutive sampling on the subjects who met the inclusion and exclusion criteria until the sample size requirements for each group were met during March – May 2020 in the neonatology inpatient ward of dr. Saiful Anwar General Hospital Malang. The inclusion criteria for this study were: (a) all preterm infants born and treated in the inpatient ward of dr. Saiful Anwar General Hospital Malang (b) preterm infants with a gestational age of 28-37 weeks (c) infants with exclusive or predominantly breastfeeding nutrition (d) parents or guardians willing to include their children in the study. The exclusion criteria were as follows: (a) patients suffering from congenital anomalies (congenital anomalies of kidney and urinary tract, congenital heart disease) (b) parents/guardians stated that they were not willing to participate in the study. Drop out criteria: (a) the patient died during the first 24 hours of observation (b) the parents/guardians stated that they were not willing to participate in the study. The procedure for establishing the diagnosis of necrotizing enterocolitis (NEC) was based on Bell's modification x criteria and confirmed by a neonatologist. Serum vitamin D levels were measured using the enzyme-linked immunosorbent assay (ELISA) method with blood samples taken from the umbilical cord vein of all neonatal subjects in the first 24 hours of life. The normality test of the data was carried out using the Kolmogorov- Smirnov test because the data were distributed normally and the homogeneity test was carried out using the Levene test because the data were homogeneously distributed. Then, univariate and multivariate logistic regression analysis was performed. Furthermore, the Spearman test was carried out because the data were not normally distributed. There were more preterm infants with NEC than preterm infants without NEC in this study. The average gestational age was 33.61 ± 2.08 weeks, with an average birth weight of 1953.90 ± 409 grams. The results of this study showed that there were more preterm infants with necrotizing enterocolitis (NEC) (27/51) compared to preterm infants without necrotizing enterocolitis (NEC) (24/51). The overall average level of vitamin D (25(OH)D) was 13.38 ± 5.44 ng/mL. The majority or 84.3% (43/51) of the infants had vitamin D deficiency, while 15.7% (8/51) of them had vitamin D insufficiency, and none of them had normal vitamin D levels. It was found that vitamin D levels in preterm infants with NEC were lower (10.18 ± 4.07 ng/mL) than in preterm infants without NEC (16.95 ± 4.45 ng/mL). In the preterm infants with NEC group, 26 patients had vitamin D deficiency and 1 patient had vitamin D insufficiency. Meanwhile in the group without NEC, 17 patients had vitamin D deficiency and 7 patients had vitamin D insufficiency. The univariate analysis result showed that vitamin D deficiency increased the risk of NEC by 10.7 times. In addition, intrapartum fever increased the occurrence of NEC by 3.5x with p-value = 0.09 (95% CI 0.8-14.9). Not given antenatal steroid was a factor that increased the occurrence of NEC by 4x with a p-value = 0.039 (95% CI 1-14.9). Passive smoking increased the incidence of NEC by 2.8x with a p-value = 0.049 (95% CI 0.9-8.9). Very preterm birth (gestational age <32 weeks) increased the incidence of NEC by 6.2 times with a p-value = 0.006 (95% CI 1.7-23.2) and respiratory distress increased the occurrence of NEC by 20 times with p-value = 0.000 (95% CI 4.5-88.2). Furthermore, multivariate analysis found that vitamin D deficiency increased the occurrence of NEC by 19.4 times with a p-value = 0.043 (95%CI 0.7-21.7) and respiratory distress could increase the incidence of NEC by 9.4 times with a p- value =0.02 (95%CI 1.2-70). Based on the results of the Spearman correlation test, it was concluded that there was a significant correlation between vitamin D levels and the onset of NEC (p=0.029). Vitamin D levels were positively correlated with the onset of NEC. The higher the vitamin D level, the longer the onset of NEC and vice versa. From the correlation test, we obtained the strength of the correlation of r = 0.487 which means the strength of the correlation was sufficient. Based on these results, it can be concluded that vitamin D (25(OH)D) levels were lower in preterm infants with necrotizing enterocolitis compared to preterm infants without necrotizing enterocolitis. This study showed a significant correlation between vitamin D(25(OH)D) levels and the case of necrotizing enterocolitis in preterm infants

Other obstract

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Item Type:	Thesis (Magister)
Identification Number:	0422060098
Uncontrolled Keywords:	bayi kurang bulan, necrotizing enterocolitis, kadar vitamin D 25(OH)D, cohort,- preterm infants, necrotizing enterocolitis, vitamin D 25(OH)D levels, cohort.
Subjects:	600 Technology (Applied sciences) > 618 Gynecology, obstetrics, pediatrics, geriatrics > 618.9 Pediatrics and geriatrics
Divisions:	Profesi Kedokteran > Spesialis Ilmu Kesehatan Anak, Fakultas Kedokteran
Depositing User:	Endang Susworini
Date Deposited:	25 Jan 2023 05:23
Last Modified:	25 Jan 2023 05:23
URI:	http://repository.ub.ac.id/id/eprint/196932

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