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Ketersediaan hayati besi, kadar hemoglobin dan cadangan besi setelah suplementasi besi sesaat dan 2 jam setelah makan pada ibu hamil trimester 2 dan 3 dengan anemia defisiensi besi

KRISTIN, Erna, Promotor Prof. dr. M. Hakimi, M.Sc., Ph.D, SpOG(K)

2008 | Disertasi |

Tujuan dari penelitian ini ada 2 yaitu untuk mengetahui pengaruh pemberian tablet Ferrous Sulphate @ 300 mg yang diberikan sesaat dan 2 jam setelah makan terhadap profil farmakokinetika besi pada 12 wanita dengan anemia defisiensi besi dan mengetahui ketersediaan hayati besi, kadar hemoglobin dan feritin setelah pemberian tablet besi dosis berulang 2 kali sehari yang diberikan sesaat dan 2 jam setelah makan selama 12 minggu pada wanita dan wanita hamil dengan anemia defisiensi besi. Penelitian dosis tunggal dilakukan dengan rancangan sama subyek, sehingga setiap subyek menjalani 2 perlakuana. Tablet Ferrous Sulphate @ 300 mg diminum sesaat dan 2 jam setelah makan.. Sampel serum diambil secara serial pada jam ke 0; 0,25; 0,5; 1; 1,5; 2; 2,5; 3; 4; 6; 8; 10, dan 12 jam setelah minum tablet besi. Kadar besi dalam serum (sebagai ferri) ditetapkan dengan cara Vitros Fe Slides, parameter farmakokinetika besi dihitung menggunakan metode non kompartemen. Penelitian dosis berulang dilakukan dengan rancangan non randomized controlled clinical trial pada subyek dengan anemia defisiensi besi sehingga subyek dibagi dalam beberapa kelompok dan mendapat perlakuan sebagai sebagai berikut: 12 wanita tidak hamil, 12 wanita hamil trimester 2, 12 wanita hamil trimester 3 diberi perlakuan 2 kali sehari tablet Ferrous Sulphate @ 300 mg per oral, diberikan sesaat setelah makan, selama 12 minggu. Dua belas wanita tidak hamil, 12 wanita hamil trimester 2, 12 wanita hamil trimester 3 diberi perlakuan 2 kali sehari tablet Ferrous Sulphate @ 300 mg per oral, diberikan 2 jam setelah makan, selama 12 minggu. Dilakukan pemeriksaan berat badan, tinggi badan, tekanan darah pada minggu ke 0, 4, 8 dan 12. Pemeriksaan kadar besi, hemoglobin pada minggu k e 0, 2, 4, 6, 8, 10, dan 12. Kadar feritin diukur sebelum dan setelah suplementasi. Recall makanan dilakukan pada minggu ke 3, 7, dan 11. Kadar besi dalam serum (sebagai ferri) ditetapkan dengan cara Vitros Fe Slides dan kadar feritin dalam serum ditetapkan dengan cara Enzyme-Linked Immunosorbent Assay Technique. Kadar hemoglobin diukur menggunakan metode sianmethemoglobin. Nilai-nilai parameter farmakokinetika dosis tunggal yang didapatkan pada perlakuan 1 dan 2 dibandingkan dengan uji t dengan hasil sebagai berikut (MEAN + SEM): Cmax 232,92 ± 33,25 & 274,25 ± 28,18 ug/dl, Tmax 4,25 ± 0,64 & 3,21 ± 0,30 jam, Ka 0,3808 ± 0,0065 & 0,5437 ± ,0011 jam-1, Kel 0,1855 ± 0,0048 & 0,1375 ± 0,0132 jam-1 T1/2el 5,81 ± 1,16 & 5,76 ± 0,74 jam dan AUC0-12 1869,54 ± 330,60 & 2157,37 ± 264,55 ug/dl.jam, Vd 1093,89 vs 1288,00 dl dan Cl 131,38 vs 153,63 dl/jam. Tidak ada perbedaan yang bermakna pada semua nilai parameter farmakokinetika antara kedua perlakuan. Dalam penelitian dosis berulang delta kadar besi steady state min wanita tidak hamil pada perlakuan 1 dan 2 minggu 2-0 (22,58 + 29,43 vs 52,25 + 27,20 ug/dl), 4-0 (23,33 + 25,81 vs 4,56 + 15,26 ug/dl), 6-0 (8,83 + 15,36 vs -22,82 + 14,73 ug/dl), 8-0 (11,67 + 15,23 vs 15,33 + 25,04 ug/dl), 10-0 (38,83 + 16,48 vs 8,18 + 15,07 ug/dl), 12-0 (4,42 + 19,46 vs 19,75 + 26,36 ug/dl) tidak berbeda bermakna. Pada kelompok wanita hamil trimester 2 terlihat delta kadar besi memberikan nilai positif atau kenaikan kadar besi hanya pada minggu 0-2 (5,64 + 7,10 vs -8 + 13,25 ug/dl) dengan perlakuan 2. Selain itu terjadi penurunan kadar besi yang dinyatakan dengan nilai negative pada deltanya. Perbedaan perlakuan tidak memberikan perbedaan delta kadar besi yang bermakna secara statistik. Pada wanita hamil trimester 3, kadar besi perlakuan 1 dan 2 pada minggu 0-2 (27,82 + 14,12 vs 31,09 + 30,96 ug/dl), 0-4 (22,18 + 16,94 vs -9,91 + 17,74 ug/dl), 0-6 (25,83 + 9,17 vs 4,08 + 17,79 ug/dl), 0-8 (24,08 + 14,18 vs 13,45 + 20,41ug/dl), 0-10 (44,42 + 16,69 vs 21,22 + 16,49 ug/dl), 0-12 (41,78 + 12,73 vs -0,33 + 19,11 ug/dl). Pada wanita hamil trimester 2, kadar besi perlakuan 1 dan 2 pada minggu 0-2 (5,64 + 7,10 vs -8 + 13,25 ug/dl), 0-6 (-2,18 + 8,51 vs -16,67 + 14,85 ug/dl), 0-8 (-1,90 + 8,19 vs -27,33 + 14,36 ug/dl), 0-10 (- 18,40 + 13,68 vs -16,33 + 12,00 ug/dl). Tidak ada perbedaan yang bermakna secara statistik antara delta kadar besi perlakuan 1 dan perlakuan 2. Rata-rata kadar hemoglobin pada kelompok wanita tidak hamil (12,23 ± 0,29 vs 13,03 ± 0,19 g/dl), hamil trimester 2 (11,49 ± 0,27 vs 11,25 ± 0,28 g/dl) dan 3 (11,43 ± 0,29 vs 13,15 ± 0,35 g/dl) tidak berbeda secara bermakna. Peningkatan kadar Hb pada wanita tidak hamil setelah perlakuan 1 dari 11,025 + 0,32 g/dl menjadi 13,05 + 0,28 g/dl. Pada perlakuan 2 peningkatan kadar Hb dari 10,88 + 0,33 g/dl (sebelum perlakuan) menjadi 13 + 0,27 g/dl (12 minggu setelah perlakuan 2). Setelah dianalisis secara statistik, data kadar Hb pada kedua kelompok perlakuan tidak berbeda bermakna. Demikian juga rata-rata peningkatan kadar Hb setelah pemberian tablet besi antara dua kelompok perlakuan, mulai dari 2 minggu hingga 12 minggu pasca perlakuan. Pada wanita hamil trimester 2, setelah perlakuan 1, rata-rata kadar Hb subyek tampak meningkat secara cukup bermakna 2 minggu setelah perlakuan 2, yaitu dari 9,75 g/dl menjadi 11,43 g/dl dan nilai ini bertahan hingga 8 minggu setelah pemberian tablet besi. Peningkatan kadar Hb setelah perlakuan 1 tidak berbeda bermakna secara statistik jika dibandingkan dengan kelompok yang mendapat perlakuan 2. Tidak berbeda dengan wanita hamil trimester 2, pemberian tablet besi sesaat setelah makan pada wanita hamil trimester 3 selama 12 minggu mampu menaikkan kadar Hb rata-rata secara bermakna, yaitu dari 9,68 g/dl (+ 0,26) menjadi 13,52 g/dl (+ 0,43). Dari penelitian dengan dosis tunggal dapat disimpulkan bahwa tidak terdapat perbedaan nilai parameter farmakokinetika besi pada sampel serum setelah pemberian tablet Ferrous Sulphate @ 300 mg pada wanita dengan anemia defisiensi besi sesaat dan 2 jam setelah makan. Tidak terdapat perbedaan ketersediaan hayati besi, kadar hemoglobin dan kadar feritin setelah pemberian tablet besi dosis berulang selama 12 minggu yang diberikan sesaat setelah makan dan 2 jam setelah makan pada wanita tidak hamil dan wanita hamil dengan anemia defisiensi besi. Tidak terdapat perbedaan ketersediaan hayati besi, rata-rata kenaikan kadar hemoglobin dan kenaikan kadar feritin setelah pemberian tablet besi dosis berulang selama 12 minggu sesaat dan 2 jam setelah makan pada wanita hamil trimester 2 dan 3 dengan anemia defisiensi besi .Meskipun secara statistic tidak berbeda bermakna, rata-rata kenaikan kadar hemoglobin lebih tinggi pada wanita hamil trimester 3 dari pada trimester 2. Rata-rata kenaikan kadar hemoglobin paling tinggi terjadi pada kelompok wanita hamil trimester 3 setelah pemberian tablet besi dosis berulang sesaat setelah makan. Kadar feritin awal memberikan pengaruh yang bermakna terhadap delta kenaikan kadar hemoglobin.

The aims of this study were to understand the effect of ferrous sulphate tablet @ 300 mg taken shortly after meal and 2 hours after meal on the iron pharmacokinetic profile in 12 women with iron deficiency anaemia and to find out the iron bioavailability, haemoglobin and feritin level after repeated-dose iron tablet taken twice a day shortly after meal and 2 hours after meal for 12 weeks in nonpregnant women and pregnant women with iron deficiency anaemia. The single-dose study was conducted with cross-over design, so that each subject group was went through 2 kinetic studies. Ferrous sulphate tablet @ 300 mg was taken shortly after meal and 2 hours after meal. Serum samples were obtained in serial at the hour of 0, 0.25, 0.5, 1, 1.5, 2.5, 3, 4, 6, 8, 10, and 12, after the intake of iron tablet. Ferric iron level in serum was determined with Vitros Fe Slides, and the iron pharmacokinetic parameters were estimated with non-compartmental method. Repeated-dose study was conducted with non-randomized controlled clinical trial design, and In the repeated-dose study, subjects with iron deficiency anaemia were classified into several groups and treated as follows: 12 non-pregnant women, 12 pregnant women in their second trimester, and 12 pregnant women in their third trimester were treated 2 times a day with ferrous sulphate tablet @ 300 mg, taken orally shortly after meal, for 12 weeks. Twelve non-pregnant women, 12 pregnant women in their second trimester, and 12 pregnant women in their third trimester were treated twice a day with ferrous sulphate tablet @ 300 mg, taken orally 2 hours after meal, for 12 weeks. The body height, weight and blood pressure were measured at the week of 0, 4, 8 and 12. The measurement of iron and haemoglobin level was conducted at the week of 0, 2, 4, 6, 8, 19, and 12. The measurement of feritin level was conducted before and after supplementation. Food recall was conducted at the week of 3, 7, and 11. Serum ferric iron level was determined with Vitros Fe Slides (1995) and serum feritin level was determined by Enzyme-Linked Immunosorbent Assay Technique. Haemoglobin level was determined with cyanmethaemoglobin method. The pharmacokinetic parameter values obtained from the intervention 1 and 2 were compared using t-test, and the result were as follows (MEAN±SEM): Cmax 232.92 ± 33.25 and 274.25±28.18 ug/dl, Tmax 4.25±0.64 and 3.21±0.30 hours, Ka 0.3808±0.0065 and 0.5437±,0011 hours-1, Kel 0.1855±0.0048 and 0.1375±0.0132 hours-1, T1/2el 5.81± 1.16 and 5.76±0.74 hours, and AUC0-12 1869.54±330.60 and 2157.37±264.55 ug/dl.hours, Vd 1093,89 and 1288,00 dl, Cl 131,38 and 153,63 dl/hours.There were no significant differences in all pharmacokinetic parameter values between the two intervention. In repeated-dose study, delta values (MEAN+SEM) of iron level of nonpregnant women in the intervention 1 and 2 at week 2-0 (22.58±29.43 vs 52.25±27.20 ug/dl), 4-0 (23.33±25.81 vs 4.56±15.26 ug/dl), 6-0 (8.83± 15.36 vs -22.82±14.73 ug/dl), 8-0 (11.67±15.23 vs 15.33±25.04 ug/dl), 10-0 (38.83±16.48 vs 8.18± 15.07 ug/dl), and 12-0 (4.42±19.46 vs 19.75±26.36 ug/dl), were not significantly different. The delta value of iron level in pregnant women in their second trimester was positive, and the increase of iron level was occurred only in week 0-2 (5.64±7.10 vs - 8± 13.25 ug/dl) in intervention 2. Aside of that, there was a decrease in iron level, showed by the negative delta value. The difference in intervention did not produce a significant difference in iron level delta value. iron level of trimester 3 pregnant women in the intervention 1 and 2 in week 0-2 (27.82±14.12 vs 31.09± 30.96 ug/dl), 0-4 (22.18±16.94 vs -9.91±17.74 ug/dl), 0-6 (25.83±9.17 vs 4.08±17.79 ug/dl), 0-8 (24.08±14.18 vs 13.45±20.41 ug/dl), 0-10 (44.42±16.69 vs 21.22±16.49 ug/dl), and 0-12 (41.78±12.73 vs -0.33±19.11 ug/dl). The differences of iron level of trimester 2 pregnant women in the intervention 1 and 2 in week 0-2 (5.64±7.10 vs -8±13.25 ug/dl), 0-4 (-6.56 + 6.97vs -10.82 + 11.61 ug/dl), 0-6 (-2.18±8.51 vs -16.67±14.85 ug/dl), 0-8 (-1.90±8.19 vs -27.33±14.36 ug/dl), 0-10 (-18.40±13.68 vs -16.33±12.00 ug/dl), 0-12 (-3,60 + 11,08 vs -30,58 + 11,72 ug/dl). There was no significant difference between iron levels in intervention 1 and 2. The average haemoglobin levels between non-pregnant women (12.23±0.29 vs 13.03±0.19 g/dl), pregnant women in their second (11.49±0.27 vs 11.25±0.28 g/dl) and third (11.43±0.29 vs 13.15±0.35 g/dl) trimester were not significantly different, both in 2 weeks after the intervention and until 12 weeks after the intervention. The increase in haemoglobin level in non-pregnant women after intervention 1 was from 11.025±0.32 g/dl to 13.05±0.28 g/dl. In intervention 2, there was an increase of haemoglobin level from 10.88±0.33 g/dl (before treatmnet) to 13±0.27 g/dl (12 weeks of intervention 2). After statistical analysis, there was no significant difference in haemoglobin level of both groups. It was also occurred in the average of haemoglobin level increase after iron tablet supplementation between the two groups, starting from 2 weeks to 12 weeks of intervention. In pregnant women in their second trimester, after intervention 1, the average of haemoglobin level increased significantly after 2 weeks of intervention 2, from 9.75 g/dl to 11.43 g/dl and these values were maintained until 8 weeks of iron tablet supplementation. The difference in the increase in haemoglobin level after intervention 1 was not statistically significant compared to intervention group 2. Iron tablet supplementation taken after meal for 12 weeks in pregnant women in their third trimester could increase the average haemoglobin level significantly, from 9.68 g/dl (±0.26) to 13.52 g/dl (±0.43). From the single-dose study, it was concluded that there were no differences in iron pharmacokinetic parameters in serum samples after the intake of ferrous sulphate 300 mg tablets by women with iron deficiency anaemia, taken shortly after meal and 2 hours after meal. There were no differences in iron bioavailability, haemoglobin level, and feritin level after the repeated-dose iron tablet taken after meal and 2 hours after meal in non-pregnant women and pregnant women with iron deficiency anaemia. There were no differences in iron bioavailability, the average of the increase in haemoglobin level and feritin level after repeated-dose of iron tablet for 12 weeks taken shortly after meal and 2 hours after meal in pregnant women with iron deficiency anaemia in their second and third trimester. Even though it was not statistically different, the average of the increase in haemoglobin level was higher in pregnant women in their third trimester compared to that of pregnant women in their second trimester. The average of the increase in haemoglobin level was higher in pregnant women in their third trimester after repeated-dose iron tablet taken shortly after meal. The initial feritin level had a significant effect on the delta of the increase in haemoglobin level.

Kata Kunci : Kadar hemoglobin,Cadangan besi,Wanita hamil dengan anemia, Haemoglobin, pregnant


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