ENDOKRİNOLOJİK BOZUKLUKLAR ve TEKRARLAYAN GEBELİK KAYIPLARI

TEKRARLAYAN ABORTUS Kontrolsüz diyabet Tiroid disfonksiyonu Tiroid otoimmünitesi

Östrojen  TBG  hCG tirotropik Serbest hormon  TSH  STİMÜLASYON İyot klirensi Serbest hormon  TSH  (normal sınırlar) STİMÜLASYON

T4 FETUS term Konsepsiyon midgestasyon T4 MATERNAL TRANSFER

Relatif hipotiroksinemi (ST4) I:250g/gün ID< 100 İyot eksikliği Relatif hipotiroksinemi (ST4) Tiroid stimülasyonu-guvatr Fetal sonuçlar: Ortalama IQ 5-6 puan 4-7 puan

Kaynak Parametre 1. TM 2. TM 3. TM İtalya, 2008 (1) TSH U/mL ST4 pmol/L 0.03-2.30 11.9-20.8 0.29-2.80 10.4-18.7 0.34-3.00 10.3-16.4 ABD, 2008 (2) 0.12-3.37 10.4-17.8 0.35-3.35 9.3-16.2 - Hindistan, 2008 (3) 0.60-5.00 12.0-19.4 0.44-5.78 9.5-19.6 0.74-5.70 11.3-17.7 Çin, 2010 (4) 0.03-4.51 11.8-21.0 0.05-4.50 10.6-17.6 0.47-4.54 9.2-16.7 Endocrine Society,* 2007 (5) <2.5 <3 BJOG. 2008 Apr;115(5):602-6. Establishment of reference range for thyroid hormones in normal pregnant Indian women. Marwaha RK, Chopra S, Gopalakrishnan S, Sharma B, Kanwar RS, Sastry A, Singh S. Division of Endocrinology and Thyroid Research, Institute of Nuclear Medicine and Allied Sciences, Delhi, India. marwaha_raman@hotmail.com <marwaha_raman@hotmail.com> Abstract BACKGROUND: Interpretation of thyroid function tests during pregnancy needs trimester-related reference intervals from pregnant populations with minimal risk for thyroid dysfunction. While India has become iodine sufficient after two decades of salt iodisation, there is no normative data for thyroid function from healthy pregnant women of this country. AIMS AND OBJECTIVES: To determine trimester-specific reference ranges for free triiodothyronine (FT(3)), free thyroxine (FT(4)) and thyrotropin (TSH) from healthy pregnant Indian women. DESIGN: Cross-sectional study in a reference population of pregnant women. SETTING: Primary care level obstetric department in India. POPULATION: Women with uncomplicated pregnancy in any trimester. METHODS: Five hundred and forty-one apparently healthy pregnant women with uncomplicated single intrauterine gestations reporting to the Armed Forces Clinic in any trimester were consecutively recruited. Clinical examination, thyroid ultrasound for echogenicity and nodularity and estimation of FT(3), FT(4), TSH and antithyroid antibodies (antithyroperoxidase [anti-TPO] and antithyroglobulin [anti-Tg]) using electrochemiluminescence technique were carried out. From this entire sample, a disease- and risk-free reference population was obtained by excluding those with any known factor that could affect thyroid function or those who were being treated for thyroid dysfunction. MAIN OUTCOME MEASURE: None. RESULTS: Of the 541 consecutive pregnant women in different trimesters enrolled for the study, 210 women were excluded. The composition of reference population comprising 331 women was 107 in first trimester, 137 in second trimester and 87 in third trimester. The 5th and 95th percentiles values were used to determine the reference ranges for FT(3), FT(4) and TSH. The trimester-wise values in the first, second and third trimesters were: FT(3) (1.92-5.86, 3.2-5.73 and 3.3-5.18 pM/l), FT(4) (12-19.45, 9.48-19.58 and 11.32-17.7 pM/l) and TSH (0.6-5.0, 0.44-5.78 and 0.74-5.7 iu/ml), respectively. Analysis of mean, median values for FT(3), FT(4) and TSH between each trimester showed no significant difference in FT(3) and TSH values (95% CI). However, FT(4) showed significant variation between trimesters with values decreasing with advancing gestational age (P value: first versus second = 0.015, first versus third = 0.003 and second versus third = not significant). Women with antibody positivity and hypoechogenicity of thyroid gland had significantly higher TSH values when compared with women with antibody 1. J Clin Endocrinol Metab, 93:2616, 2008. 2. Am J Obstet Gynecol 199:62e1, 2008. 3. BJOG 115:602, 2008. 4. Yan et al. Clin Endocrinol 2010, ePub 5. J Cin Endocrinol Metab, 92:S1-S47, 2007.

Otoimmünite “marker”ı Ötiroid antikor pozitifliği  gebelikte TSH OTOİMMÜNİTESİ ABORTUS Otoimmünite “marker”ı Ötiroid antikor pozitifliği  gebelikte TSH Yaş  Tiroid antikorlarının plasenta üzerine etkisi İlk defa 1990 da Stagnaro-green glinoer 1991 de a dikkati çekti. J Clin Endocrinol Metab 91:258, 2006

ABORTUS N: 552 %19.6 tiroid AK (+) Stagnaro-Green, JAMA,264:1453, 1990 Antikardiyolipin AK bağımsız. N: 552 %19.6 tiroid AK (+) Stagnaro-Green, JAMA,264:1453, 1990

YARDIMCI ÜREME TEKNİKLERİ Abortus oranı 2-3 kat yüksek, fakat antikorların negatif oldugu grupta farlı olmadıgını ifade edenler de var. Yardımcı ureme teknikleri de ozellikle otoantikoru pozitif olanlarda tiroid foonksiyonu uzerine etkili. Negro, Hum Reprod, 20:1529,2005

ABORTUS N: 58 (PTD) N: 0 (PTD) N: 876 % 12.3 tiroid AK (+) Anrifosfolipid AK katkısı (?) N: 876 % 12.3 tiroid AK (+) Bagış, Thyroid 11:1049, 2001

% 9 % 36 % 5 REKÜRREN ABORTUS 22 nullipar Kadın (RA-) 22 gebe olmayan 22 multipar Antitiroid AK (+) % 9 % 36 % 5 Otoimmüniteye bagli rekurren abortus icin marker Antitiroid AK (+)  MARKER Bussen, Steck, Hum Reprod 11:2938, 1995

% 58 REKÜRREN ABORTUS Ötiroid antitiroid AK (+) (% 19) AK (-) Gebelik başarı oranı % 58 Tiroid antikorları ve abortus arasındaki ilişki, genel populasyndaki abortus antikor ilişkisi kadar guclu degil. N: 870 (RA +)-normal karyotip Rushworth, Hum Reprod 15:1637,2000

Tiroid otoimmünitesi prevalansı Endometriosis  (%29) İNFERTİLİTE Tiroid otoimmünitesi prevalansı Endometriosis  (%29) 438 infertil çift 438 kadın Sağlıklı fertil 100 kadın p TSH Tiroid AK (+) 1.3  0.9 % 14 % 18 * 1.1  0.8 % 8 <0.05 AD Kdın infertilitesi % 45. Erkek infertilitesi ve idyopatik nedenler geri kalanlar, %38 ve % 17. Kadınlarda neden endometrioz, tubal nedenler, over idsfonksiyonuantikotrlar endometriozlularda en sık. Kadın infertlitesi olan grupta Poppe, Thyroid 12:997,2002

TSH > 2U/mL antiTPO>2000IU/L Gebelik Başlangıcı TSH > 2U/mL antiTPO>2000IU/L Aşikar HİPOTİROİDİ TEDAVİ? L-T4 IVIG Heparin/aspirin Management of thyroid dysfunction during pregnancy: An Endocrine Society Guideline, J Cin Endocrinol Metab, 92:S1-S47, 2007.

TSH N yaş 10 hafta 20 hafta 30 hafta Doğum Abortus Prematür Doğum TPO (+)+T4 TPO (+) TPO (-) 57 58 869 30  5 30  6 28  5 1.6  0.5 1.7  0.5 1.1  0.4 2.3  0.5 1.2  0.4 2.5  0.6 1.4  0.4 1.9  0.5 3.5  0.7 2.1  0.6 Abortus Prematür Doğum TPO (+)+T4 TPO (+) TPO (-) % 3.5 % 13.8 % 2.4 % 7 % 22.4 % 8.2 TPOAb titers were checked and thyroid function tests were performed at the first gynecological visit, at 20 and 30 wk gestation, and 3 d after delivery. One hundred fifteen of 984 (11.7%) subjects were TPOAb. The 115 TPOAb women were divided into two groups, an intervention group (group A, n57) treated with LT4 and another group (group B, n 58) without treatment. The TPOAb women (group C, n 869) served as a normal control group. In group A, the patients treated with LT4 received a dose of 0.5g/kgd if they had TSH less than 1.0 mIU/liter, 0.75g/kgd for TSH between 1.0 and 2.0 mIU/liter, and 1g/kgd for TSH higher than 2.0 mIU/liter or a TPOAb titer exceeding 1500 kIU/liter. These dosages were maintained throughout gestation. LT4 administration was started on the first endocrinological J Clin Endocrinol Metab 91:258, 2006

4123 anti-TPO (-) gebe (TSH< 2.5 U/mL) (TSH 2.5-5.0 U/mL) P=0.006 Gebelik kaybı: < 20 hafta düşük, > 20 hafta ölü doğum (TSH< 2.5 U/mL) (TSH 2.5-5.0 U/mL) 4123 anti-TPO (-) gebe J Clin Endocrinol Metab 95:E44, 2010

Rutin tarama*?/Kişiye göre tarama? Tedavi (L-T4 kullanan kadınlar-TSH <2.5- < 3 U/mL) -2007 Anti-TPO (+)-ötiroid (?) Anti-TPO (+)-TSH > 2.5 U/mL (?) Anti-TPO (-)-TSH > 2.5 U/mL (??) Gebelik öncesi ? *J Clin Endocrinol Metab 95:1699, 2010

Yüksek Riskli Kadınlar* Otoimmün tiroid hastalığı aile öyküsü Tiroid hastalığı öyküsü Pozitif tiroid antikorları (biliniyorsa) Guvatr Tiroid disfonksiyonuna işaret eden bulgular Tip1 diyabet / otoimmün hastalık öyküsü Baş/boyuna yönelik radyoterapi öyküsü Düşük/prematür doğum öyküsü İnfertilite öyküsü % 30** *J Clin Endocrinol Metab 92:S1, 2010 **J Clin Endocrinol Metab, 92:203, 2007