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Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: A retrospective case control study.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Obstetrisk forskning/Högberg)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Klinisk och experimentell reproduktionsbiologi/Olovsson)
Department of Clinical Sciences, Division of Obstetrics and Gynaecology, Karolinska Institutet and Danderyd Hospital, Stockholm, Sweden.
Department of Clinical Sciences, Division of Obstetrics and Gynaecology, Karolinska Institutet and Danderyd Hospital, Stockholm, Sweden.
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2012 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, 121- p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Recurrent miscarriage affects approximately 1% of all couples. There is a known relation between hypothyroidism and recurrent miscarriage. Phosphodiesterase 8B (PDE8B) is a regulator of cyclic adenosine monophosphate (cAMP) with important influence on human thyroid metabolism. Single nucleotide polymorphism (SNP) rs 4704397 in the PDE8B gene has been shown to be associated with variations in serum Thyroid Stimulating Hormone (TSH) and thyroxine (T4) levels. The aim of this study was to investigate whether there is an association between the SNP rs 4704397 in the PDE8B gene and recurrent miscarriage. METHODS: The study was designed as a retrospective case control study. 188 cases with recurrent miscarriage were included and compared with 391 controls who had delivered at least once and with no history of miscarriage or assisted reproduction. RESULTS: No difference between cases and controls concerning age was found. Bivariate associations between homozygous A/A (OR 1.57, 95% CI 0.98-2.52) as well as G/G carriers (OR 1.52, 95% CI 1.02-2.25) of SNP rs 4704397 in PDE8B and recurrent miscarriage were verified (test for trend across all 3 genotypes, p = 0.059). After adjustment for known confounders such as age, BMI and smoking the association between homozygous A/A (AOR 1.63, 95% CI 1.01 - 2.64, p = 0.045) and G/G (AOR 1.52, 95% CI 1.02 - 2.27, p = 0.039) carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage remained. CONCLUSIONS: Our findings suggest that there is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage.

Place, publisher, year, edition, pages
2012. Vol. 13, 121- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-188671DOI: 10.1186/1471-2350-13-121ISI: 000314113200001PubMedID: 23237535OAI: oai:DiVA.org:uu-188671DiVA: diva2:578633
Available from: 2012-12-18 Created: 2012-12-18 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Hypothyroidism and Pregnancy
Open this publication in new window or tab >>Hypothyroidism and Pregnancy
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Hypothyroidism is a common endocrine disorder affecting women of reproductive age. On a global level, iodine deficiency is still the most common cause of hypothyroidism. Also genetic variations, in particular SNP rs4704397 in the PDE8B gene, are responsible for a significant proportion of TSH variations.  Untreated hypothyroidism has significant adverse effects on pregnancy and fetal outcome. Most international guidelines suggest targeted thyroid testing in pregnant women with risk factors for thyroid disturbances.

In a case-control study, an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage was found. The explanation for this association is unknown.

In a nationwide survey, all guidelines for thyroid testing and management of hypothyroidism during pregnancy in Sweden were collected and compared with international guidelines. The local guidelines were variable and poorly compliant with the international guidelines.

In a follow-up in one district, 5,254 pregnant women were included for subsequent review of their medical reports. We found a targeted thyroid testing rate of 20.1% in clinical practice, with an overall frequency of women with trimester-specific elevated TSH of 18.5%. More disturbingly, half of the women who were on levothyroxine treatment at the time of conception had an elevated TSH level at thyroid testing.

In a subsequent cohort study of the 5,254 women, we found the prevalence of trimester-specific elevated TSH and overt hypothyroidism to be equal in targeted thyroid tested and untested women.

In a cross-sectional study, a median urinary iodine concentration (UIC) of 98 μg/l was found in the study population. According to WHO/UNICEF/IGN criteria, the population-based median UIC during pregnancy should be 150-249 μg/l.

In conclusion, genetic variations may contribute to adverse pregnancy outcomes. In clinical practice, thyroid testing and the management of hypothyroidism during pregnancy is unsatisfactory, regarding the whole chain from development of local guidelines to their implementation and to targeted thyroid testing. Moreover, our results indicate insufficient iodine status in the pregnant population of Sweden.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2015. 69 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1081
Keyword
phosphodiesterase 8B, recurrent miscarriage, single nucleotide polymorphism, thyroid, guidelines, hypothyroidism, pregnancy, survey, thyroid testing, screening, iodine, iodine deficiency, median urinary iodine concentration
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-247090 (URN)978-91-554-9201-4 (ISBN)
Public defence
2015-05-08, Rosénsalen, Akademiska sjukhuset, ingång 95/96. Barn- och kvinnosjukhuset. NBV (nedre bottenvåning)., Uppsala, 09:00 (Swedish)
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Available from: 2015-04-17 Created: 2015-03-13 Last updated: 2015-07-07

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Granfors, MichaelaKarypidis, HelenaStavreus-Evers, AnneliSundström-Poromaa, IngerWikström, Anna-KarinAkerud, Helena
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