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  • 1.
    Endler, M.
    et al.
    Karolinska Inst, Dept Clin Sci & Educ, Södersjukhuset, Stockholm, Sweden.
    Cnattingius, S.
    Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.
    Granfors, Michaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden.
    The inherited risk of retained placenta: a population based cohort study.2018In: British Journal of Obstetrics and Gynecology, ISSN 1470-0328, E-ISSN 1471-0528, Vol. 125, no 6, p. 737-744Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate whether retained placenta in the first generation is associated with an increased risk of retained placenta in the second generation.

    Design: Population‐based cohort study.

    Setting: Sweden.

    Population: Using linked generational data from the Swedish Medical Birth Register 1973–2012, we identified 494 000 second‐generation births with information on the birth of the mother (first‐generation index birth). For 292 897 of these births there was information also on the birth of the father.

    Methods: Risk of retained placenta in the second generation was calculated as adjusted odds ratios (aOR) by unconditional logistic regression with 95% confidence intervals (95% CI) according to whether retained placenta occurred in a first generation birth or not.

    Main outcome: Retained placenta in the second generation.

    Results: The risk of retained placenta in a second‐generation birth was increased if retained placenta had occurred at the mother's own birth (aOR 1.66, 95% CI 1.52–1.82), at the birth of one of her siblings (aOR 1.58, 95% CI 1.43–1.76) or both (aOR 2.75, 95% CI 2.18–3.46). The risk was slightly increased if retained placenta had occurred at the birth of the father (aOR 1.23, 95% CI 1.07–1.41). For preterm births in both generations, the risk of retained placenta in the second generation was increased six‐fold if retained placenta had occurred at the mother's birth (OR 6.55, 95% CI 2.68–16.02).

    Conclusion: There is an intergenerational recurrence of retained placenta on the maternal and most likely also on the paternal side. The recurrence risk seems strongest in preterm pregnancies.

    Tweetable abstract: A population‐based cohort study suggests that there is an intergenerational recurrence of retained placenta.

  • 2.
    Granfors, Michaela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hypothyroidism and Pregnancy2015Doctoral 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.

    List of papers
    1. Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: A retrospective case control study.
    Open this publication in new window or tab >>Phosphodiesterase 8B gene polymorphism in women with recurrent miscarriage: A retrospective case control study.
    Show others...
    2012 (English)In: BMC Medical Genetics, ISSN 1471-2350, E-ISSN 1471-2350, Vol. 13, p. 121-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.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-188671 (URN)10.1186/1471-2350-13-121 (DOI)000314113200001 ()23237535 (PubMedID)
    Available from: 2012-12-18 Created: 2012-12-18 Last updated: 2017-12-06Bibliographically approved
    2. Thyroid Testing and Management of Hypothyroidism During Pregnancy: A Population-based Study
    Open this publication in new window or tab >>Thyroid Testing and Management of Hypothyroidism During Pregnancy: A Population-based Study
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    2013 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 98, no 7, p. 2687-2692Article in journal (Refereed) Published
    Abstract [en]

    Context: There are international guidelines on thyroid function testing and management of hypothyroidism during pregnancy. Few studies have evaluated how they are implemented into clinical practice. Objective: In this descriptive study, we assessed the implementation of international guidelines in this field into local guidelines and also into clinical practice. Design and Participants: In a nationwide survey, all guidelines in Sweden were collected (n = 29), and the adherence of the local guidelines to The Endocrine Society Guidelines 2007 was evaluated. In a follow-up in 1 district, 5254 pregnant women with an estimated date of delivery between January 1, 2009, and December 31, 2011, were included for subsequent review of their medical reports. Results: All but 1 district had guidelines on the subject. All local guidelines included fewer than the 10 listed reasons for thyroid testing recommended by The Endocrine Society Guidelines. Furthermore, most guidelines recommended additional types of thyroid function tests to TSH sampling and lower trimester-specific TSH upper reference limits for women on levothyroxine treatment (P < .001). In the follow-up, the thyroid testing rate was 20%, with an overall frequency of women with trimester-specific elevated TSH of 18.5%. More than half of the women (50.9%) who were on levothyroxine treatment at conception had an elevated TSH level at thyroid testing according to The Endocrine Society Guidelines. Conclusions: The local guidelines are variable and poorly compliant with international guidelines. Performance of thyroid testing is not optimal, and rates of elevated TSH at testing are extremely high in subgroups.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-208672 (URN)10.1210/jc.2013-1302 (DOI)000322780600030 ()
    Available from: 2013-10-07 Created: 2013-10-07 Last updated: 2017-12-06Bibliographically approved
    3. Targeted Thyroid Testing During Pregnancy in Clinical Practice
    Open this publication in new window or tab >>Targeted Thyroid Testing During Pregnancy in Clinical Practice
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    2014 (English)In: Obstetrics and Gynecology, ISSN 0029-7844, E-ISSN 1873-233X, Vol. 124, no 1, p. 10-15Article in journal (Refereed) Published
    Abstract [en]

    OBJECTIVE:To evaluate the efficacy of a targeted thyroid testing approach during pregnancy in clinical practice.

    METHODS:This is a retrospective cohort study performed within Uppsala County, Sweden. Data were derived from the population-based Uppsala Biobank of Pregnant Women, in which blood samples are collected in conjunction with the routine ultrasound screening in gestational week 17-19. For this study, 5,254 pregnant women with an estimated date of delivery between January 1, 2009, and December 31, 2011, were included. On review of their medical records, women who were tested for thyroid dysfunction during pregnancy in clinical practice were identified (n=891). From the remaining untested women, 1,006 women were randomly selected for analyses of thyrotropin (TSH), free thyroxine levels, and thyroid peroxidase antibodies. Thyroid-stimulating hormone levels in both groups were analyzed with regard to trimester-specific upper reference levels as recommended by the International Endocrine Society Guidelines.

    RESULTS:The proportion of trimester-specific TSH elevation was 12.6% in the targeted thyroid testing group and 12.1% in the untested group (P=.8; odds ratio [OR] 1.04, 95% confidence interval [CI] 0.79-1.37). The proportion of overt hypothyroidism was 1.1% and 0.7% in the groups, respectively (P=.4; OR 1.57, 95% CI 0.55-4.45).

    CONCLUSIONS:The prevalence of trimester-specific elevated TSH and overt hypothyroidism was equal in targeted thyroid tested and untested women. When implemented in clinical practice, targeted thyroid testing is unsatisfactory. If ongoing studies provide support for treatment of pregnant women with elevated TSH, universal thyroid testing appears the most reasonable approach.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Identifiers
    urn:nbn:se:uu:diva-228696 (URN)10.1097/AOG.0000000000000344 (DOI)000337734000004 ()
    Available from: 2014-07-21 Created: 2014-07-21 Last updated: 2017-12-05Bibliographically approved
    4. Iodine deficiency in a study population of pregnant women in Sweden
    Open this publication in new window or tab >>Iodine deficiency in a study population of pregnant women in Sweden
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    2015 (English)In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 94, no 11, p. 1168-1174Article in journal (Refereed) Published
    Abstract [en]

    Introduction

    Iodine deficiency in utero may impair neurological development of the fetus. In Sweden, iodine nutrition is considered to be adequate in the general population. The aim of this study was to evaluate iodine nutrition during pregnancy in Sweden.

    Material and methods

    In this cross-sectional study, the total study population (= 459) consisted of two cohorts (Värmland County, = 273, and Uppsala County, = 186) of pregnant non-smoking women without pre-gestational diabetes mellitus or known thyroid disease before or during pregnancy. Spot urine samples were collected in the third trimester of pregnancy for median urinary iodine concentration (UIC) analysis.

    Results

    The median UIC in the total study population was 98 μg/L (interquartile range 57–148 μg/L).

    Conclusions

    According to WHO/UNICEF/IGN criteria, population-based median UIC during pregnancy should be 150–249 μg/L. Thus, our results indicate insufficient iodine status in the pregnant population of Sweden. There is an urgent need for further assessments in order to optimize iodine nutrition during pregnancy.

    National Category
    Obstetrics, Gynecology and Reproductive Medicine
    Research subject
    Obstetrics and Gynaecology
    Identifiers
    urn:nbn:se:uu:diva-247420 (URN)10.1111/aogs.12713 (DOI)000362844400004 ()26292156 (PubMedID)
    Available from: 2015-03-18 Created: 2015-03-18 Last updated: 2018-01-24Bibliographically approved
  • 3.
    Granfors, Michaela
    et al.
    Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden;Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden.
    Stephansson, Olof
    Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden;Karolinska Inst, Dept Womens & Childrens Hlth, Div Obstet & Gynecol, Stockholm, Sweden.
    Endler, Margit
    Karolinska Inst, Dept Womens & Childrens Hlth, Div Obstet & Gynecol, Stockholm, Sweden.
    Jonsson, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics.
    Sandström, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden.
    Wikström, Anna-Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Clinical Obstetrics. Karolinska Inst, Dept Med, Div Clin Epidemiol, Stockholm, Sweden.
    Placental location and pregnancy outcomes in nulliparous women: A population-based cohort study2019In: Acta Obstetricia et Gynecologica Scandinavica, ISSN 0001-6349, E-ISSN 1600-0412, Vol. 98, no 8, p. 988-996Article in journal (Refereed)
    Abstract [en]

    Introduction: The impact of placenta previa on pregnancy, delivery and infant outcomes has been extensively studied. However, less is known about the possible association of placental location other than previa with pregnancy outcomes. The aim of this study was to investigate if placental location other than previa is associated with adverse pregnancy, delivery and infant outcomes.

    Material and methods: This is a population-based cohort study, with data from the regional population-based Stockholm-Gotland Obstetric Cohort, Sweden, from 2008 to 2014. The study population included 74 087 nulliparous women with singleton pregnancies resulting in live-born infants, with information about placental location from the second-trimester ultrasound screening. The association between placental location (fundal, lateral, anterior or posterior) and pregnancy outcomes was estimated using logistic regression analysis. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated, and adjustments were made for maternal age, height, country of birth, smoking in early pregnancy, sex of the infant and in vitro fertilization. Main outcome measures were pregnancy, delivery and infant outcomes.

    Results: Compared with posterior placental location, fundal and lateral placental locations were associated with a number of adverse pregnancy outcomes, the most important being: very preterm birth (<32 weeks of gestation) (adjusted OR [aOR] 1.78, 95% CI 1.18-2.63 and aOR 2.12, 95% CI 1.39-2.25, respectively), moderate preterm birth (32-36 weeks of gestation) (aOR 1.23, 95% CI 1.001-1.51 and aOR 1.62, 95% CI 1.32-2.00, respectively), small-for-gestational-age birth (aOR 1.67, 95% CI 1.34-2.07 and aOR 1.77, 95% CI 1.39-2.25, respectively) and manual removal of the placenta in vaginal births (aOR 3.27, 95% CI 2.68-3.99 and aOR 3.27, 95% CI 2.60-4.10, respectively). Additionally, lateral placental location was associated with preeclampsia (aOR 1.30, 95% CI 1.03-1.65) and severe postpartum hemorrhage (aOR 1.42, 95% CI 1.27-1.82).

    Conclusions: Compared with posterior placental location, fundal and lateral placental locations are associated with a number of adverse pregnancy, delivery and infant outcomes.

  • 4.
    Kullinger, Merit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Granfors, Michaela
    Department of Medicine, Solna, Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Science, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Kieler, Helle
    Department of Medicine, Solna; Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Adherence to Swedish national pregnancy dating guidelines and management of discrepancies between pregnancy dating methods: a survey study2019In: Reproductive Health, ISSN 1742-4755, E-ISSN 1742-4755, Vol. 16, article id 95Article in journal (Refereed)
    Abstract [en]

    Background. Swedish national guidelines for pregnancy dating were published in 2010. Follow-up is needed to assess adherence and to identify whether any clinical topics are not covered in the guidelines.

    Methods. All units in Sweden that performed ultrasound-based pregnancy dating were asked to complete a web-based questionnaire comprising multiple-response questions and commentary fields. Information was collected regarding baseline information, current and previous clinical practice, and management of discrepancies between last-menstrual-period- and ultrasound-based methods for pregnancy dating.

    Results. The response rate was 88% (38/43 units). Half of the units offered first-trimester ultrasound to all pregnant women. However, contrary to the guidelines, the crown–rump length was not used for ultrasound-based pregnancy dating in most units. Ultrasound-based pregnancy dating was performed only if the biparietal diameter was between 21 and 55 mm. The methods for management of discrepancies between methods for pregnancy dating varied widely.

    Conclusions. The units reported high adherence to national guidelines, except for early pregnancy dating, for which many units followed unwritten or informal guidelines. The management of discrepancies between last-menstrual-period-based and ultrasound-based estimated day of delivery varied widely. These findings emphasize the need for regular updating of national written guidelines and efforts to improve their implementation in all units.

  • 5.
    Kullinger, Merit
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health). Region Västmanland – Uppsala University, Center for Clinical Research, Hospital of Västmanland Västerås, Sweden.
    Granfors, Michaela
    Department of Clinical Science, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden.
    Kieler, Helle
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Discrepancy between pregnancy dating methods affects obstetric and neonatal outcomes: a population-based register cohort study2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 6936Article in journal (Refereed)
    Abstract [en]

    To assess associations between discrepancy of pregnancy dating methods and adverse pregnancy, delivery, and neonatal outcomes, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for discrepancy categories among all singleton births from the Medical Birth Register (1995–2010) with estimated date of delivery (EDD) by last menstrual period (LMP) minus EDD by ultrasound (US) -20 to +20 days. Negative/positive discrepancy was a fetus smaller/larger than expected when dated by US (EDD postponed/changed to an earlier date). Large discrepancy was <10th or >90th percentile. Reference was median discrepancy ± 2 days. Odds for diabetes and preeclampsia were higher in pregnancies with negative discrepancy, and for most delivery outcomes in case of large positive discrepancy (+9 to +20 days): shoulder dystocia [OR 1.16 (95% CI 1.01–1.33)] and sphincter injuries [OR 1.13 (95% CI 1.09–1.17)]. Odds for adverse neonatal outcomes were higher in large negative discrepancy (–4 to –20 days): low Apgar score [OR 1.18 (95% CI 1.09–1.27)], asphyxia [OR 1.18 (95% CI 1.11–1.25)], fetal death [OR 1.47 (95% CI 1.32–1.64)], and neonatal death [OR 2.19 (95% CI 1.91–2.50)]. In conclusion, especially, large negative discrepancy was associated with increased risks of adverse perinatal outcomes. 

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