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Genetic and epidemiological aspects of implantation defects: Studies on recurrent miscarriage, preeclampsia and oocyte donation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Obstetrics and Gynaecology. (Reproductive Health)
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Implantation requires complex molecular and cellular events involving coagulation, angiogenesis and immunological processes that need to be well regulated for a pregnancy to establish and progress normally.  The overall aim of this thesis was to study different models associated with atypical angiogenesis, impaired implantation and/or placentation, such as recurrent miscarriage (RM), oocyte donation (OD) and preeclampsia.

Histidine-rich glycoprotein (HRG), a serum protein with angiogenic potential has been previously shown to have an impact on implantation and fertility.  In two retrospective case-control studies, women suffering from RM (Study I) and gestational hypertensive disorders (GHD) (Study IV) have been compared to healthy control women, regarding carriership of HRG genotypes (HRG A1042G and C633T SNP, respectively).  According to the findings of this thesis, heterozygous carriers of the HRG A1042G SNP suffer from RM more seldom than homozygous carriers (Study I).  Additionally, the presence of the HRG 633T allele was associated with increased odds of GHD (GHD IV).  Studies II and III comprised a national cohort of relatively young women with optimal health status conceiving singletons with donated oocytes versus autologous oocytes (spontaneously or via IVF).  We explored differences in various obstetric (Study II) and neonatal (Study III) outcomes from the Swedish Medical Birth Register.  Women conceiving with donated oocytes had a higher risk of GHD, induction of labor and cesarean section, as well as postpartum hemorrhage and retained placenta, when compared to autologously conceiving women.  OD infants had higher odds of prematurity and lower birthweight and length when born preterm, compared to neonates from autologous oocytes.  With regard to the indication of OD treatment, higher intervention but neverthelss favourable neonatal outcomes were observed in women with diminished ovarian reserve; the risk of GHD did not differ among OD recipients after adjustment.

In conclusion, HRG genetic variation appears to contribute to placental dysfunction disorders.  HRG is potential biomarker that may contribute in the prediction of the individual susceptibility for RM and GHD.  Regarding OD in Sweden, the recipients-despite being of optimal age and health status- need careful preconceptional counselling and closer prenatal monitoring, mainly due to increased prevalence of hypertensive disorders and prematurity.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1270
Keyword [en]
Angiogenesis, genetic polymorphism, gestational hypertensive disorders, Histidine-rich glycoprotein, HRG, implantation defect, oocyte donation, placentation, preeclampsia, recurrent miscarriage, SNP.
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
URN: urn:nbn:se:uu:diva-305852ISBN: 978-91-554-9736-1OAI: oai:DiVA.org:uu-305852DiVA: diva2:1039317
Public defence
2016-12-09, Rosensalen, Kvinnokliniken, Ing 95/96, Akademiska Sjukhuset, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2016-11-16 Created: 2016-10-22 Last updated: 2016-11-28
List of papers
1. The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study
Open this publication in new window or tab >>The histidine-rich glycoprotein A1042G polymorphism and recurrent miscarriage: a pilot study
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2014 (English)In: Reproductive Biology and Endocrinology, ISSN 1477-7827, Vol. 12, 70- p.Article in journal (Refereed) Published
Abstract [en]

Background: Histidine-rich Glycoprotein (HRG) has previously been shown to have an impact on implantation and fertility. The aim of this study was to investigate if there is an association between the HRG A1042G single nucleotide polymorphism (SNP) and recurrent miscarriage. Methods: The study was designed as a case-control study and the women were included at University Hospitals in Sweden. 186 cases with recurrent miscarriage were compared with 380 pregnant controls with no history of miscarriage. Each woman was genotyped for the HRG A1042G SNP. Results: The results indicated that the frequency of heterozygous HRG A1042G carriers was higher among controls compared to cases (34.7% vs 26.3%; p < 0.05). In a bivariate regression analysis, a negative association was found between recurrent miscarriage and heterozygous A/G carriers both in the entire study population (OR 0.67, 95% CI 0.45 - 0.99; p < 0.05) as well as in a subgroup of women with primary recurrent miscarriage (OR 0.37, 95% CI 0.16 - 0.84; p < 0.05). These results remained even after adjustment for known confounders such as age, BMI and thyroid disease (OR 0.36, 95% CI 0.15 - 0.84; p < 0.05). Conclusions: Women who are heterozygous carriers of the HRG A1042G SNP suffer from recurrent miscarriage more seldom than homozygous carriers. Thus, analysis of the HRG A1042G SNP might be of importance for individual counseling regarding miscarriage.

Keyword
Histidine-rich glycoprotein, Recurrent miscarriage, Single nucleotide polymorphism
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-231117 (URN)10.1186/1477-7827-12-70 (DOI)000339590200001 ()25064236 (PubMedID)
Available from: 2014-09-05 Created: 2014-09-04 Last updated: 2016-10-23Bibliographically approved
2. Adverse obstetric outcomes in pregnancies resulting from oocyte donation: a retrospective cohort case study in Sweden
Open this publication in new window or tab >>Adverse obstetric outcomes in pregnancies resulting from oocyte donation: a retrospective cohort case study in Sweden
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2015 (English)In: BMC Pregnancy and Childbirth, ISSN 1471-2393, E-ISSN 1471-2393, Vol. 15, 247Article in journal (Refereed) Published
Abstract [en]

Background: Oocyte donation has been associated to gestational diabetes, hypertensive disorders, placental abnormalities, preterm delivery and increased rate of caesarean delivery while simultaneously being characterized by high rates of primiparity, advanced maternal age and multiple gestation constituting the individual risk of mode of conception difficult to assess. This study aims to explore obstetrical outcomes among relatively young women with optimal health status conceiving singletons with donated versus autologous oocytes (via IVF and spontaneously). Methods: National retrospective cohort case study involving 76 women conceiving with donated oocytes, 150 nulliparous women without infertility conceiving spontaneously and 63 women conceiving after non-donor IVF. Data on obstetric outcomes were retrieved from the National Birth Medical Register and the medical records of oocyte recipients from the treating University Hospitals of Sweden. Demographic and logistic regression analysis were performed to examine the association of mode of conception and obstetric outcomes. Results: Women conceiving with donated oocytes (OD) had a higher risk of hypertensive disorders [adjusted Odds Ratio (aOR) 2.84, 95 % CI (1.04-7.81)], oligohydramnios [aOR 12.74, 95 % CI (1.24-130.49)], postpartum hemorrhage [aOR 7.11, 95 % CI (2.02-24.97)] and retained placenta [aOR 6.71, 95 % CI (1.58-28.40)] when compared to women who conceived spontaneously, after adjusting for relevant covariates. Similar trends, though not statistically significant, were noted when comparing OD pregnant women to women who had undergone non-donor IVF. Caesarean delivery [aOR 2.95, 95 % CI (1.52-5.71); aOR 5.20, 95 % CI (2.21-12.22)] and induction of labor [aOR 3.00, 95 % CI (1.39-6.44); aOR 2.80, 95 % CI (1.10-7.08)] occurred more frequently in the OD group, compared to the group conceiving spontaneously and through IVF respectively. No differences in gestational length were noted between the groups. With regard to the indication of OD treatment, higher intervention was observed in women with diminished ovarian reserve but the risk for hypertensive disorders did not differ after adjustment. Conclusion: The selection process of recipients for medically indicated oocyte donation treatment in Sweden seems to be effective in excluding women with severe comorbidities. Nevertheless, oocyte recipients-despite being relatively young and of optimal health status-need careful counseling preconceptionally and closer monitoring prenatally for the development of hypertensive disorders.

Keyword
Hypertensive disorders, Indication for oocyte donation, Oocyte donation, Pregnancy complications
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:uu:diva-265819 (URN)10.1186/s12884-015-0687-9 (DOI)000362473900002 ()26450684 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2015-11-03 Created: 2015-11-03 Last updated: 2016-10-23Bibliographically approved
3. Neonatal outcomes in pregnancies resulting from oocyte donation: a cohort study in Sweden
Open this publication in new window or tab >>Neonatal outcomes in pregnancies resulting from oocyte donation: a cohort study in Sweden
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2016 (English)In: BMC Pediatrics, ISSN 1471-2431, E-ISSN 1471-2431, Vol. 16, 170Article in journal, Editorial material (Refereed) Published
Abstract [en]

Background: Pregnancies resulting through oocyte doantion have been associated with increased risk for adverse outcomes for the mother, such as gestational hypertensive disorders. However, little is known about possible neonatal complications of such pregnancies. The purpose of this study was to evaluate the neonatal health outcomes among singleton pregnancies in a population of relatively young and healthy oocyte recipients in Sweden, taking into account the medical indication leading to treatment.

Methods: This cohort study involved 76 women conceiving with donated oocytes, 149 age-matched nulliparous women conceiving spontaneously and 63 women conceiving after non-donor IVF. Participants were recruited during 2005-2008 and followed up until delivery. Data on neonatal outcomes were retrieved from the National Birth Medical Register and the medical records of oocyte recipients from seven Swedish University Hospitals with IVF clinics. Logistic regression analyses were performed to examine the association of mode of conception and neonatal outcomes, adjusted for maternal age and BMI, gestational age and delivery by cesarean section.

Results: Infants conceived through oocyte donation had higher odds for premature delivery( OR 2.36, 95%CI(1.02-5.45)), for being small for gestational age (OR 4.23, 95%CI(1.03-17.42)), and having Apgar score below 7 at 5 min(OR 10.57, 95%CI(1.21-92.20)) compared to spontaneously conceived infants. Similar trends were observed when comparing infants conceived through oocyte donatiion to those conceived by traditional IVF. Furthermore, donor oocyte infants had a lower mean birthweight and length compared to autologous oocyte neonates (p=0.0013); however, no differences were noted among infants born at term. Neonatal outcomes were more favorable among women with diminished ovarian reserve compared to those with other indications for oocyte donation.

Conclusions: Infants conceived after oocyte donation in Sweden have higher odds of being born prematurely and having lower mean birthweight in comparison to non-donor infants. It seems that these unfavorable neonatal outcomes are present despite the age, weight and health restrictions applied to recipients before oocyte donation treatment in Sweden.

Keyword
Donor conception, indication for oocyte donation, IVF, neonatal morbidity, neonatal outcomes, newborns, oocyte donation.
National Category
Pediatrics
Research subject
Pediatrics
Identifiers
urn:nbn:se:uu:diva-305848 (URN)10.1186/s12887-016-0708-5 (DOI)000385897800003 ()27769207 (PubMedID)
Funder
Forte, Swedish Research Council for Health, Working Life and Welfare
Available from: 2016-10-22 Created: 2016-10-22 Last updated: 2016-11-21Bibliographically approved
4. HRG C688T polymorphism and risk of gestational hypertensive disorders: a pilot study
Open this publication in new window or tab >>HRG C688T polymorphism and risk of gestational hypertensive disorders: a pilot study
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2016 (English)Article in journal, Editorial material (Refereed) Submitted
National Category
Obstetrics, Gynecology and Reproductive Medicine
Research subject
Obstetrics and Gynaecology
Identifiers
urn:nbn:se:uu:diva-305849 (URN)
Available from: 2016-10-22 Created: 2016-10-22 Last updated: 2016-10-23

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