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ABSTRACT: Association between the histidine-rich glycoprotein (HRG) C633T single nucleotide polymorphism (SNP) and recurrent miscarriage was investigated in a case-control study. The cases constituted 187 women with recurrent miscarriage that were compared with 395 controls who had delivered a child and had no history of miscarriage. Blood samples were collected from each woman, genomic DNA was extracted and genotyped for the HRG C633T SNP. In the whole study population, the percentage of miscarriage was the same, regardless of genotype (C/C 31.2%, C/T 32.9% and T/T 32.5%). However, an association between homozygous T/T carriers and recurrent miscarriage was detected in a subgroup of women with primary recurrent miscarriage (odds ratio 2.44, 95% CI 1.01-5.92). Our results indicate an important role for the HRG C633T SNP in the occurrence of recurrent miscarriage.
Acta Obstetricia Et Gynecologica Scandinavica 04/2013; · 1.77 Impact Factor
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ABSTRACT: BACKGROUND: Obesity among fertile women is a global problem. 25% of pregnant Swedish women are overweight at admission to the antenatal clinic and 12% of them are considered as obese. Previous studies have shown an increased risk of delivery complications with an elevated maternal BMI. The aim of this study was to evaluate delivery outcomes in relation to maternal BMI on admission to the antenatal clinic.A healthy group of 787 women with full-term pregnancies and spontaneous onset of labor were included in the study. Delivery outcome was assessed in relation to maternal BMI when attending the antenatal clinic. RESULTS: The results indicated that in deliveries where the maternal BMI was >30 a high frequency of abnormal CTG trace during the last 30 minutes of labor was shown. A blood sample for evaluation of risk of fetal hypoxia was performed in only eight percent of these deliveries. A spontaneous vaginal delivery without intervention was noted in 85.7 %, and 12% of neonates were delivered with an adverse fetal outcome compared to 2.8% in the group with a maternal BMI<30 (p<0.001) CONCLUSION: These results indicate an increased risk at delivery for healthy, but obese women in labor. Furthermore, the delivery management may not always be optimal in these deliveries.
BMC Research Notes 02/2013; 6(1):50.
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ABSTRACT: 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.
BMC Medical Genetics 12/2012; 13(1):121. · 2.33 Impact Factor
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ABSTRACT: Background
Preeclampsia is associated with both maternal and perinatal morbidity and mortality. Histidine-rich glycoprotein (HRG) is a protein interacting with angiogenesis, coagulation, and inflammatory responses, processes known to be altered in preeclamptic pregnancies. Significantly lower levels of HRG have been demonstrated as early as in the first trimester in women later developing preeclampsia compared with normal pregnancies. The aim of this study was to investigate whether the combination of HRG and uterine artery Doppler ultrasonography can be used as a predictor of preeclampsia.MethodsA total of 175 women were randomly selected from a case-control study; 86 women had an uncomplicated pregnancy and 89 women later developed preeclampsia. Blood samples and pulsatility index (PI) were obtained from both cases and controls in gestational week 14.ResultsHRG levels were significantly lower in women who developed preterm preeclampsia compared with controls, but not for women developing preeclampsia in general. PI was significantly higher in the preeclampsia group compared with controls, especially in preterm preeclampsia. The combination of HRG and PI revealed a sensitivity of 91% and a specificity of 62% for preterm preeclampsia.Conclusions
The combination of HRG and uterine artery Doppler may predict preterm preeclampsia in early pregnancy.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.112.
American Journal of Hypertension 08/2012; · 3.18 Impact Factor
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ABSTRACT: The human µ-opioid receptor (MOR) is the major site of action of endogenous opioids and most of the clinically used opioid analgesics. The single-nucleotide polymorphism (SNP), A118G of the MOR 1 gene (OPRM1), has been associated with altered pain perception. The aim of this study was to investigate whether this polymorphism of OPRM1 is associated with a number of pain-related behaviors during labor. In this observational retrospective population-based study, pregnant women (n = 814) were recruited at gestational week 18. A plasma sample was collected from each participant and an SNP genotyping assay was performed. No differences in sociodemographic variables or labor pain-related outcomes, such as stage of cervical dilation on arrival at the delivery unit or use of any type of second-line analgesia during spontaneous labor, were found between noncarriers and G-allele carriers of OPRM1. We conclude that there is no association between the A118G polymorphism of OPRM1 regarding pain-related behavior during labor.
Reproductive sciences (Thousand Oaks, Calif.) 04/2012; 19(9):962-7. · 2.31 Impact Factor
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ABSTRACT: Stress regulation during pregnancy is considered to be connected to the timing of labour initiation. Although increasing knowledge is emerging on the regulation of parturition, there is currently no way to predict the start of spontaneous labour in women. The main aim of this study was to assess pain threshold and the sympathetic nervous system response to cold pain in relation to the onset of labour in healthy pregnant women. Ninety-three pregnant women were recruited and assessed for skin conductance (SC) activity during a cold pressor test in gestational week 38. Pain threshold and cold endurance were also measured and the results were compared with data obtained from hospital records. Seventy-four women had a spontaneous labour onset and a valid SC measurement. SC activity during the cold pressor test decreased significantly with the number of days left to spontaneous parturition. This may indicate a gradual decrease in sympathetic autonomic nervous system reactivity even during the last weeks of pregnancy. Measuring SC activity during mild stress provocation is a rapid and non-invasive means to study variation in sympathetic reactivity during pregnancy, and may be useful in research on stress regulation in pregnancy and its relation to labour initiation.
Stress (Amsterdam, Netherlands) 09/2011; 14(6):627-33. · 3.21 Impact Factor
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ABSTRACT: To estimate whether a high lactate concentration in amniotic fluid, together with cardiotocography, can be used as an indicator for an increased risk of adverse neonatal outcome at delivery.
A prospective cohort study was performed at two tertiary center labor wards in Sweden. Healthy women with full-term, singleton pregnancies and cephalic presentation in spontaneous active labor were included in the study (N=825). Lactate concentration in samples of amniotic fluid collected in the course of vaginal examinations during labor were correlated with cardiotocography 30 minutes before delivery and a composite score for adverse neonatal outcome.
High lactate concentration in amniotic fluid (greater than 10.1 mmol/L) was associated with an adverse neonatal outcome (odds ratio [OR] 4.4, 95% confidence interval [CI] 2.3-8.2). Fetal bradycardia within 30 minutes before delivery was also associated with an increased risk of adverse neonatal outcome (OR 7.4, 95% CI 3.04-18.11). If lactate in amniotic fluid was greater than 10.1 mmol/L and bradycardia was seen together, the risk of delivering a neonate with an adverse neonatal outcome was increased 11-fold (OR 10.7, 95% CI 3.7-31.7).
High lactate concentration in amniotic fluid and fetal bradycardia during the last 30 minutes before delivery indicate an increased risk of adverse neonatal outcome at delivery.
Obstetrics and Gynecology 07/2011; 118(1):135-42. · 4.73 Impact Factor
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ABSTRACT: To evaluate the rate of discrepancy between pH and lactate values in fetal blood sampling (FBS). To evaluate differences in obstetric management in response to combined tests (pH and lactate) and single tests (pH or lactate).
Descriptive study.
Uppsala University Hospital, Sweden.
Labors monitored by FBS during one year (n=241).
Discrepancy in the combined tests was defined as a test having one abnormal and one normal value. Abnormal pH was defined as 7.24 or lower and abnormal lactate as 4.2 or higher. The results were categorized according to whether the test was normal or abnormal and according to whether it was a combined or single analysis.
Discrepancy between pH and lactate values in combined tests. Frequency of operative delivery for fetal distress (ODFD). Time interval from the last FBS to ODFD.
In the combined tests with abnormality, a discrepancy between pH and lactate values occurred in 55%. The mean time interval from the last FBS to ODFD was longer in combined tests with one abnormal compared with two abnormal test results, 75 vs. 37 minutes (p<0.05). Operative delivery for fetal distress was performed less often after combined tests than after single tests: 41/62 (66%) vs. 19/20 (95%) (p<0.05).
In the combined test, discrepancies were common and occurred in half of the samples with an abnormality. Obstetric management was influenced by the discrepancy between test results with respect to ODFD rates and the time interval from the last FBS to delivery.
Acta Obstetricia Et Gynecologica Scandinavica 06/2011; 90(10):1088-93. · 1.77 Impact Factor
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ABSTRACT: The primary aim was to assess pain subjectively and objectively in women during insertion of a Foley catheter for induction of labor. A secondary aim was to assess pain during cervical ripening and to evaluate maternal satisfaction.
Randomized controlled trial.
University hospital, Sweden.
Forty-two women undergoing induction of labor and cervical ripening with a Foley catheter.
Women were randomly allocated to digital (n=21) or to speculum (n=21) placement of a Foley catheter. A visual analogue scale (VAS) was used for subjective assessment of pain and, for objective measurements, a skin conductance algesimeter was used and the area under the curve (AUC) was calculated (μSs). Maternal satisfaction was evaluated in a questionnaire.
Pain sensation during placement of the Foley catheter.
There was a significant difference between groups in pain measurements during insertion of the Foley catheter. The speculum group had higher median pain scores than the digital group, VAS=5 vs. = 3 (p=0.03) and greater median AUC measurements: 1840 vs. 823 μSs (p=0.04). There was no difference in pain assessments during cervical ripening. Overall satisfaction scores were high and comparable between groups.
Digital placement of the Foley catheter is subjectively and objectively less painful compared to the use of a speculum. Digital placement should therefore be considered as an alternative in the management of these patients. Ripening of the cervix with the Foley catheter is well tolerated and the overall satisfaction rate among patients induced with this method is high.
Acta Obstetricia Et Gynecologica Scandinavica 05/2011; 90(9):997-1004. · 1.77 Impact Factor
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ABSTRACT: Histidine-rich glycoprotein (HRG) is involved in fibrinolysis and coagulation, the immune system and angiogenesis. These processes are all crucial in establishing and maintaining pregnancy. The primary aim of this pilot study was to determine if HRG affects pregnancy outcome. The secondary aim was to investigate if a specific genetic polymorphism (rs9898 C/T) in the HRG gene is associated with pregnancy results. The polymorphism leads to expression of either a serine or proline residue at position 186 in the protein sequence. In this study, women undergoing IVF were included. The genetic polymorphism in the HRG gene was analysed by Western blot and single nucleotide polymorphism analysis. None of the women homozygous for the serine at residue 186 became pregnant whereas the women homozygous for proline at residue 186 had higher than expected pregnancy rates. As far as is known,this is the first study to show that a specific genetic polymorphism in the HRG gene of a woman affects her chances of becoming pregnant after IVF. The results may be essential in improving advice and IVF treatment for couples with unexplained infertility.
Reproductive biomedicine online 04/2011; 23(2):213-9. · 2.04 Impact Factor
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ABSTRACT: Prediction of preeclampsia is of great interest and the coagulation system as well as the angiogenic pathway is known to be dysfunctional in preeclampsia. Histidine-rich glycoprotein (HRG) is a protein interacting with both these biological systems and the purpose of this prospective, longitudinal cohort study was to analyze whether there is a difference in circulating levels of HRG during pregnancy in women developing preeclampsia compared to normal healthy pregnancies. We furthermore wanted to evaluate whether HRG has the potential of being an early biomarker of preeclampsia.
A cohort of healthy pregnant women (n = 469) was enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37 and analyzed with an enzyme-linked immunosorbent assay.
The levels of HRG decreased during pregnancy in all women, but the levels were significantly lower at gestational weeks 10, 25, and 28 in women who later developed preeclampsia than in normal pregnant women (P < 0.05, P < 0.05, and P < 0.05).
Our data indicates that HRG levels in plasma might be a possible biomarker already in gestational week 10 for prediction of later onset of preeclampsia in a low risk population.
American Journal of Hypertension 01/2011; 24(4):496-501. · 3.18 Impact Factor
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ABSTRACT: A well-regulated angiogenesis is crucial for proper embryo implantation, embryogenesis, and pregnancy development. Monitoring the presence and distribution of angiogenic regulators in the female reproductive tract and in the early embryo is important for a broader understanding of the molecular aspects of fertility, embryogenesis, and pregnancy. Histidine-rich glycoprotein (HRG) is a glycoprotein involved in angiogenesis. Its presence in the female reproductive tract or in embryos has not previously been studied. Follicular fluid, culture medium, and embryos were obtained from patients undergoing in vitro fertilization (IVF). Biopsies from inner genitalia and placenta were collected at surgery. Histidine-rich glycoprotein presence was investigated by immunohistochemistry and Western blot. Polymerase chain reaction (PCR) was used to determine HRG expression in tissues or by embryos. We identified HRG in follicular fluid, the female reproductive tract, and placenta, as well as in the embryos. Moreover, HRG expression was observed in blastocysts. Thus, the angiogenic properties of HRG might affect fertility.
Reproductive sciences (Thousand Oaks, Calif.) 10/2010; 17(10):941-7. · 2.31 Impact Factor
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ABSTRACT: Previous publications have suggested that high levels of lactate in amniotic fluid (AF) correlate with dysfunctional labor. The aim of this study was to investigate whether lactate concentration in AF together with the partogram is a better predictor of operative intervention in dysfunctional labor than the partogram alone.
A prospective observational study was carried out of 825 laboring women. Samples of AF were collected and the lactate concentration was analyzed at the bedside during labor. The main outcome of the study was the method of delivery (operative/spontaneous vaginal) in relation to the concentration of lactate in AF. Logistic regression was used to estimate the association between lactate concentration in AF and labor outcome and to adjust for well-known risk factors for dysfunctional labor.
385/825 women had an arrested labor according to the partogram, and 193 of them were delivered operatively. High lactate in AF (>10.1 mmol/l) when labor arrested was associated with an increased risk of operative intervention due to dysfunctional labor (adjusted OR, 5.4, 95% CI, 3.2-9.1). Low levels of lactate in AF (<10.1 mmol/l) were associated with an increased probability of spontaneous vaginal delivery (adjusted OR, 2.7, 95% CI, 1.7-4.8).
The partogram together with the concentration of lactate in AF is a better predictor of operative intervention in dysfunctional labor than the partogram alone.
European journal of obstetrics, gynecology, and reproductive biology 09/2010; 152(1):34-8. · 1.97 Impact Factor
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ABSTRACT: Beta-endorphins are endogenous opioid substances produced by the pituitary gland and placenta. The aims of this project were to longitudinally follow plasma levels of beta-endorphin during pregnancy in women with a healthy pregnancy and to investigate whether plasma levels of beta-endorphin in late pregnancy are associated with need for additional pain medication beyond nitrous oxide during labor. Plasma samples from 45 women were collected at gestational weeks 10, 25, 28, 33 and 37, and beta-endorphin was analyzed by radioimmunoassay (RIA). Plasma levels of beta-endorphin displayed a significant decrease in gestational weeks 28 and 33 compared to week 10, followed by a subsequent increase between gestational weeks 28 and 37. However, there was no change in levels of beta-endorphin between gestational weeks 10 and 37. Low levels of beta-endorphin at the end of pregnancy were associated with need for additional pain medication beyond nitrous oxide during labor, although the causal relationship is unclear.
Reproductive sciences (Thousand Oaks, Calif.) 08/2010; 17(8):742-7. · 2.31 Impact Factor
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ABSTRACT: The aim of this study was to investigate if there is an association between different SNP combinations in the guanosine triphosphate cyclohydrolase (GCH1) gene and a number of pain behavior related outcomes during labor. A population-based sample of pregnant women (n = 814) was recruited at gestational week 18. A plasma sample was collected from each subject. Genotyping was performed and three single nucleotide polymorphisms (SNP) previously defined as a pain-protective SNP combination of GCH1 were used.
Homozygous carriers of the pain-protective SNP combination of GCH1 arrived to the delivery ward with a more advanced stage of cervical dilation compared to heterozygous carriers and non-carriers. However, homozygous carriers more often used second line labor analgesia compared to the others.
The pain-protective SNP combination of GCH1 may be of importance in the limited number of homozygous carriers during the initial dilation of cervix but upon arrival at the delivery unit these women are more inclined to use second line labor analgesia.
Molecular Pain 01/2010; 6:41. · 3.53 Impact Factor
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Asa Thulin,
Maria Ringvall,
Anna Dimberg,
Karin Kårehed,
Timo Väisänen,
Marja-Riitta Väisänen,
Osama Hamad,
Jian Wang,
Rolf Bjerkvig,
Bo Nilsson,
Taina Pihlajaniemi, Helena Akerud,
Kristian Pietras,
Wilhelm Jahnen-Dechent,
Agneta Siegbahn,
Anna-Karin Olsson
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ABSTRACT: The angiogenesis inhibitor histidine-rich glycoprotein (HRG) constitutes one of several examples of molecules regulating both angiogenesis and hemostasis. The antiangiogenic properties of HRG are mediated via its proteolytically released histidine- and proline-rich (His/Pro-rich) domain. Using a combination of immunohistochemistry and mass spectrometry, we here provide biochemical evidence for the presence of a proteolytic peptide, corresponding to the antiangiogenic domain of HRG, in vivo in human tissue. This finding supports a role for HRG as an endogenous regulator of angiogenesis. Interestingly, the His/Pro-rich peptide bound to the vessel wall in tissue from cancer patients but not to the vasculature in tissue from healthy persons. Moreover, the His/Pro-rich peptide was found in close association with platelets. Relesate from in vitro-activated platelets promoted binding of the His/Pro-rich domain of HRG to endothelial cells, an effect mediated by Zn(2+). Previous studies have shown that zinc-dependent binding of the His/Pro-rich domain of HRG to heparan sulfate on endothelial cells is required for inhibition of angiogenesis. We describe a novel mechanism to increase the local concentration and activity of an angiogenesis inhibitor, which may reflect a host response to counteract angiogenesis during pathologic conditions. Our finding that tumor angiogenesis is elevated in HRG-deficient mice supports this conclusion.
Molecular Cancer Research 11/2009; 7(11):1792-802. · 4.29 Impact Factor
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ABSTRACT: To determine whether plasma levels of fibrinogen and the placental tissue distributions of fibrinogen and histidine-rich glycoprotein (HRG) differ between early- and late-onset preeclampsia.
The study comprised 18 women with early-onset (gestational weeks 24-32) and 19 women with late-onset (gestational weeks 35-42) preeclampsia. As controls concerning the plasma levels of fibrinogen, we used samples from non-pregnant fertile women, healthy pregnant women at gestational weeks 24-32 and healthy pregnant women at gestational weeks 35-42. Placental samples from women with healthy pregnancies at gestational weeks 35-42 served as controls in the immunohistochemical staining.
Uppsala University Hospital, Uppsala.
Plasma fibrinogen levels were analyzed and the placental tissue expression of fibrinogen and HRG determined by immunohistochemistry.
Plasma level of fibrinogen was increased in early-onset, but not late-onset, preeclampsia. Levels of fibrinogen were significantly lower, and that of HRG significantly higher, in placentas from women with early-onset preeclampsia as compared with control placentas (p = 0.01 and 0.001).
HRG and fibrinogen might be involved in the hypercoagulability and the angiogenic imbalance seen in early-onset preeclampsia.
Acta Obstetricia Et Gynecologica Scandinavica 11/2009; 89(1):131-9. · 1.77 Impact Factor
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ABSTRACT: It is generally believed that a relationship exists between muscle fatigue and intracellular accumulation of lactate. This reasoning is relevant to obstetrical issues. Myocytes in uterus work together during labor, and the contractions need to be strong and synchronized for a child to be delivered. At labor dystocia, the progress of labor becomes slow or arrested after a normal beginning. It has been described that, during labor dystocia, when the force of the contractions is low, the uterus is under hypoxia, and anaerobic conditions with high levels of lactate in amniotic fluid dominate. The purpose of this study was to examine whether myometrial cells are involved in the production of lactate in amniotic fluid and whether there are differences in production and distribution of lactate in cells incubated under aerobic and anaerobic conditions. We also wanted to elucidate the involvement of specific membrane-bound lactate carriers. Women undergoing elective caesarean section were included. Myometrial biopsies from uteri were collected and subjected to either immunohistochemistry to identify lactate carriers or in vitro experiments to analyze production of lactate. The presence of lactate carriers named monocarboxylate transporters 1 and 4 was verified. Myometrial cells produced lactate extracellularly, and the lactate carriers operated differently under anaerobic and aerobic conditions; while being mainly unidirectional under anaerobic conditions, they became bidirectional under aerobic conditions. Human myometrial cells produced and delivered lactate to the extracellular medium under both anaerobic and aerobic conditions. The delivery was mediated by lactate carriers.
AJP Endocrinology and Metabolism 10/2009; 297(6):E1414-9. · 4.75 Impact Factor
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ABSTRACT: Changes in circulating angiogenic factors seem to play a key role in the pathogenesis of preeclampsia and it seems as if these changes are of greater importance in the pathogenesis of early-onset than of late-onset disease. Endostatin is a potent, broad spectrum antagonist of angiogenesis whose role in preeclampsia is poorly investigated. The aim of this study was to estimate whether circulating endostatin levels are altered in preeclampsia, and whether women with early-onset (before 32 weeks of gestation; n = 16) and late-onset (after 35 weeks of gestation; n = 19) preeclampsia differ in this regard. Women with early-onset, but not of late-onset preeclampsia had higher levels of endostatin than healthy pregnant women in corresponding lengths of gestation. The results of the study support the hypothesis that there is heterogeneity between early- and late-onset preeclampsia, with a stronger association between an altered angiogenic balance and early-onset than late-onset disease.
Reproductive sciences (Thousand Oaks, Calif.) 07/2009; 16(10):995-1000. · 2.31 Impact Factor
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ABSTRACT: A number of different biophysical and biochemical markers have been proposed as predictors of preeclampsia. Factors involved in the angiogenic balance are suggested as candidate markers. The purpose of this prospective, longitudinal cohort study was to determine whether a ratio between Angiopoietin-1 (Ang-1) and Angiopoietin-2 (Ang-2) can be used to predict preeclampsia in a low-risk population.
A cohort of healthy pregnant women (n = 469) were enrolled at gestational weeks 8-12. Plasma samples were collected at gestational weeks 10, 25, 28, 33, and 37. By using commercially available enzyme-linked immunosorbent assay kits Ang-1 and Ang-2 were analyzed.
The median Ang-1/Ang-2 ratio increased during pregnancy in all women, but the ratios were significantly lower at gestational weeks 25 and 28 in women who later developed preeclampsia than in normal pregnant women (1.49 compared to 2.19 and 2.12 compared to 3.54, P < 0.05 and P < 0.05).
Our data indicate that in a low-risk population of women the Ang-1/Ang-2 ratio in plasma constitutes a possible biomarker for prediction of later onset of preeclampsia.
American Journal of Hypertension 05/2009; 22(8):891-5. · 3.18 Impact Factor
