Veli-Matti Ulander

Cesarean delivery in Finland: maternal complications and obstetric risk factors

Objective. To assess the rate of maternal complications related to cesarean section (CS) and to compare morbidity between elective, emergency and crash‐emergency CS. To establish risk factors associated with maternal CS morbidity. Design. A prospective multicenter cohort study. Setting. Twelve delivery units in Finland. Population. Women delivering by CS (n = 2,496) during a 6 months period in the study hospitals. Methods. Data on pregnant women, CS, and maternal recovery during the hospital stay was collected prospectively on report forms. The complication rates by different CSs were calculated, and factors associated with morbidity were analyzed by odds ratios (OR). Main outcome measures. Maternal complication rates in different types of CS. The association of risk factors with morbidity. Results. About 27% of women delivering by CS had complications; 10% had severe complications. The complication rate was higher in emergency CS than in elective CS, and highest in crash‐emergency CS. Significant independent risk factors for maternal morbidity were emergency CS and crash‐emergency CS compared to elective CS (OR 1.8; 95% confidence interval (CI) 1.5–2.2), pre‐eclampsia (OR 1.5; CI 1.1–2.0), maternal obesity (OR 1.4; CI 1.1–1.8) and maternal increasing age (OR 1.1; CI 1.03–1.2 per each 5 years). Conclusions. Maternal complications are frequent in CS, and although performing CS electively reduces the occurrence of complications, the frequency is still high. The complication rate depends on the degree of emergency, and increases with maternal obesity, older age and pre‐eclampsia.

Chorionic Gonadotropin β-Gene Variants Are Associated with Recurrent Miscarriage in Two European Populations

CONTEXT The incidence of recurrent miscarriage (RM) (>or=3 consecutive pregnancy losses) is estimated as 1-2% in fertile couples. Familial clustering of RM has suggested the contribution of a genetic component. OBJECTIVE A low level of human chorionic gonadotropin (HCG) in maternal serum during the first trimester of the pregnancy is a clinically accepted risk factor for miscarriage. We sought to study whether variation in chorionic gonadotropin beta-subunit genes (CGBs) expressed in placenta may contribute to the risk of RM. DESIGN Resequencing of CGB5 and CGB8, the two most actively transcribed loci of the four HCG beta-duplicate genes, was performed. SETTING A case-control study involving two sample sets, from Estonia (n = 194) and Finland (n = 185), was performed. PATIENTS RM patients (n = 184) and fertile controls (n = 195) participated in the study. RESULTS From 71 identified variants in CGB5 and CGB8, 48 polymorphisms were novel. Significant protective effect was associated with two single nucleotide polymorphisms located at identical positions in intron 2 in both CGB5 [P = 0.007; odds ratio (OR) = 0.53] and CGB8 (P = 0.042; OR = 0.15), and with four CGB5 promoter variants (P < 0.03; OR = 0.54-0.58). The carriers of minor alleles had a reduced risk of RM. The haplotype structure of the CGB8 promoter was consistent with balancing selection; a rare mutation in CGB8 initiator element was detected only among patients (n = 3). In addition, three rare nonsynonymous substitutions were identified among RM cases as possible variants increasing the risk of recurrent pregnancy loss. CONCLUSION The findings encourage studying the functional effect of the identified variants on CGB expression and HCG hormone activity to elucidate further the role of CGB variation in RM.

Are health expectations of term breech infants unrealistically high

Background.  The aim of this study was to compare the effect of fetal presentation and mode of delivery on infant outcome in a nation‐wide study.

Treatment of deep venous thrombosis with low-molecular-weight heparin during pregnancy.

Low-molecular-weight (LMW) heparins have been shown to be at least as effective as unfractionated (UF) heparin in the treatment of deep venous thrombosis (DVT) in nonpregnant subjects. LMW heparins have been shown to be safe when used during pregnancy as they do not cross the placenta. Up to now, they have been used mainly in thromboprophylaxis during pregnancy and rarely in the treatment of acute DVT in pregnant women. In a prospective observational study, we compared the effectiveness and safety of the LMW heparin, dalteparin, with UF heparin in the initial treatment (first week) of DVT during pregnancy. After confirmation of DVT by ultrasonography, 10 women were treated with UF heparin (25,430 IU/day, mean) and 21 women with dalteparin (16,000 IU/day, mean) for 7 days and, thereafter, all women were given treatment doses of LMW heparin for another 2 weeks. The dose was then gradually decreased and kept at a high prophylactic dose until delivery. One patient in the dalteparin group had recurrence of DVT 2 weeks after starting the treatment. No differences were observed between the groups in symptoms or bleeding complications during pregnancy and delivery. Our results indicate that LMW heparin is as effective and safe as UF heparin for the first week of treatment, but LMW heparin has the advantage of being easily administered and few laboratory controls are required.

Sex chromosome characteristics and recurrent miscarriage

OBJECTIVE To investigate whether skewed X chromosome inactivation (XCI) and Y chromosome microdeletions are associated with recurrent miscarrige (RM). DESIGN A retrospective study. SETTING University hospital and genetic laboratory. PATIENT(S) Altogether, 46 women with a history of RM, defined as at least three miscarriages, and a control group of 95 women with no history of miscarriage were included in the XCI study. In the Y chromosome microdeletion study 40 male partners of women with RM were studied. INTERVENTION(S) Blood samples for DNA extraction. MAIN OUTCOME MEASURE(S) X chromosome inactivation patterns in the females were analyzed using a methylation-sensitive assay. The DNA from males was tested for Y chromosome microdeletions by analyzing 37 sequence tagged sites. RESULTS Mildly skewed XCI (>85% inactivation of one allele) was detected in 4 of 43 (9.3%) patients, and 9 of 81 (11.1%) controls. Among these women, extremely skewed XCI (>90% inactivation of one allele) was detected in 2 of 43 (4.7%) patients, and 4 of 81 (4.9%) controls. No statistical differences could be shown between the groups. No microdeletions were found in the male partners. CONCLUSION(S) The frequency of both extremely and mildly skewed XCI was similar in patients and control women. Y chromosome microdeletions were not found in spouses of patients. Based on these results we conclude that skewed X inactivation and Y chromosome microdeletions are not associated with RM in our study couples.

Variation in cesarean section rates is not related to maternal and neonatal outcomes

The aim of this study was to compare the rate of cesarean sections in 12 delivery units in Finland, and to assess possible associations between cesarean section rates and maternal and neonatal complications.

Study of p53 gene mutations and placental expression in recurrent miscarriage cases

This study aimed to investigate the role of p53 in early human development by screening patients with recurrent miscarriages (RM) for mutations in the p53 gene and by studying p53 expression in placental tissue. A total of 46 women with RM and 191 control women were included in the study. A sample was also obtained from 40 male partners of RM patients. The samples were screened for p53 sequence variations using denaturing high-performance liquid chromatography, sequencing and allele-specific polymerase chain reaction. Placental tissue was available from 19 miscarriages. p53 expression in placental tissue was studied by immunohistochemical staining. The C11992A polymorphism in p53 was found to be associated with RM in Finnish patients. The C/A or A/A genotype was detected in 32.6% of the women with RM and in 18.9% of the controls (P = 0.0414, odds ratio 2.083, confidence interval 1.018-4.259). The results suggest that women carrying the C/A or A/A genotype have a two-fold higher risk for RM than women with the C/C genotype. Further studies are, however, necessary to define whether the intronic polymorphism has functional consequences. The immunohistochemical staining of placental tissues revealed no abnormal p53 expression patterns in the samples studied.

The incidence and risk factors of recurrent venous thromboembolism during pregnancy.

INTRODUCTION Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode. MATERIALS AND METHODS This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis). RESULTS AND CONCLUSIONS The incidence of recurrent VTE was 7.6% (n=28). Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis. In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p<0.001; group A vs. C: 5.7% vs. 30.0%, p=0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p=0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p=0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p<0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population.

Do mitochondrial mutations cause recurrent miscarriage

The cause of recurrent miscarriage (RM) can be identified in approximately 50% of cases, whereas in others, unknown genetic factors are actively being sought. As mitochondrial functions, and therefore also the mitochondrial genome [mitochondrial DNA (mtDNA)], have an important role in human development, through ATP production and participation in apoptosis, we aimed to study the role of mtDNA variations in RM. We screened 48 women with RM and 48 age-matched control women for heteroplasmic mitochondrial mutations using denaturing high performance liquid chromatography, a sensitive method that can detect approximately 5% heteroplasmy. As a result, we detected a heteroplasmic mtDNA variation in 13 RM women (27%) and in 9 control women (19%). Seven synonymous and five non-synonymous changes were detected within coding regions. In addition, seven heteroplasmic variations were detected within the non-coding control region. We were also able to show the presence of the variations in eight placental samples from three heteroplasmic women. In three of these cases, the proportion of variant mtDNA was higher in the placenta compared with that in the mother. We conclude that our sensitive methodology revealed a higher frequency of samples with heteroplasmic variations than expected in women with both RM and controls. However, no apparent increased frequency of heteroplasmic mtDNA variations or amounts of aberrant mtDNA was detected in the RM group. In addition, none of the detected variations were previously known to be pathogenic and therefore they are an unlikely cause of miscarriage.

The procoagulant effects of factor V Leiden may be balanced against decreased levels of factor V and do not reflect in vivo thrombin formation in newborns

Thrombin regulation in newborns remains incompletely understood. We studied tissue factor-initiated thrombin formation in cord plasma in vitro, and the effects of Factor V(Leiden) (FVL) heterozygosity on thrombin regulation both in vitro and in vivo in newborns. Pregnant women with known thrombophilia (n=27) were enrolled in the study. Cord blood and venous blood at the age of 14 days were collected from 11 FVL heterozygous newborns (FVL-positive) and from 16 FVL-negative newborns. Prothrombin fragment F1 +2 and coagulation factors were measured. Tissue factor-initiated thrombin formation was studied in cord platelet-poor plasma (PPP) of FVL-negative and -positive newborns, and in both PPP and platelet-rich plasma (PRP) of healthy controls. The endogenous thrombin potential (ETP) in cord PPP or PRP was approximately 60% of that in adult plasma, while thrombin formation started approximately 55% and approximately 40% earlier in cord PPP and PRP, respectively. Further, in FVL-positive newborns thrombin formation started significantly earlier than in FVL-negative newborns. Exogenous activated protein C (APC) decreased ETP significantly more in cord than in adult PRP. In FVL-negative cord plasma 5 nM APC decreased ETP by 17.4+/-3.5% (mean+/-SEM) compared with only 3.5+/-3.8% in FVL-positive cord plasma (p=0.01). FVL-positive newborns showed similar levels of F1 +2 but significantly decreased levels of factorV compared with FVL-negative newborns both in cord plasma (FV 0.82+/-0.07 U/ml vs. 0.98+/- 0.05 U/ml, p=0.03) and at the age of two weeks (FV 1.15+/-0.04 U/ml vs. 1.32+/- 0.05 U/ml, p=0.03). In conclusion, newborn plasma showed more rapid thrombin formation and enhanced sensitivity to APC compared with adult plasma. FVL conveyed APC resistance and a procoagulant effect in newborn plasma. Lack of elevated F1+2 levels in FVL-positive infants, however, suggested the existence of balancing mechanisms; one could be the observed lower level of factor V in FVL heterozygous newborns.