Seppo Heinonen

Preeclampsia complicated by advanced maternal age: a registry-based study on primiparous women in Finland 1997-2008.

BackgroundPreeclampsia is a frequent syndrome and its cause has been linked to multiple factors, making prevention of the syndrome a continuous challenge. One of the suggested risk factors for preeclampsia is advanced maternal age. In the Western countries, maternal age at first delivery has been steadily increasing, yet few studies have examined women of advanced maternal age with preeclampsia. The purpose of this registry-based study was to compare the obstetric outcomes in primiparous and preeclamptic women younger and older than 35 years.MethodsThe registry-based study used data from three Finnish health registries: Finnish Medical Birth Register, Finnish Hospital Discharge Register and Register of Congenital Malformations. The sample contained women under 35 years of age (Nu2009=u200915,437) compared with those 35 and over (Nu2009=u20092,387) who were diagnosed with preeclampsia and had their first singleton birth in Finland between 1997 and 2008. In multivariate modeling, the main outcome measures were Preterm delivery (before 34 and 37 weeks), low Apgar score (5 min.), small-for-gestational-age, fetal death, asphyxia, Cesarean delivery, induction, blood transfusion and admission to a Neonatal Intensive Care Unit.ResultsWomen of advanced maternal age (AMA) exhibited more preeclampsia (9.4%) than younger women (6.4%). They had more prior terminations (<0.001), were more likely to have a body mass index (BMI) >25 (<0.001), had more in vitro fertilization (IVF) (<0.001) and other fertility treatments (<0.001) and a higher incidence of maternal diabetes (<0.001) and chronic hypertension (<0.001). Multivariate logistic regression indicated that women of AMA had higher rates of: preterm delivery before 37 weeks 19.2% (OR 1.39 CI 1.24 to 1.56) and before 34 weeks 8.7% (OR 1.68 CI 1.43 to 2.00) low Apgar scores at 5 min. 7.1% (OR 1.37 CI 1.00 to 1.88), Small-for-Gestational Age (SGA) 26.5% (OR 1.42 CI 1.28 to 1.57), Asphyxia 12.1% (OR 1.54 CI 1.34 to 1.77), Caesarean delivery 50% (OR 2.02 CI 1.84 to 2.20) and admission to a Neonatal Intensive Care Unit (NICU) 31.6% (OR 1.45 CI 1.32 to 1.60).ConclusionsPreeclampsia is more common in women with advanced maternal age. Advanced maternal age is an independent risk factor for adverse outcomes in first-time mothers with preeclampsia.

Genome-Wide Association Scan Identifies a Risk Locus for Preeclampsia on 2q14, Near the Inhibin, Beta B Gene

Elucidating the genetic architecture of preeclampsia is a major goal in obstetric medicine. We have performed a genome-wide association study (GWAS) for preeclampsia in unrelated Australian individuals of Caucasian ancestry using the Illumina OmniExpress-12 BeadChip to successfully genotype 648,175 SNPs in 538 preeclampsia cases and 540 normal pregnancy controls. Two SNP associations (rs7579169, pu200a=u200a3.58×10−7, ORu200a=u200a1.57; rs12711941, pu200a=u200a4.26×10−7, ORu200a=u200a1.56) satisfied our genome-wide significance threshold (modified Bonferroni p<5.11×10−7). These SNPs reside in an intergenic region less than 15 kb downstream from the 3′ terminus of the Inhibin, beta B (INHBB) gene on 2q14.2. They are in linkage disequilibrium (LD) with each other (r2u200a=u200a0.92), but not (r2<0.80) with any other genotyped SNP ±250 kb. DNA re-sequencing in and around the INHBB structural gene identified an additional 25 variants. Of the 21 variants that we successfully genotyped back in the case-control cohort the most significant association observed was for a third intergenic SNP (rs7576192, pu200a=u200a1.48×10−7, ORu200a=u200a1.59) in strong LD with the two significant GWAS SNPs (r2>0.92). We attempted to provide evidence of a putative regulatory role for these SNPs using bioinformatic analyses and found that they all reside within regions of low sequence conservation and/or low complexity, suggesting functional importance is low. We also explored the mRNA expression in decidua of genes ±500 kb of INHBB and found a nominally significant correlation between a transcript encoded by the EPB41L5 gene, ∼250 kb centromeric to INHBB, and preeclampsia (pu200a=u200a0.03). We were unable to replicate the associations shown by the significant GWAS SNPs in case-control cohorts from Norway and Finland, leading us to conclude that it is more likely that these SNPs are in LD with as yet unidentified causal variant(s).

Lateral episiotomy protects primiparous but not multiparous women from obstetric anal sphincter rupture.

Objective. To identify the risk factors for obstetric anal sphincter rupture (OASR). Design and setting. Retrospective population‐based register study. Population. A total of 514,741 women with singleton pregnancy and vaginal delivery between 1997 and 2007 in Finland. Methods. Primiparous (n = 2,315) and multiparous women (n = 534) with OASR were compared with primiparous and multiparous women without OASR by using stepwise logistic regression analysis. Main outcome measure. The OASR risk. Results. Episiotomy decreased the likelihood of OASR for the primiparous [odds ratio (OR) 0.83, 95% CI (confidence interval) 0.75–0.92], but not the multiparous women (OR 2.01, 95% CI 1.67–2.44). The strongest risk factors for OASR among the primiparous women were forceps delivery (OR 10.20, 95% CI 3.60–28.90), birth weight over 4,000 g (OR 4.66, 95% CI 3.86–5.63), vacuum assisted delivery (OR 3.88, 95% CI 3.25–4.63), occiput posterior presentation (OR 3.17, 95% CI 1.64–6.15), and prolonged active second stage of birth (OR 2.06, 95% CI 1.65–2.58). Episiotomy was associated with decreased risks for OASR in vacuum assisted deliveries (OR 0.70, 95% CI 0.57–0.85). Risk factors for OASR among the multiparous women included forceps delivery (OR 10.13, 95% CI 2.46–41.81), prolonged active second stage of the birth (OR 7.18, 95% CI 4.32–11.91), birth weight over 4,000 g (OR 5.84, 95% CI 3.40–10.02), and vacuum assisted delivery (OR 4.17, 95% CI 3.17–5.48). Conclusions. The results support the restrictive use of episiotomy, since 909 episiotomies appear to be needed to prevent one OASR among primiparous women. Equivalent estimate in vacuum assisted deliveries among primiparous women was 66, favoring routine use of episiotomy in such cases.

Fear of childbirth predicts postpartum depression: A population-based analysis of 511 422 singleton births in Finland

Objectives To study how reproductive risks and perinatal outcomes are associated with postpartum depression treated in specialised healthcare defined according to the International Classification of Diseases (ICD)-10 codes, separately among women with and without a history of depression. Design A retrospective population-based case–control study. Setting Data gathered from three national health registers for the years 2002−2010. Participants All singleton births (n=511u2005422) in Finland. Primary outcome measures Prevalence of postpartum depression and the risk factors associated with it. Results In total, 0.3% (1438 of 511u2005422) of women experienced postpartum depression, the prevalence being 0.1% (431 of 511u2005422) in women without and 5.3% (1007 of 18u2005888) in women with a history of depression. After adjustment for possible covariates, a history of depression was found to be the strongest risk factor for postpartum depression. Other strong predisposing factors for postpartum depression were fear of childbirth, caesarean birth, nulliparity and major congenital anomaly. Specifically, among the 30% of women with postpartum depression but without a history of depression, postpartum depression was shown to be associated with fear of childbirth (adjusted OR (aOR 2.71, 95% CI 1.98 to 3.71), caesarean birth (aOR 1.38, 95% CI 1.08 to 1.77), preterm birth (aOR 1.65, 95% CI 1.08 to 2.56) and major congenital anomaly (aOR 1.67, 95% CI 1.15 to 2.42), compared with women with no postpartum depression and no history of depression. Conclusions A history of depression was found to be the most important predisposing factor of postpartum depression. Women without previous episodes of depression were at an increased risk of postpartum depression if adverse events occurred during the course of pregnancy, especially if they showed physician-diagnosed fear of childbirth.

Comparison of the pregnancy outcomes of subfertile women after infertility treatment and in naturally conceived pregnancies

BACKGROUNDnAdverse obstetric outcomes in pregnancies achieved through assisted reproductive technology (ART) could either be due to the technology or to the underlying subfertility or to both. To address this issue, we compared the pregnancy outcomes of singletons conceived naturally after a long time to pregnancy (TTP) with those of ART pregnancies.nnnMETHODSnWe analysed an existing birth database. Altogether 428 ART pregnancies were compared with 928 spontaneously conceived pregnancies with TTP of 2 years or more, during the period 1989-2007 at Kuopio University Hospital, Finland. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for pregnancy outcomes.nnnRESULTSnBetween treated and untreated subfertile women no significant differences were found in the rates of Caesarean sections (OR 1.21, 95% CI 0.89-1.64), preterm births (OR 1.28, 95% CI 0.81-2.03), small for gestational age (SGA) birthweight (OR 0.95, 95% CI 0.65-1.39), need of neonatal intensive care (OR 1.28, 95% CI 0.88-1.88) or low Apgar scores (OR 1.19, 95% CI 0.47-3.04). However, compared with pregnancies of women with TTP 0-6 months, ART pregnancies had significantly increased risks of preterm or very preterm birth, low birthweight and need of neonatal intensive care.nnnCONCLUSIONSnThe risks of preterm birth, SGA, need for neonatal intensive care and low Apgar scores were not significantly different between subfertile women who conceived spontaneously and those who conceived through ART indicating that maternal factors relating to subfertility and not only infertility treatment are associated with adverse pregnancy outcomes.

The Burden of Childhood Asthma and Late Preterm and Early Term Births

OBJECTIVEnTo evaluate the association between gestational age at birth and the risk of subsequent development of asthma.nnnSTUDY DESIGNnWe conducted a retrospective observational hospital-based birth case-control study in a university-based obstetrics and gynecology department in Finland. A total of 44,173 women delivering between 1989 and 2008 were linked with the social insurance register to identify asthma reimbursements for their offspring (n = 2661). Pregnancy factors were recorded during pregnancy. Infants were categorized as moderately preterm (≤ 32 weeks), late preterm (33-36 weeks), early term (37-38 weeks), term (39-40 weeks), or late term and postterm (≥ 41 weeks). The main outcome measure was asthma among the infants.nnnRESULTSnChildren born moderately preterm (≤ 32 weeks gestation) had a significantly increased risk of asthma (aOR, 3.9; 95% CI, 3.2-4.8). The risk of asthma was also increased in those born late preterm (aOR, 1.7; 95% CI, 1.4-2.0) and early term (aOR, 1.2; 95% CI, 1.1-1.4). In contrast, delivery at 41 weeks or later seemed to decrease the risk of asthma (aOR, 0.9; 95% CI, 0.8-1.0). The burden of asthma associated with preterm birth was associated mainly with early term infants, in whom 108 extra cases of asthma were observed.nnnCONCLUSIONnEven though the individual risk of asthma was inversely correlated with gestational age at birth, the overall burden brought about by delivery before term was associated with late preterm and early term deliveries. Furthermore, delivery after term was protective against asthma.

Risk factors for and perinatal outcomes of major depression during pregnancy: a population-based analysis during 2002-2010 in Finland

Objectives To identify risk factors for and the consequences (several adverse perinatal outcomes) of physician-diagnosed major depression during pregnancy treated in specialised healthcare. Design A population-based cross-sectional study. Setting Data were gathered from Finnish health registers for 1996–2010. Participants All singleton births (n=511u2005938) for 2002–2010 in Finland. Primary outcome measures Prevalence, risk factors and consequences of major depression during pregnancy. Results Among 511u2005938 women, 0.8% experienced major depression during pregnancy, of which 46.9% had a history of depression prior to pregnancy. After history of depression, the second strongest associated factor for major depression was fear of childbirth, with a 2.6-fold (adjusted OR (aOR=2.63, 95% CI 2.39 to 2.89) increased prevalence. The risk profile of major depression also included adolescent or advanced maternal age, low or unspecified socioeconomic status (SES), single marital status, smoking, prior pregnancy terminations, anaemia and gestational diabetes regardless of a history of depression. Outcomes of pregnancies were worse among women with major depression than without. The contribution of smoking was substantial to modest for small-for-gestational age newborn (<−2 SD below mean birth), low birth weight (<2500u2005g), preterm birth (<37u2005weeks) and admission to neonatal intensive care associated with major depression, whereas SES made only a minor contribution. Conclusions Physician-diagnosed major depression during pregnancy was found to be rare. The strongest risk factor was history of depression prior to pregnancy. Other associated factors were fear of childbirth, low SES, lack of social support and unhealthy reproductive behaviour such as smoking. Outcomes of pregnancies were worse among women with major depression than without. Smoking during pregnancy made a substantial to modest contribution to adverse outcomes associated with depression during pregnancy.

Association of risk variants for type 2 diabetes and hyperglycemia with gestational diabetes

OBJECTIVEnThe aim of this study was to investigate the association of risk variants for type 2 diabetes (T2D) and hyperglycemia with gestational diabetes (GDM).nnnDESIGN AND METHODSnFive hundred and thirty-three Finnish women who were diagnosed with GDM and 407 controls with normal glucose tolerance during the pregnancy were genotyped for 69 single-nucleotide polymorphisms (SNPs) which have been previously verified as susceptibility risk variants for T2D and hyperglycemia. All participants underwent an oral glucose tolerance test at the follow-up study after the index pregnancy.nnnRESULTSnRisk variants rs10830963 and rs1387153 of MTNR1B were significantly associated with GDM (odds ratio (OR)=1.62 (95% CI 1.34-1.96), P=4.5 × 10⁻⁷ and 1.38 (1.14-1.66), P=7.6 × 10⁻⁴ respectively). Both SNPs of MTNR1B were also significantly associated with elevated fasting glucose level and reduced insulin secretion at follow-up. Additionally, risk variants rs9939609 of FTO, rs2796441 of TLE1, rs560887 of G6PC2, rs780094 of GCKR, rs7903146 of TCF7L2 and rs11708067 of ADCY5 showed nominally significant associations with GDM (OR range from 1.25 to 1.30).nnnCONCLUSIONSnOur study suggests that GDM and T2D share a similar genetic background. Our findings also provide further evidence that risk variants of MTNR1B are associated with GDM by increasing fasting plasma glucose and decreasing insulin secretion.

Decreased PAPP-A is associated with preeclampsia, premature delivery and small for gestational age infants but not with placental abruption.

OBJECTIVEnTo investigate links between first trimester Downs syndrome screening markers and adverse pregnancy outcomes; preeclampsia (PE), small for gestational age (SGA), preterm delivery (PD) and placental abruption (PA) in spontaneous, chromosomally normal pregnancies.nnnSTUDY DESIGNnCohort study in a university hospital. Data during pregnancy were routinely collected from a total study population of 2844 pregnant women between 2005 and 2007. Four study groups were pregnancies with PE (N=175), PA (N=17), PD (N=213) and SGA (N=275) plus a reference group with normal outcome (N=2164). The median MOMs of maternal serum concentrations of pregnancy associated plasma protein A (PAPP-A) and free beta human chorionic gonadotropin (fβ-hCG) were compared using two-tailed pooled t-tests, continuous variables were compared using Students two-way t-tests, and Chi-square tests were used to analyse dichotomous variables. Fishers exact test was used when there were fewer than five units in any of the classes.nnnRESULTSnThe median MOM of maternal serum PAPP-A was significantly lower in women with PE, PD and SGA (0.79, 0.80 and 0.79 MOM, respectively) than in the reference group (0.99 MOM) (p<0.01). The median MOM of maternal serum fβ-hCG was also significantly lower in the SGA group (0.90 MOM) and in the PE and PD groups (0.86 and 0.92 MOM) than in the reference group (0.99 MOM, p=0.02). There was no detectable difference between the biochemical markers in the PA group and the reference group. No statistical difference was found between NT MOMs in the reference and study groups.nnnCONCLUSIONnThe concentrations of first trimester screening (FTS) serum markers were lower in pregnancies where PE, PD and SGA occurred. In the latter two cases, there was an inverse association between incidence and PAPP-A and fβ-hCG values. However, the development of PA during pregnancy could not be predicted from biochemical marker concentrations. The mechanism behind PA is probably less dependent on the placenta than on the decidua.

Fear of childbirth in nulliparous and multiparous women: a population-based analysis of all singleton births in Finland in 1997-2010

To identify risk factors for fear of childbirth (FOC) according to parity and socioeconomic status, and to evaluate associations between FOC and adverse perinatal outcomes.