Cost-effectiveness of cervical length screening and progesterone treatment to prevent spontaneous preterm delivery in Sweden.

OBJECTIVE: To estimate the cost-effectiveness of strategies to prevent spontaneous preterm delivery (PTD) in asymptomatic singleton pregnancies, using prevalence and healthcare cost data from the Swedish healthcare context. METHODS: We designed a decision analytic model based on the Swedish CERVIX study to estimate the cost-effectiveness of strategies to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy. The model was constructed as a combined decision-tree model and Markov model with a time horizon of 100 years. Four preventive strategies, namely 'Universal screening', 'High-risk-based screening' (i.e. screening of high-risk women only), 'Low-risk-based screening' (i.e. treatment of high-risk population and screening of remaining women) and 'Nullipara screening' (i.e. treatment of high-risk population and screening of nulliparous women only), included second-trimester cervical length (CL) screening by transvaginal ultrasound followed by vaginal progesterone treatment in the case of a short cervix. A fifth preventive strategy involved vaginal progesterone treatment of women with previous spontaneous PTD or late miscarriage but no CL screening ('No screening, treat high-risk group'). For comparison, we used a sixth strategy implying no specific intervention to prevent spontaneous PTD, reflecting the current situation in Sweden ('No screening'). Probabilities for a short cervix (CL ≤ 25 mm; base-case) and for spontaneous PTD at < 33 + 0 weeks and at 33 + 0 to 36 + 6 weeks were derived from the CERVIX study, and probabilities for stillbirth, neonatal mortality and long-term morbidity (cerebral palsy) from Swedish health data registers. Costs were based on Swedish data, except costs for cerebral palsy, which were based on Danish data. We assumed that vaginal progesterone reduces spontaneous PTD before 33 weeks by 30% and spontaneous PTD at 33-36 weeks by 10% (based on the literature). All analyses were from a societal perspective. We expressed the effectiveness of each strategy as gained quality-adjusted life years (QALYs) and presented cost-effectiveness as average (ACER; average cost per gained QALY compared with 'No screening') and incremental (ICER; difference in costs divided by the difference in QALYs for each of two strategies being compared) cost-effectiveness ratios. We performed deterministic and probabilistic sensitivity analysis. The results of the latter are shown as cost-effectiveness acceptability curves. Willingness-to-pay was set at a maximum of 500 000 Swedish krona (56 000 US dollars (USD)), as suggested by the Swedish National Board of Health and Welfare. RESULTS: All interventions had better health outcomes than did 'No screening', with fewer screening-year deaths and more lifetime QALYs. The best strategy in terms of improved health outcomes was 'Low-risk-based screening', irrespective of whether screening was performed at 18 + 0 to 20 + 6 weeks (Cx1) or at 21 + 0 to 23 + 6 weeks (Cx2). 'Low-risk-based screening' at Cx1 was cost-effective, while 'Low-risk-based screening' at Cx2 entailed high costs compared with other alternatives. The ACERs were 2200 USD for 'Low-risk-based screening' at Cx1 and 36 800 USD for 'Low-risk-based screening' at Cx2. Cost-effectiveness was particularly sensitive to progesterone effectiveness and to productivity loss due to sick leave during pregnancy. The probability that 'Low-risk-based screening' at Cx1 is cost-effective compared with 'No screening' was 71%. CONCLUSION: Interventions to prevent spontaneous PTD in asymptomatic women with a singleton pregnancy, including CL screening with progesterone treatment of cases with a short cervix, may be cost-effective in Sweden. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Technological readiness and implementation of genomic-driven precision medicine for complex diseases.

The fields of human genetics and genomics have generated considerable knowledge about the mechanistic basis of many diseases. Genomic approaches to diagnosis, prognostication, prevention and treatment - genomic-driven precision medicine (GDPM) - may help optimize medical practice. Here, we provide a comprehensive review of GDPM of complex diseases across major medical specialties. We focus on technological readiness: how rapidly a test can be implemented into health care. Although these areas of medicine are diverse, key similarities exist across almost all areas. Many medical areas have, within their standards of care, at least one GDPM test for a genetic variant of strong effect that aids the identification/diagnosis of a more homogeneous subset within a larger disease group or identifies a subset with different therapeutic requirements. However, for almost all complex diseases, the majority of patients do not carry established single-gene mutations with large effects. Thus, research is underway that seeks to determine the polygenic basis of many complex diseases. Nevertheless, most complex diseases are caused by the interplay of genetic, behavioural and environmental risk factors, which will likely necessitate models for prediction and diagnosis that incorporate genetic and non-genetic data.

Obstetric anal sphincter injury after episiotomy in vacuum extraction: an epidemiological study using an emulated randomised trial approach.

OBJECTIVE: To emulate a randomised controlled trial investigating whether lateral or mediolateral episiotomy compared with no episiotomy reduces the prevalence of obstetric anal sphincter injury (OASIS) in nulliparous women delivered with vacuum extraction. DESIGN: A population-based observational study. SETTING: Sweden. POPULATION: 63 654 nulliparous women delivered with vacuum extraction derived from the Swedish Medical Birth Register 2000-2011, with a live singleton baby with no known malformations in cephalic presentation in gestational week ≥34+0 , and subject to lateral or mediolateral episiotomy or no episiotomy. METHODS: The effect of episiotomy was calculated using a causal doubly robust estimation method based on propensity scores. Results are presented as the average treatment effect and numbers needed to treat (NNT). MAIN OUTCOME MEASURES: OASIS (third- and fourth-degree perineal injury) in nulliparous women delivered with vacuum extraction. RESULTS: Episiotomy was associated with a reduction in OASIS from 15.5% to 11.8%, average treatment effect of -3.66% (95% CI -4.31 to -3.01) and NNT 27. Third-degree perineal injuries were reduced from 14.0% to 10.9% (-3.08, 95% CI -3.71 to -2.42) with NNT 32. Fourth-degree perineal injuries were reduced from 1.6% to 1.0 % (-0.58%, 95% CI -0.79 to -0.37) with NNT 172. CONCLUSIONS: Lateral or mediolateral episiotomy reduced the prevalence of OASIS in nulliparous women delivered with vacuum extraction, compared to women with no episiotomy. TWEETABLE ABSTRACT: To prevent one case of OASIS in first-time mothers delivered with vacuum, 27 episiotomies had to be performed.

Second-trimester transvaginal ultrasound measurement of cervical length for prediction of preterm birth: a blinded prospective multicentre diagnostic accuracy study.

OBJECTIVE: To estimate the diagnostic performance of sonographic cervical length for the prediction of preterm birth (PTB). DESIGN: Prospective observational multicentre study. SETTING: Seven Swedish ultrasound centres. SAMPLE: A cohort of 11 456 asymptomatic women with a singleton pregnancy. METHODS: Cervical length was measured with transvaginal ultrasound at 18-20 weeks of gestation (C×1) and at 21-23 weeks of gestation (C×2, optional). Staff and participants were blinded to results. MAIN OUTCOME MEASURES: Area under receiver operating characteristic curve (AUC), sensitivity, specificity, positive and negative predictive values (PPV and NPV), positive and negative likelihood ratios (LR+ and LR-), number of false-positive results per true-positive result (FP/TP), number needed to screen to detect one PTB (NNS) and prevalence of 'short' cervix. RESULTS: Spontaneous PTB (sPTB) at <33 weeks of gestation occurred in 56/11 072 (0.5%) women in the C×1 population (89% white) and in 26/6288 (0.4%) in the C×2 population (92% white). The discriminative ability of shortest endocervical length was better the earlier the sPTB occurred and was better at C×2 than at C×1 (AUC to predict sPTB at <33 weeks of gestation 0.76 versus 0.65, difference in AUC 0.11, 95% CI 0.01-0.23). At C×2, the shortest endocervical length of ≤25 mm (prevalence 4.4%) predicted sPTB at <33 weeks of gestation with sensitivity 38.5% (10/26), specificity 95.8% (5998/6262), PPV 3.6% (10/274), NPV 99.7% (5988/6014), LR+ 9.1, LR- 0.64, FP/TP 26 and NNS 629. CONCLUSIONS: Second-trimester sonographic cervical length can identify women at high risk of sPTB. In a population of mainly white women with a low prevalence of sPTB its diagnostic performance is at best moderate. TWEETABLE ABSTRACT: Cervical length screening to predict preterm birth in a white low-risk population has moderate performance.

Prediction of small-for-gestational-age status by symphysis-fundus height: a registry-based population cohort study.

OBJECTIVE: To develop a chart for risk of small-for-gestational-age (SGA) at birth depending on deviations in symphysis-fundus (SF) height values for gestational age during pregnancy weeks 24-42. DESIGN: Registry-based population cohort study. SETTING: Antenatal clinics, Västra Götaland County, Sweden, 2005-2010. POPULATION: The study included 42 018 women with ultrasound-dated singleton pregnancies who delivered at Sahlgrenska University Hospital. Data (including 282 713 SF height measurements) were extracted from the hospital's computerised obstetric database. METHODS: Linear and binary regression analyses were used to derive prediction models with deviations in birthweight (BW) and SF height by gestational age as dependent and independent variables, respectively. Receiver operating characteristic curves were generated to evaluate the predictive value of the model in detecting SGA. MAIN OUTCOME MEASURES: Birthweight and small-for-gestational-age. RESULTS: Symphysis-fundus height accounted for 3% of individual BW variance at 24 weeks, increasing gradually to 20% at 40 weeks. Maternal factors explained an additional 10 percentage points of BW variance. Receiver operating characteristic curves confirmed that SF height was a stronger SGA predictor in late than in early pregnancy. Using an SGA relative risk cut-off limit of ≥2-fold, the overall sensitivity was 50% and the overall specificity 80%. Only the most recent SF measurement was useful in predicting BW deviation; previous measurements added nothing to the predictive value. CONCLUSIONS: The ability of SF measurements to detect SGA status at birth increases with gestational age. Only the most recent SF measurement has predictive value; a static or falling pattern of SF values did not increase SGA likelihood. TWEETABLE ABSTRACT: New SF curves predict SGA best in late pregnancy; only the most recent SF measurement has predictive value.

Gastric fluid cytokines are associated with chorioamnionitis and white blood cell counts in preterm infants.

AIM: The aim of this study was to determine whether the concentration of cytokines in the gastric fluid at birth was associated with chorioamnionitis or funisitis and with the white blood cell counts of very premature newborns. METHODS: We retrieved gastric fluid from 27 preterm infants with a gestational age of <29 weeks within 1 h of birth and used enzyme-linked immunosorbent assay to measure the concentrations of interleukin (IL)-1beta, epithelial cell-derived neutrophil-activating peptide (ENA)-78, IL-8 and growth-related oncogene (Gro)-alpha. The presence of histologic chorioamnionitis or funisitis in the placentas and the highest white blood cell count of the infants during the first week of life were compared to the cytokine concentrations. RESULTS: Gastric fluid concentrations of IL-1beta, ENA-78, IL-8 and Gro-alpha were strongly associated with chorioamnionitis and funisitis. In addition, chorioamnionitis and funisitis and gastric aspirate cytokine levels were associated with the highest white blood cell counts of the infants during the first week of life. CONCLUSION: This study suggests that levels of inflammatory cytokines in the gastric fluid of premature infants at birth can be used to assess the exposure of the infants to antenatal inflammation.

Antibiotic use during pregnancy alters the commensal vaginal microbiota.

Antibiotics may induce alterations in the commensal microbiota of the birth canal in pregnant women. Therefore, we studied the effect of antibiotic administration during pregnancy on commensal vaginal bacterial colonization at gestational week 36. Six hundred and sixty-eight pregnant women from the novel unselected Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010 ) pregnancy cohort participated in this analysis. Detailed information on oral antibiotic prescriptions during pregnancy filled at the pharmacy was obtained and verified prospectively. Vaginal samples were obtained at pregnancy week 36 and cultured for bacteria. Women who received oral antibiotics during any pregnancy trimester had an increased rate of colonization by Staphylococcus species in the vaginal samples as compared with samples obtained from women without any antibiotic treatment during pregnancy (adjusted OR 1.63, 95% CI 1.06-2.52, p 0.028). Oral antibiotic administration in the third trimester were also associated with increased colonization by Staphylococcus species (adjusted OR 1.98, 95% CI 1.04-3.76, p 0.037). These bacteriological changes were associated with urinary tract infection antibiotics. Women treated in the third trimester of pregnancy were more often colonized by Escherichia coli than women without antibiotic treatment in the third trimester (adjusted OR 1.91, 95% CI 1.04-3.52, p 0.038). This change was associated with respiratory tract infection (RTI) antibiotics. We did not observe any significant changes in vaginal Streptococcus agalactiae (group B streptoccocus) or Staphylococcus aureus colonization following antibiotic treatment in pregnancy. Antibiotic administration during pregnancy leads to alterations in the vaginal microbiological ecology prior to birth, with potential morbidity, and long-term effects on the early microbial colonization of the neonate.

European non-invasive trisomy evaluation (EU-NITE) study: a multicenter prospective cohort study for non-invasive fetal trisomy 21 testing.

OBJECTIVE: To evaluate the performance of a directed non-invasive prenatal testing method of cell-free DNA analysis for fetal trisomy 21 (T21) by shipping the whole blood samples from Europe to a laboratory in the USA. METHODS: A European multicenter prospective, consecutive cohort study was performed enrolling pregnant women from Sweden and the Netherlands. Blood samples were drawn just prior to a planned of invasive diagnostic procedure in a population at increased risk for fetal T21 and then shipped to the USA without any blood processing. Chromosome-selective sequencing was carried out on chromosome 21 with reporting high risk or low risk of T21. Karyotyping or rapid aneuploidy detection was used as the clinical reference standard. RESULTS: Of the 520 eligible study subjects, a T21 test result was obtained in 504/520 (96.9%). Risk assessment was accurate in 503/504 subjects (99.8%). There was one false negative result for T21 (sensitivity 17/18, 94.4%, and specificity 100%). CONCLUSION: This is the first prospective European multicenter study showing that non-invasive prenatal testing using directed sequencing of cell-free DNA applied to blood samples shipped across the Atlantic Ocean, is highly accurate for assessing risk of fetal T21.

Non-infectious risk factors for different types of cerebral palsy in term-born babies: a population-based, case-control study.

OBJECTIVE: To identify non-infectious antenatal and perinatal risk factors for cerebral palsy (CP) and its subtypes in children born at term. DESIGN: A population-based, case-control study. SETTING: The western healthcare region of Sweden. POPULATION: A population-based series of children with CP born at term during 1983-94 (n=309) was matched with a control group (n=618). METHODS: A total of 62 variables, maternal characteristics, and prepartal, intrapartal and postpartal variables were retrieved from obstetric records. Both univariate and multivariate analyses were performed for spastic and dyskinetic CP, and for the total CP group. MAIN OUTCOME MEASURES: Cerebral palsy (CP) and subtypes. RESULTS: Univariate analysis resulted in 26 significant risk factors for CP. Birthweight (OR 0.54, 95% CI 0.39-0.74), not living with the baby's father (OR 2.58, 95% CI 1.11-5.97), admittance to a neonatal intensive care unit (NICU) (OR 4.43, 95% CI 3.03-6.47), maternal weight at 34 weeks of gestation (OR 1.02, 95% CI 1.00-1.03) and neonatal encephalopathy (OR 69.2, 95% CI 9.36-511.89) were found to be risk factors for CP in the total CP group in our multivariate analysis. Factors during the periods before, during and after delivery were all shown to increase the risk of spastic diplegia and tetraplegia, whereas mostly factors during the period before delivery increased the risk of spastic hemiplegia, and only factors during delivery increased the risk of dyskinetic CP. Admittance to an NICU was a risk factor for all CP subtypes. CONCLUSIONS: The risk factor pattern differed by CP subtype. The presented risk factors may be useful indicators for identifying children at risk of developing CP, and helpful for targeting individuals for early intervention programmes.

Prediction of spontaneous preterm delivery in women with threatened preterm labour: a prospective cohort study of multiple proteins in maternal serum.

OBJECTIVE: To analyse whether specific proteins in maternal serum and cervical length, alone or in combination, can predict the likelihood that women with intact membranes with threatened preterm labour will deliver spontaneously within 7 days of sampling. DESIGN: Cohort study. SETTING: Sahlgrenska University Hospital, Gothenburg, Sweden. POPULATION: Women at between 22 and 33 weeks of gestation with threatened preterm labour (n = 142) admitted to the Sahlgrenska University Hospital, Gothenburg, Sweden, in 1995-2005. METHODS: Maternal serum was tested for 27 proteins using multiplex xMAP technology. Individual levels of each protein were compared, and calculations were performed to investigate potential associations between different proteins, cervical length and spontaneous preterm delivery. Receiver operating characteristic curves were used to find the best cut-off values for continuous variables in relation to spontaneous preterm delivery within 7 days of sampling. Prediction models were created based on a stepwise logistic regression using binary variables. MAIN OUTCOME MEASURE: Spontaneous preterm delivery within 7 days. RESULTS: In order to determine the best prediction model, we analysed models of serum proteins alone, cervical length alone, and the combination of serum proteins and cervical length. We found one multivariable combined model through the data analysis that more accurately predicted spontaneous preterm delivery within 7 days. This model was based on serum interleukin-10 (IL-10) levels, serum RANTES levels and cervical length (sensitivity 74%, specificity 87%, positive predictive value 76%, negative predictive value 86%, likelihood ratio 5.8 and area under the curve 0.88). CONCLUSIONS: A combination of maternal serum proteins and cervical length constituted the best prediction model, and would help determine whether women with threatened preterm labour are likely to deliver within 7 days of measurement.

Oral health in young individuals with foreign and Swedish backgrounds--a ten-year perspective.

AIM: To investigate oral health status and coherent determinants in children with foreign backgrounds compared with children with a Swedish background, during a ten year period. DESIGN AND METHODS: In 1993 and 2003, cross-sectional studies with random samples of individuals in the age groups 3, 5, 10 and 15 years were performed in Jönköping, Sweden. All the individuals were personally invited to a clinical and radiographic examination of their oral health status. They were also asked about their attitudes to and knowledge of teeth and oral health care habits. The final study sample comprised 739 children and adolescents, 154 with a foreign background (F cohort) and 585 with a Swedish background (S cohort). RESULTS: In both 1993 and 2003, more 3- and 5 year olds in the S cohort were caries-free compared with the F cohort. In 1993, dfs was higher among 3- and 5 year olds in the F cohort (p<0.01) compared with the S cohort. In 2003, dfs/DFS was statistically significantly higher in all age groups among children and adolescents in the F cohort compared with the S cohort. When it came to proximal tooth surfaces, the percentages of individuals who were caries-free, with initial carious lesions, with manifest carious lesions and with restorations among 10-year-olds in the F cohort were 55%, 23%, 4% and 18% in 1993. The corresponding figures for the S cohort were 69%, 20%, 6% and 5% respectively. In 2003, the values for the F cohort were 54%, 29%, 4% and 13% compared with 82%, 12%, 1% and 5% in the S cohort. In 2003, the odds of being exposed to dental caries among 10- and 15-yearolds in the F cohort, adjusted for gender and age, were more than six times higher (OR=6.3, 95% CI:2.51-15.61; p<0.001) compared with the S cohort. CONCLUSIONS: There has been a decline in caries prevalence between 1993 and 2003 in all age groups apart from 3-year-olds. However, the improvement in dfs/DFS was greater in the S cohort compared with the F cohort in all age groups. The difference between the F and S cohorts in terms of dfs/ DFS was larger in 2003 compared with 10 years earlier. In 2003, the odds ratio for being exposed to dental caries was almost six times higher for 10- and 15-year-olds with two foreign-born parents compared with their Swedish counterparts.

Prediction of microbial invasion of the amniotic cavity in women with preterm labour: analysis of multiple proteins in amniotic and cervical fluids.

OBJECTIVE: Microbial invasion of the amniotic cavity is a major cause of preterm delivery and the diagnosis is dependent on invasive amniocentesis. The objective was to determine whether specific proteins in amniotic and cervical fluids alone, or in combination, could identify bacterial invasion. DESIGN: A prospective follow-up study. POPULATION: Women with singleton pregnancies presenting with preterm labour between 22 and 33 weeks of gestation (n = 89). SETTING: Sahlgrenska University Hospital, Gothenburg, Sweden. METHODS: Amniotic and cervical fluid was analysed with polymerase chain reaction for Mycoplasmas, and was cultured for aerobic and anaerobic bacteria. Twenty-seven proteins were analysed using multiplex technology. Individual levels of each protein were compared in order to find associations between different proteins and microbial invasion of the amniotic cavity. Predictive models based on multiple proteins were created using stepwise binary logistic regression. MAIN OUTCOME MEASURE: The main outcome measure was microbial invasion of the amniotic cavity. RESULTS: Microbial invasion of the amniotic cavity was present in 17% (15/89) of the women. Concentration levels of several amniotic and cervical proteins were significantly higher in women with microbial invasion of the amniotic cavity. Three multivariate predictive models were found. The predictive power of the non-invasive model (73% sensitivity, 88% specificity, 55% positive predictive value, 94% negative predictive value) was as good as the invasive models. Area under the receiver operating characteristic (ROC) curve and likelihood ratio were 0.87 and 6.0, respectively. CONCLUSIONS: Prediction of intra-amniotic infection using selected cervical proteins was equally good as prediction using the same proteins collected from amniotic fluid, or a combination of cervical and amniotic proteins.

Antimicrobial resistance in colonizing group B Streptococci before the implementation of a Swedish intrapartum antibiotic prophylaxis program.

The prevalence of antibiotic resistance and their genetic determinants in colonizing group B streptococci (GBS) sampled in a Swedish nationwide survey was examined. In five GBS isolates (1.3%), kanamycin/amikacin resistance and the presence of the aphA-3 gene was identified. Three of these isolates carried the aad-6 gene and were streptomycin-resistant. Screening with kanamycin and streptomycin 1,000-µg disks enabled a rapid and easy detection of these isolates. In all, 312/396 (79%) GBS were tetracycline-resistant and 95% of the examined isolates harbored the tetM gene. Among the 22 (5.5%) GBS resistant to erythromycin and/or clindamycin, the ermB gene was detected in nine isolates (41%) and erm(A/TR) in ten isolates (45%). A high level of erythromycin and clindamycin resistance with minimum inhibitory concentrations (MICs) >256 mg/L was found in four serotype V isolates that harbored ermB. The erythromycin/clindamycin resistance was distributed among all of the common serotypes Ia, Ib, II, III, IV, and V, but was not present in any of the 44 serotype III isolates associated to clonal complex 17. Screening for penicillin resistance with 1-µg oxacillin disks showed a homogenous population with a mean inhibition zone of 20 mm. A change in the present oxacillin breakpoints for GBS is suggested.

Multiplicity and early gestational age contribute to an increased risk of cerebral palsy from assisted conception: a population-based cohort study.

BACKGROUND: This paper assesses the risk of cerebral palsy (CP) in children born after assisted conception compared with children born after natural conception (NC). METHODS: This population based follow-up study included all 588,967 children born in Denmark from 1995 to 2003. Assisted conception was defined as IVF, with or without ICSI, and ovulation induction (OI), with or without subsequent insemination. RESULTS: There were 33 139 (5.6%) children born in Denmark from 1995 to 2003 as a result of assisted conception and through to June 2009, 1146 (0.19%) children received a CP diagnosis. Children born after assisted conception had an increased risk of a CP diagnosis, crude hazard rate ratio (HRR) 1.90 (95% CI: 1.57-2.31) compared with NC children. Divided into IVF and OI children compared with NC children, the risk was HRR 2.34 (95% CI: 1.81-3.01) and HRR 1.55 (95% CI: 1.17-2.06), respectively. When we included the intermediate factors multiplicity and gestational age in multivariate models, the risk of CP in assisted conception disappeared. In general, children with CP born after assisted conception had similar CP subtypes and co-morbidities as children with CP born after NC. CONCLUSION: The risk of CP is increased after both IVF and OI. The increased risk of CP in children born after assisted conception, and in particular IVF, is strongly associated with the high proportion of multiplicity and preterm delivery in these pregnancies. A more widespread use of single embryo transfer warrants consideration to enhance the long-term health of children born after IVF.

Asphyxia-related risk factors and their timing in spastic cerebral palsy.

OBJECTIVE: To investigate the association of asphyxia-related conditions (reducing blood flow or blood oxygen levels in the fetus) with spastic cerebral palsy (CP) considering different gestational age groups and the timing of risk. DESIGN: Population-based case-control study. SETTING: Danish Cerebral Palsy Register in eastern Denmark and Danish Medical Birth Register. POPULATION OR SAMPLE: 271 singletons with spastic CP and 217 singleton controls, frequency matched by gestational age group, born 1982-1990 in eastern Denmark. METHODS: Data were abstracted from medical records, and a priori asphyxia-related conditions and other risk factors were selected for analysis. Each factor was classified according to the time at which it was likely to first be present. MAIN OUTCOME MEASURES: Spastic CP. RESULTS: Placental and cord complications accounted for the majority of asphyxia conditions. In multivariate analysis, placental infarction was significantly associated with a four-fold increased risk for spastic quadriplegia and cord around the neck was significantly associated with a three-fold increased risk for spastic CP overall. The combination of placental infarction and being small for gestational age (SGA) afforded an especially high risk for spastic quadriplegia. Placental and cord complications were present in 21% of cases and 12% of controls. CONCLUSIONS: The risk for spastic quadriplegia from placental infarction may be linked in some cases with abnormal fetal growth (17% of all children with spastic quadriplegia and 3% of control children both had an infarction and were SGA) -- suggesting an aetiologic pathway that encompasses both factors. The risk for spastic CP from cord around the neck is not accounted for by other prepartum or intrapartum factors we examined. Considering the relative timing of risk factors provides a useful framework for studies of CP aetiology.

Cerebral palsy and restricted growth status at birth: population-based case-control study.

OBJECTIVE: To evaluate the association between growth status at birth and subsequent development of cerebral palsy in preterm and term infants. DESIGN: Population-based case-controlled study. SETTING: Cerebral palsy register in Western Sweden. Subjects Cohort of 334 singletons born between 1983 and 1990, with cerebral palsy diagnosed from age 4, and 668 singletons matched for gestation, gender and delivery unit. METHOD: Growth status at birth was determined using small for gestational age (SGA) categories, with customised birthweight percentiles (SGAcust) based on the Swedish population. MAIN OUTCOME MEASURES: Proportion of babies that were SGAcust, comparing cases and controls in three gestational age categories: early preterm (24-33 weeks), late preterm (34-36 weeks) and term (37+ weeks). RESULTS: Of the 334 children with cerebral palsy, 87 (26.6%) were born early preterm, 27 (8.1%) late preterm and 218 (66%) at term. Children who had been born at term were more likely to have been SGA <1st customised percentile (SGAcust1) than their matched controls (OR 6.6, 95% CI 2.3-18.6). In contrast, children with cerebral palsy born preterm were not more likely to have been SGAcust1 (OR 0.9, 95% CI 0.4-1.9), and this applied to early preterm as well as late preterm births. For less severely small babies (SGA between 1st and 5th customised percentiles), the association with cerebral palsy remained significant for term births (OR 5.2, 95% CI 2.7-10.1) but was again not significant for preterm births. CONCLUSIONS: Term singletons with severely SGA birthweights had a five- to seven-fold risk of developing cerebral palsy compared with gestational age-matched infants with birthweights within normal limits. For children born preterm, SGA was not more likely to be present in cases than in controls. These findings support the concept of cerebral palsy as a multifactorial condition and highlight the importance of antenatal surveillance of fetal growth.

Interleukin-18 and interleukin-12 in maternal serum and spontaneous preterm delivery.

INTRODUCTION: Mice disrupted for the interleukin (IL)-18 gene appear more disposed to preterm delivery (PTD) induced by inflammation. A synergy between IL-18 and IL-12 has been suggested. The objective of this study was to investigate a possible relation between human maternal serum levels of IL-18, IL-12 and spontaneous PTD. MATERIALS AND METHODS: A cohort of 93 consecutive women with symptoms of threatening PTD on admission was enrolled at the delivery ward, Aarhus University Hospital, Denmark. MEASURES: Serum IL-18 and IL-12 measured using Luminex xMAP technology. Endpoint: PTD before 34 weeks gestation. RESULTS: Pregnant women admitted with symptoms of threatening PTD and delivering before 34 weeks of gestation had significantly lower levels of IL-18 compared to women delivering at or after 34 weeks of gestation (medians: 14.5 versus 26.6 pg/ml; p=0.035). IL-12 levels were not different in women delivering before or after 34 weeks of gestation. Patients having low IL-18 (below the 25-percentile) and high IL-12 (above the 75-percentile) had a twofold increase in risk of delivering before 34 weeks of gestation (RR 2.1 [1.7-2.6]). CONCLUSION: Results from this study indicate, that low serum IL-18 level could be associated with PTD in women with symptoms of PTD. A possible interaction between IL-18 and IL-12 was found, as the risk of delivering before 34 weeks is increased with the combination of low IL-18 and high IL-12, but further studies are warranted to investigate these interleukins and their possible role in PTD.

Increased bioavailability of TNF-alpha in African Americans during in vitro infection: predisposing evidence for immune imbalance.

OBJECTIVE: The objective of this study is to examine TNF-alpha and its soluble and membrane bound receptors in fetal membranes derived from blacks and whites in response to in vitro infectious stimulus, and the balance between TNF-alpha and the receptors. Fetal membranes collected from black and white women at term were maintained in an organ explant system and stimulated with lipopolysaccharide (LPS). TNF-alpha, soluble TNF receptors (sTNFR1 and sTNFR2) in culture media and membrane bound TNF receptors (TNFR1 and TNFR2) in tissue homogenates were measured. Molar ratio (TNF/sTNFR) was calculated between LPS stimulated and unstimulated (controls) cultures in both races. TNF-alpha was increased in both races after LPS stimulation and showed no difference between races (p=0.7). LPS decreased sTNFR1 in blacks, but increased in whites, showing a significant difference between races (p=0.001). In blacks sTNFR2 also decreased and increased in whites, but the results were not significant between races (p=0.4). Both TNFR1 and TNFR2 were increased in blacks after LPS stimulation whereas no such changes were seen in whites compared to controls that were also significant between races. After LPS stimulation TNF-alpha bioavailability was increased in blacks with a drop in soluble receptors and with an increase in membrane receptors. This was not evident in whites because in whites soluble receptors were increased with no change in membrane receptors. Our data demonstrated that LPS stimulation results in a molar ratio switch favoring TNF-alpha biofunction in blacks, but not in whites.

Cervical length in women in preterm labor with intact membranes: relationship to intra-amniotic inflammation/microbial invasion, cervical inflammation and preterm delivery.

OBJECTIVE: Intra-amniotic infection, diagnosed by microbial invasion of the amniotic cavity (MIAC) and/or the presence of intra-amniotic inflammation (IAI), is related to adverse perinatal outcome in women with preterm labor. Due to the subclinical nature of IAI, a correct diagnosis depends on amniocentesis, which is an invasive method not performed as a clinical routine. The aim of this study was to evaluate if cervical length measured by transvaginal sonography could assist in the identification of women at high risk for IAI. METHODS: Cervical length was assessed by transvaginal sonography in 87 women with singleton pregnancies in preterm labor (<34 weeks of gestation). Cervical (n=87) and amniotic (n=55) fluids were collected. Polymerase chain reactions for Ureaplasma urealyticum and Mycoplasma hominis, and culture for aerobic and anaerobic bacteria, were performed. Interleukin (IL)-6 and IL-8 were analyzed by enzyme-linked immunosorbent assay. RESULTS: IAI was present in 25/55 (45%) of the patients presenting with preterm labor who underwent amniocentesis. Women with IAI had a significantly shorter cervical length (median, 10 (range, 0-34) mm) than had those without IAI (median, 21 (range, 11-43) mm) (P<0.0001). Receiver-operating characteristics curve analysis showed that a cervical length (cut-off of 15 mm) predicted IAI (relative risk, 3.6; CI, 1.9-10.0) with a sensitivity of 72%, specificity of 83%, positive predictive value of 78% and negative predictive value of 78%. Cervical length was also significantly associated with preterm birth up to 7 days from sampling and at