Associations between VEGF isoforms and impending retinopathy of prematurity.

BACKGROUND/OBJECTIVE: Vascular Endothelial Growth Factor (VEGF) is the main driver of angiogenesis during neurodevelopment (i.e., brain and retina). VEGF165 and VEGF121 are the two most prevalent human VEGF isoforms. Although retinopathy of prematurity (ROP), a neuroretinal disorder, is associated with VEGF dysregulation, little is known about the interaction of VEGF isoforms on neuroretinal angiogenesis. We hypothesized that: (a) A specific VEGF165/VEGF121 correlation, at a given time point, is associated with normal retinal development (no ROP) and (b) An altered correlation, of such, is associated with aberrant retinal development (ROP). Utilizing pre-collected dried blood spots (DBS) from <1-week-old preterm infants, we aimed to determine whether correlations between VEGF165 and VEGF121 precede the diagnosis of early stage, non-proliferative ROP (NP-ROP). METHODOLOGY: We conducted a case/control study, utilizing DBS from 65 preterm infants. We measured DBS levels of VEGF165 on the Mesoscale Discovery Platform and VEGF121 via Cloud Clone Elisa Assay. RESULTS: In infants with NP-ROP, VEGF165 is significantly higher in males (than females). In infants without ROP, there is a significant correlation between VEGF165 and VEGF121 in females (but not males). In infants with NP-ROP, the opposite is so; there is a significant correlation between VEGF165 and VEGF121 in males (but not females). CONCLUSIONS: This pilot study, utilizing de-identified data, suggests the potential importance of examining interactions between VEGF isoforms, at <1 week after birth, to better understand ROP development. Our study also suggests that retinal angiogenesis may not be a sex-neutral process. A prospective study is needed to confirm our novel findings.

The association between high levels of luteinizing hormone and proliferative retinopathy of prematurity in female preterm infants.

BACKGROUND: Luteinizing hormone (LH) and human chorionic gonadotropin (hCG), generally considered reproductive hormones, have potent proangiogenic properties. Both of these hormones and their joint receptor (CG/LH receptor) are found in the human eye. We hypothesized that an excess of these hormones is associated with proliferative retinopathy of prematurity (P-ROP). METHODS: Dried blood spots (DBS) were used to perform a cross-sectional study of infants (gestational age of <26 weeks) with and without P-ROP, born in Michigan between August 1, 2012, and March 15, 2015. The DBS were collected at 1 week and 4 weeks of age from 45 preterm infants (27 no-ROP and 18 P-ROP). The DBS were linked to hospital records and then deidentified. ICD-9 codes were used to identify P-ROP cases. Hormones levels were measured via electrochemiluminescence assays on the Meso Scale Discovery platform. Associations between hormone levels at 1 and 4 weeks of age and the presence or absence of P-ROP were assessed. RESULTS: In female infants, we noted a trend toward higher LH levels in ROP cases at week 1 (P = 0.11) and significantly higher LH levels in cases at week 4 (P = 0.03). In male infants, no ROP-related differences in LH levels were found at either time point. For hCG levels, no associations with P-ROP were found in either sex at either time point. CONCLUSIONS: The association of high LH with P-ROP in female but not male infants raises the possibility that there are sex-specific hormonal determinants of aberrant retinal angiogenesis.

Feasibility of neonatal haemoglobin A1C as a biomarker for retinopathy of prematurity.

INTRODUCTION: Retinopathy of prematurity (ROP) is a potentially serious eye disorder affecting very preterm infants. Non-proliferative ROP (NP-ROP), also known as Early Stage ROP, is characterized by deficient retinal angiogenesis. Proliferative ROP (P-ROP), also known as Late Stage ROP, is characterized by pathologic angiogenesis. The use of neonatal haemoglobin A1C as a biomarker for ROP has not yet been evaluated. MATERIALS AND METHODS: We modified the Haemoglobin A1C assay for use with neonatal dried blood spots (DBS) and then assessed A1C levels via Elisa immunoassay on DBS from 43 preterm infants (with gestational ages 26-28 weeks). We measured A1C on DBS collected at <1 week and 4 weeks of chronological age. RESULTS: Compared to matched counterparts without ROP, there is significantly lower HbA1c in infants who develop NP-ROP, this occurs at Week 4 (p=0.004), but is not seen at Week 1; there is significantly higher HbA1c in infants with P-ROP, this occurs both at Week 1 (p<0.05) and Week 4 (p=0.005). CONCLUSIONS: The A1C test, modified for use with DBS, is a feasible biomarker for ROP; low A1C is a potential biomarker for non-proliferative ROP and high A1C is for proliferative ROP.

Demonstrating a Linear Relationship Between Vascular Endothelial Growth Factor and Luteinizing Hormone in Kidney Cortex Extracts.

Vascular endothelial growth factor (VEGF) helps to control angiogenesis and vascular permeability in the kidney. Renal disorders, such as diabetic nephropathy, are associated with VEGF dysregulation in the kidney. The factors that govern VEGF under physiologic conditions in the kidney are not well-understood. Luteinizing hormone (LH), a pro-angiogenic hormone, helps regulate physiologic VEGF expression in reproductive organs. Given that LH receptors are found in the kidney, we, at Zietchick Research Institute, hypothesized here that LH also helps regulate VEGF expression in the kidney as well. To provide evidence, we aimed to show that LH levels are able to predict VEGF levels in the mammalian kidney. Most VEGF-related investigations involving the kidney have used lower order mammals as models (i.e., rodents and rabbits). To translate this work to the human body, it was decided to examine the relationship between VEGF and LH in higher order mammals (i.e., bovine and porcine models). This protocol uses the total protein lysate from the kidney cortex. Keys to this method's success include procurement of kidneys from slaughterhouse animals immediately after death as well as normalization of analyte levels (in the kidney extract) by total protein. This study successfully demonstrates a significant linear relationship between LH and VEGF in both bovine and porcine kidneys. The results are reproducible in two different species. The study provides supporting evidence that the use of kidney extracts from cows and pigs are an excellent, economical, and abundant resource for the study of renal physiology, particularly for examining the correlation between VEGF and other analytes.

The postnatal presence of human chorionic gonadotropin in preterm infants and its potential inverse association with retinopathy of prematurity.

BACKGROUND: Human chorionic gonadotropin (hCG) and luteinizing hormone (LH) are pro-angiogenic gonadotropic hormones, which classically target the reproductive organs. However, hCG, LH, and their shared CG/LH receptor are also present in the human eye. The possibility that a deficiency of these hormones may be involved in the pathogenesis of retinopathy of prematurity (ROP) during its early non-proliferative phase has not been explored. METHODS: We conducted a cross-sectional study of Michigan-born preterm infants utilizing dried blood spots. We analyzed hCG and LH blood levels at 1 week and 4 weeks of age from 113 study participants (60 without ROP; 53 with non-proliferative ROP). We utilized electrochemiluminescence assays on the Mesoscale Discovery platform. RESULTS: Similar levels of hCG are found in preterm infants at both 1 week and 4 weeks after birth. Preterm infants with non-proliferative ROP, after adjusting for sex and gestational age, have 2.42 [95% CI: 1.08-5.40] times the odds of having low hCG at fourth week of age. CONCLUSIONS: We found that hCG is present postnatally in preterm infants and that a deficiency of hCG at 4 weeks of age is potentially associated with non-proliferative ROP. This provides novel evidence to suggest that hCG may participate in human retinal angiogenesis.

The potential effect of human chorionic gonadotropin on vasoproliferative disorders of the immature retina.

Human chorionic gonadotropin (hCG) is known to be a powerful vascular endothelial growth factor (VEGF)-regulating hormone. It stimulates vascularization of the gravid uterus by upregulating VEGF expression. In the body, hCG activates the same receptor as luteinizing hormone (LH). Like hCG, LH is also strongly proangiogenic. Recently, it has been shown that LH/hCG receptors are present in the retina and that both LH and hCG are found in the eye. In fact, the human eye can synthesize its own hCG. We have previously shown that LH and VEGF are significantly correlated in mammalian eyes, potentially implicating LH-receptor/hCG-receptor activation in intraocular VEGF regulation. Given that elevated VEGF is associated with progression of two vasoproliferative pediatric retinal disorders, retinopathy of prematurity and retinoblastoma, our objective was to determine whether hCG may potentially affect VEGF production and pathologic retinal vascularization in vasoproliferative disorders affecting the immature retina. In this study, we used (a) oxygen-induced retinopathy mouse model (standard model for retinopathy of prematurity) and (b) Y79 retinoblastoma cells (a human cell line derived from immature retinal cells). In the oxygen-induced retinopathy model, number of preretinal nuclei (representing pathologic retinal neovascularization) significantly increases by 57% (P<0.05) in hCG-treated mice. In Y79 cells, VEGF production significantly increases by 37% (P<0.05) in hCG-treated cells. These findings suggest that hCG is potentially able to influence retinal vascularization and VEGF production and thus, the hCG receptor may potentially represent a therapeutic target for vasoproliferative retinal disorders affecting the young eye.

Elimination of Signaling by the Luteinizing Hormone Receptor Reduces Ocular VEGF and Retinal Vascularization during Mouse Eye Development.

Purpose/Aim: Vascular endothelial growth factor (VEGF) dysregulation is implicated in the pathogenesis of retinopathy of prematurity (ROP). Identifying the factors that contribute to VEGF regulation during normal retinal vascularization is the key to ROP prevention. Currently, physiologic hypoxia is thought to be responsible for retinal VEGF regulation in utero. However, a potential hormonal contribution to VEGF regulation during eye development has not been fully investigated. The placental hormone, human chorionic gonadotropin and the pituitary hormone, and luteinizing hormone (LH) induce VEGF expression in several tissue types. Both of these gonadotropins activate the same LH receptor (LHR) in the human body; LHRs are expressed in the retina. In this study, we aimed to show that LHR signaling participates in VEGF regulation in the developing eye. METHODS: When offspring from breeding pairs of LHR knockout mice (lhrkos) reached 21 days old, eyes and serum were extracted from homozygote lhrkos and wildtype (WT) siblings. VEGF levels were measured using Mouse VEGF Quantikine immunoassay kit. Retinas were incubated with isolectin for endothelial cell staining, flat mounted and imaged by confocal microscopy. Retinal vascular density was quantified using Imaris software. Some eyes were sectioned and stained for histopathologic review. RESULTS: Ocular VEGF and retinal vascular volumes were significantly reduced by ~ 15% in lhrko eyes. Serum VEGF was not changed. The lhrko retinas did not display any anomalies. CONCLUSIONS: We provide evidence that LHR signaling plays a role in VEGF regulation and vascularization in the developing eye. Given that human preterm infants may have altered LHR-activity, the effect of gonadotropins on eye development should be further studied to identify novel strategies for ROP prevention.

Confirmation of Luteinizing Hormone (LH) in Living Human Vitreous and the Effect of LH Receptor Reduction on Murine Electroretinogram.

Luteinizing hormone (LH), produced in the anterior pituitary, has been detected in cadaver eyes and LH receptors (LHRs) have been identified in the retina, with the highest density in cone photoreceptors. Our aim was to confirm the presence of LH in the living, human eye as well as to examine the potential impact of a reduction in LHR signaling on visual processing. Vitreous samples were collected from 40 patients (23 diabetics, 17 non-diabetics) who were undergoing vitrectomies for various indications. LH concentration was quantified in each sample via an electro-chemiluminescence immunoassay and Meso Scale Discovery platform and normalized to total protein. In addition, full-field electroretinography (ERG) was performed on 11 adult LHR knockout heterozygous mice (B6;129X1-Lhcgrtm1Zmlei/J) and 11 wild types using the Celeris-Diagnosys system. The median LH values (pg/mg total protein) for non-diabetics, diabetics without proliferative diabetic retinopathy (PDR) and diabetics with PDR were 40.7, 41.9 and 167.8 respectively. LH levels were significantly higher in diabetics with PDR. In our ERG investigation, heterozygous LHRKOs were found to have significantly reduced amplitudes of a-wave and b-waves at high stimulus intensities with no significant change in a-wave or b-wave amplitudes at lower intensities; this is consistent with a selective impairment of cone-mediated responses. Our findings confirm LH is present in the adult human eye. Our findings also suggest that a reduction in LH receptor signaling negatively impacts visual processing of the cone photoreceptors. Overall, our study results support the theory that LH likely plays a physiologic role in the eye.

Vitreous Levels of Luteinizing Hormone and VEGF are Strongly Correlated in Healthy Mammalian Eyes.

Purpose/Aim: Luteinizing hormone (LH) is known to function as a key regulator of vascular endothelial growth factor (VEGF) expression in reproductive organs. In recent years, LH has also been detected in human vitreous and LH receptors have been identified in human retina. This study was aimed to investigate a potential correlation between LH and VEGF levels in healthy mammalian eyes to provide supporting evidence of LH's potential involvement in intraocular VEGF regulation. METHODS: 18 bovine and 30 porcine eyes were procured from an abattoir and VEGF and LH levels were measured in the vitreous extracted from these eyes by commercially available bovine & porcine ELISA assay kits. Total protein of the vitreous was measured by using Micro BSA protein assay kit. RESULTS: After total protein normalization, the Pearson Correlation Coefficients (PCC) showed a strong and significant correlation between LH and VEGF levels. (Bovine LH/VEGF PCC: 0.89, p < 0.001; Porcine LH/VEGF PCC: 0.80, p < 0.001). Linear regression analyses, adjusted for gender, showed significant linear relationships between LH and VEGF levels in both bovine and porcine vitreous. (Bovine: t-value = 7.69, p < 0.0001, adjusted r2 = .79; Porcine: t-value = 6.71, p < 0.001, adjusted r2 = .62) Conclusions: We show that VEGF and LH are strongly correlated in healthy, adult mammalian eyes. The robustness of the correlation is shown both by its strength of association and reproducibility in two species. Given that LH is well known to regulate VEGF levels in several tissue types, the LH/VEGF linear relationship in vitreous potentially implicates LH in homeostatic VEGF regulation of the eye. Because we also found that the correlation between LH and VEGF only became manifest when our targeted analytes were normalized by total amount of protein, preclinical and clinical investigators should consider normalizing analytes in vitreous by total protein when assessing potential correlations among them.

Pretreatment with Human Chorionic Gonadotropin Protects the Neonatal Brain against the Effects of Hypoxic-Ischemic Injury.

INTRODUCTION: Though the human fetus is exposed to placentally derived human chorionic gonadotropin (hCG) throughout gestation, the role of hCG on the fetal brain is unknown. Review of the available literature appears to indicate that groups of women with higher mean levels of hCG during pregnancy tend to have offspring with lower cerebral palsy (CP) risk. Given that newborn cerebral injury often precedes the development of CP, we aimed to determine whether hCG may protect against the neurodegenerative effects of neonatal brain injury. METHODS: We utilized the Rice-Vannucci model of neonatal cerebral hypoxia-ischemia (HI) in postnatal day 7 mice to examine whether intraperitoneal administration of hCG 15-18 h prior, 1 h after or immediately following HI decrease brain tissue loss 7 days after injury. We next studied whether hCG has pro-survival and trophic properties in neurons by exposing immature cortical and hippocampal neurons to hCG in vitro and examining neurite sprouting and neuronal survival prior and after glutamate receptor-mediated excitotoxic injury. RESULTS: We found that intraperitoneal injection of hCG 15 h prior to HI, but not at or 1 h after HI induction, resulted in a significant decrease in hippocampal and striatal tissue loss 7 days following brain injury. Furthermore, hCG reduced N-methyl-d-aspartate (NMDA)-mediated neuronal excitotoxicity in vitro when neurons were continuously exposed to this hormone for 10 days or when given at the time and following neuronal injury. In addition, continuous in vitro administration of hCG for 6-9 days increased neurite sprouting and basal neuronal survival as assessed by at least a 1-fold increase in MAP2 immunoreactivity and a 2.5-fold increase in NeuN + immunoreactivity. CONCLUSION: Our findings suggest that hCG can decrease HI-associated immature neural degeneration. The mechanism of action for this neuroprotective effect may partly involve inhibition of NMDA-dependent excitotoxic injury. This study supports the hypothesis that hCG during pregnancy has the potential for protecting the developing brain against HI, an important CP risk factor.

Ventriculomegaly in very-low-birthweight infants with Down syndrome.

AIM: The prevalence of Down syndrome in infants with fetal ventriculomegaly is 5% to 10%; however, the converse, the prevalence of cerebral ventriculomegaly in live-born infants with Down syndrome, is not well established. Because cranial ultrasounds are performed on most very-low-birthweight (VLBW) infants (birthweight <1500g), our aim was to examine ultrasound abnormalities of VLBW infants to determine prevalence of ventriculomegaly and intraventricular hemorrhage (IVH) in VLBW infants with Down syndrome, and whether VLBW infants with Down syndrome are at higher risk for cranial ultrasound abnormalities, compared with the already elevated risk in other VLBW infants. METHOD: This study comprised retrospective analysis of data from Pediatrix BabySteps Clinical Data Warehouse. The study population consisted of 121 736 VLBW infants (61 869 males, 59 867 females), born between 1996 and 2013, of whom 441 had Down syndrome (233 males, 208 females; mean gestational age 30wks, standard deviation [SD] 2.8wks). Logistic regression was used to calculate odds of ventriculomegaly and IVH for Down syndrome. RESULTS: Prevalence of ventriculomegaly in Down syndrome was 5.2% compared with 0.8% in other VLBW infants. Multivariate analysis indicated 5.8× odds (95% confidence interval [CI] 3.4-9.7) of ventriculomegaly in Down syndrome and 0.9× odds (95% CI 0.7-1.1) of IVH for Down syndrome. INTERPRETATION: Very preterm infants with Down syndrome are at increased risk for ventriculomegaly (but not for IVH) compared with other infants born very preterm.

Postnatal corticosteroids and risk of retinopathy of prematurity.

PURPOSE: To investigate the association between postnatal steroids and retinopathy of prematurity (ROP) in neonates born with birth weights at the limit of viability (<500 g). METHODS: Data from the Pediatrix BabySteps Clinical Warehouse were retrospectively reviewed. The study population consisted of 1,472 neonates with birth weights of <500 g who were discharged alive from 167 NICUs between 1996 and 2013. Statistical significance for unadjusted comparisons between groups was determined using the χ(2) or t test. Logistic regression was used to calculate odds of ROP. RESULTS: In multivariate analysis, the odds of any ROP for steroid treated infants was 1.6 (95% CI, 1.2-2.2) compared to nontreated infants; the odds of advanced ROP was 1.7 (95% CI, 1.3-2.3). CONCLUSIONS: In our large study cohort of critically low birth weight infants ROP was more common in neonates exposed to postnatal steroids.

Partner's Perspective on Long-term Sexual Dysfunction After Prostate Cancer Treatment.

OBJECTIVE: Prostate cancer is the most common type of male cancer in the United States and the negative effect of prostate cancer treatment on sexual function has been well documented. The objective of this study was to examine the long-term impact of sexual dysfunction on spouses or partners of prostate cancer survivors. METHODS: A total of 742 spouses of prostate cancer survivors was mailed surveys by the Michigan Public Health Institute, of which 379 were returned (51%). Nine surveys were excluded owing to study ineligibility. Spouses responding to the survey completed a combination of modified items from the Sexual Adjustment Questionnaire and researcher-developed items. RESULTS: Over 75% of spouses reported a decline in sex life quality after treatment. Communication about sexual issues between survivors and their health care providers was rated as good to excellent by 54.7% of partners, whereas 35.1% reported it as fair to poor. Approximately 60% of physicians initially recommended some form of sexual treatment. However, despite the persistence of sexual dysfunction, only 7% of the prostate cancer survivors were currently receiving treatment. Only 4.1% of health care providers referred the survivor to a sex therapist. CONCLUSIONS: Physicians need to understand the importance of the open, ongoing communication with prostate cancer survivors about sexual issues because sexual dysfunction seems to continue indefinitely after completion of treatment. Research on the effectiveness of behavioral interventions in restoring sexual health is critically needed for this population, especially as first-line sexual aids and medications are often not satisfactory solutions.

Trisomy 21 and Risk of Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVES: Trisomy 21 is known to decrease the risk of several (nonocular) angiogenic-mediated diseases. The objective of this study was to determine whether trisomy 21 can also be shown to be significantly protective against ocular angiogenic-mediated disorders such as retinopathy of prematurity (ROP). METHODS: A retrospective analysis of deidentified data from the Pediatrix BabySteps Clinical Warehouse. This large repository of neonatal data is approved for use in research studies by the Western Institutional Review Board. The study population consisted of 99,080 infants with very low birth weights (BWs; BW <1500 g), born between 1996 and 2013, cared for at >300 US NICUs, and who had been discharged alive from hospital. Statistical significance for unadjusted comparisons between groups was determined with Pearson's χ(2) test or Student's t test. Logistic regression models were used to calculate the odds of ROP (of any stage) and advanced ROP (stage 3 or greater) for infants with trisomy 21 compared with all other infants. RESULTS: The prevalence of trisomy 21 was 0.3% in the study population (321 of 99,080). After adjustment for BW, gestational age, oxygen exposure, and other potential confounders, there was an odds ratio of 0.6 (95% confidence interval: 0.5-0.8) for ROP in infants with trisomy 21compared with other infants and an odds ratio of 0.4 (95% confidence interval: 0.1-0.9) for advanced-stage ROP. CONCLUSIONS: Trisomy 21 significantly decreases the odds for ROP in very low BW infant survivors. This study unmasks a potentially identifiable genetic component to ROP risk, paving the way for the development of a laboratory-based ROP screening tool.

Association between transient hypothyroxinaemia of prematurity and adult autism spectrum disorder in a low-birthweight cohort: an exploratory study.

BACKGROUND: Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low-birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD). METHODS: This secondary analysis uses data from a birth cohort of newborns weighing 500 -2000 g (n = 1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two-stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z-score <-2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated. RESULTS: The mean neonatal thyroxine z-score in young adults diagnosed with ASD was 0.5 SD lower [95% CI -0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5-fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]). CONCLUSION: While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation.

Autism spectrum disorder is associated with ventricular enlargement in a low birth weight population.

OBJECTIVE: To determine the relation of neonatal cranial ultrasound abnormalities to autism spectrum disorders (ASD) in low birth weight (LBW) adult survivors, a population at increased ASD risk. STUDY DESIGN: This is a secondary analysis of a prospectively-followed regional birth cohort of 1105 LBW infants systematically screened for perinatal brain injury with cranial ultrasound in the first week of life and later assessed for ASD using a two-stage process [screening at age 16 years (n = 623) followed by diagnostic assessment at age 21 years of a systematically selected subgroup of those screened (n = 189)]; 14 cases of ASD were identified. For this analysis, cranial ultrasound abnormalities were defined as ventricular enlargement (indicative of diffuse white matter injury), parenchymal lesions (indicative of focal white matter injury), and isolated germinal matrix/intraventricular hemorrhage. RESULTS: Compared with no cranial ultrasound abnormalities, any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positively for ASD [3.0 (2.2, 4.1)]. However, the risk of being diagnosed with ASD depended on type of white matter injury. With ventricular enlargement, the risk of ASD diagnosis was almost seven-fold that of no cranial ultrasound abnormality [6.7 (2.3, 19.7)], and no elevated risk was found for parenchymal lesion without ventricular enlargement [1.8 (0.2, 13.6)]. Isolated germinal matrix/intraventricular hemorrhage did not increase risk for a positive ASD screen or diagnosis. CONCLUSION: In LBW neonates, cranial ultrasound evidence of ventricular enlargement is a strong and significant risk factor for subsequent development of rigorously-diagnosed ASD.

Does medical insurance type (private vs public) influence the physician's decision to perform Caesarean delivery?

INTRODUCTION: US data reveal a Caesarean rate discrepancy between insured and uninsured patients, with the C-section rate highest among the privately insured. The data have prompted concern that financial incentives associated with insurance status might influence American physicians' decisions to perform Caesarean deliveries. OBJECTIVE: To determine whether differences in medical risk factors account for the apparent Caesarean rate discrepancy between Medicaid and privately insured patients in Michigan, USA. METHOD: A retrospective review was performed of 617 269 live birth deliveries in Michigan hospitals during 2004-8. All live birth records that were able to be linked to their mothers' hospital discharge records were utilised. Diagnosis-related group codes from the hospitalisation records were used to identify Caesarean deliveries. Regression models determined Caesarean probability for the time period under study, adjusted for insurance type, maternal age, race, maternal medical conditions, multiple births, prematurity and birth weight. RESULTS: From 2004 to 2008, Caesarean rates were 33% for privately insured patients and 29% for Medicaid patients. The probability of Caesarean delivery was significantly greater for privately insured than Medicaid patients on univariate analysis (OR 1.2, 95% CI 1.19 to 1.22) but not on multivariate analysis (adjusted OR 1.01, 95% CI 0.99 to 1.02). CONCLUSION: No significant disparity was found in the odds of Caesarean delivery between privately insured and Medicaid patients in Michigan after adjusting for other Caesarean risk factors. A positive disparity would have provided de facto evidence that financial incentives play a role in physician decision-making regarding Caesarean delivery.

The effect of gestational age on symptom severity in children with autism spectrum disorder.

Between 2006 and 2010, two research-validated instruments, Social Communication Questionnaire (SCQ) and Social Responsiveness Scale (SRS) were filled out online by 4,188 mothers of Autism Spectrum Disorder (ASD) children, aged 4-21, as part of voluntary parental participation in a large web-based registry. Univariate and multivariate linear regression analysis (adjusted for child's sex, ability to verbalize, categorical IQ score, and fetal growth rate) demonstrated significantly higher SCQ and SRS scores for ASD children of both preterm (<37 weeks) and post-term (>42 weeks) gestational age (GA) compared to ASD children of normal GA, thus indicating that both preterm and post-term children manifest increased ASD symptomatology. Normal GA at birth appears to mitigate the severity of autistic social impairment in ASD children.