Antenatal corticosteroid treatment in singleton, small-for-gestational-age infants born at 24-31 weeks' gestation: a population-based study.

OBJECTIVE: To assess the impact of antenatal corticosteroid therapy on mortality and severe morbidities in preterm, small-for-gestational-age (SGA) neonates compared with preterm non-SGA neonates. DESIGN: Population-based study. SETTING/POPULATION: Israel National Very Low Birth Weight infant database from 1995-2012. METHODS: Singleton infants of 24-31 weeks' gestation, without major malformations. Antenatal corticosteroids were considered either any treatment or no treatment. MAIN OUTCOME MEASURES: Univariate and multivariable logistic regression analyses were performed to assess the effect of antenatal corticosteroids on neonatal mortality and a composite adverse outcome of mortality or severe neonatal morbidity. RESULTS: Among the 10 887 study infants, 1771 were SGA. Of these, 70.4% of SGA and 66.7% of non-SGA neonates were exposed to antenatal corticosteroids. Among SGA neonates, antenatal corticosteroids were associated with decreased mortality (32.2 versus 19.3%, P < 0.0001) and composite adverse outcome (54.1 versus 43.4%, P < 0.0001), similar to the effect in non-SGA neonates (mortality 26.7 versus 12.2%, P < 0.0001; composite outcome 50.5 versus 34.6%, P < 0.0001). Multivariable logistic regression analyses demonstrated a 50% reduction in mortality risk among SGA and 57% reduction in non-SGA neonates exposed to corticosteroids [OR = 0.50, 95% confidence interval (95% CI) 0.39-0.64 and OR = 0.43, 95% CI 0.38-0.47, respectively], P-value for interaction = 0.08. Composite adverse outcome risk was significantly reduced in SGA (OR = 0.67, 95% CI 0.54-0.83) and non-SGA infants (OR = 0.57, 95% CI 0.52-0.63), P-value for interaction = 0.04. CONCLUSIONS: Antenatal corticosteroids significantly reduced mortality and severe morbidities among preterm SGA neonates, with slightly a less pronounced effect compared with non-SGA preterm infants. Antenatal corticosteroids should be given to fetuses suspected of intrauterine growth retardation, at risk for preterm delivery, in order to improve perinatal outcome. TWEETABLE ABSTRACT: Antenatal steroids reduced mortality and severe morbidities among singleton, preterm SGA neonates.

Health outcomes of children born after IVF/ICSI: a review of current expert opinion and literature.

The Sixth Evian Annual Reproduction (EVAR) Workshop Group Meeting was held to evaluate the impact of IVF/intracytoplasmic sperm injection on the health of assisted-conception children. Epidemiologists, reproductive endocrinologists, embryologists and geneticists presented data from published literature and ongoing research on the incidence of genetic and epigenetic abnormalities and congenital malformations in assisted-conception versus naturally conceived children to reach a consensus on the reasons for potential differences in outcomes between these two groups. IVF-conceived children have lower birthweights and higher peripheral fat, blood pressure and fasting glucose concentrations than controls. Growth, development and cognitive function in assisted-conception children are similar to controls. The absolute risk of imprinting disorders after assisted reproduction is less than 1%. A direct link between assisted reproduction and health-related outcomes in assisted-conception children could not be established. Women undergoing assisted reproduction are often older, increasing the chances of obtaining abnormal gametes that may cause deviations in outcomes between assisted-conception and naturally conceived children. However, after taking into account these factors, it is not clear to what extent poorer outcomes are due to the assisted reproduction procedures themselves. Large-scale, multicentre, prospective epidemiological studies are needed to investigate this further and to confirm long-term health consequences in assisted-conception children. Assisted reproduction treatment is a general term used to describe methods of achieving pregnancy by artificial means and includes IVF and sperm implantation. The effect of assisted reproduction treatment on the health of children born using these artificial methods is not fully understood. In April 2011, fertility research experts met to give presentations based on research in this area and to look carefully at the evidence for the effects of assisted reproduction treatment on children's health. The purpose of this review was to reach an agreement on whether there are differences in the health of assisted-conception children with naturally conceived children. The researchers discovered no increased risk in birth defects in assisted-conception children compared with naturally conceived children. They found that IVF-conceived children have lower birth weights and higher fat under the skin, higher blood pressure and higher fasting glucose concentrations than naturally conceived children; however, growth, development and cognitive function are similar between groups. A very low risk of disorders of genetic control was observed in assisted-conception children. Overall, there did not appear to be a direct link between assisted reproduction treatment and children's health. The researchers concluded that the cause of some differences in the health of children conceived using assisted reproduction treatment may be due to the age of the woman receiving treatment. Large-scale, research studies are needed to study the long-term health of children conceived using assisted reproduction treatment.

Maternal and neonatal health outcomes following assisted reproduction.

This study assessed the risk for maternal complications in women and neonatal outcomes in children conceived following assisted reproductive treatment as compared with spontaneously conception and also separately evaluated conventional IVF and intracytoplasmic sperm injection (ICSI). The prospective cohort included 1161 women with singleton pregnancies: 561 who conceived following assisted reproduction (223 following IVF and 338 following ICSI) and 600 who conceived spontaneously. No differences were observed in pregnancy complications (including spontaneous abortion, pregnancy-induced hypertension, gestational diabetes and Caesarean delivery) except for significantly increased risk for excess vaginal bleeding in assisted reproduction pregnancies (21.4% versus 12.9%; OR 1.67, 95% CI 1.18-2.37), which was prominent in women who reported polycystic ovary syndrome. Neonates born following assisted reproduction had increased risk for prematurity (10.6% versus 5.3%; OR 1.72, 95% CI 1.04-2.87), and IVF, but not ICSI, was associated with significantly increased risk for prematurity (OR 2.36, 95% CI 1.28-4.37) and low birthweight (OR 1.89, 95% CI 1.03-3.46). In conclusion, this study observed only an increased risk for excess vaginal bleeding as a pregnancy-associated complication in singleton pregnancies following assisted compared with spontaneous conception. However, singleton neonates born following IVF, but not ICSI, were at increased risk for prematurity.

Type 1 diabetes in pre-school children--long-term metabolic control, associated autoimmunity and complications.

AIMS: To identify clinical characteristics and co-morbidity rates of children diagnosed with Type 1 diabetes mellitus at younger than 6 years of age. METHODS: Data were obtained from a retrospective chart review of 103 patients diagnosed with Type 1 diabetes at younger than 6 years (study group) and 220 patients at older than 6 years (comparison group). Measures of glycaemic control and occurrence of co-morbidities (coeliac disease, autoimmune thyroid disease, hypertension, nephropathy and retinopathy) were compared. RESULTS: The mean follow-up period was more than 8 years. For the study group, mean HbA(1c) levels ranged from 64 mmol/mol to 66 mmol/mol (8.0-8.2%) until age 10 years, and then rose to 73 mmol/mol (8.8%). The HbA(1c) levels were higher in the study than in the comparison group for comparable ages (P = 0.003). After adjustment for duration of diabetes this difference was not significant. The overall rate of severe hypoglycaemic events was greater in the study group than in the comparison group (P = 0.03). Kaplan-Meier diagnosis rates of celiac disease, 10 years after Type 1 diabetes diagnosis, were 14.4% and 4.2% in the study and comparison groups, respectively (P log-rank = 0.03). There were no differences in rates of autoimmune thyroid disease, hypertension, nephropathy or retinopathy. CONCLUSIONS: Children diagnosed with Type 1 diabetes before the age of 6 years were in greater risk of developing celiac disease, compared with children diagnosed after the age of 6 years. For children diagnosed with Type 1 diabetes aged under 6 years, good metabolic control was achievable until age 10 years, after which it deteriorated. Higher HbA(1c) levels observed in children diagnosed before the age of 6 years were associated with longer duration of disease.

Prevalence of overweight in kindergarten children in the centre of Israel - association with lifestyle habits.

OBJECTIVES: (1) To determine the prevalence of overweight and at risk for overweight in a sample of 4- to 6-year-old Israeli children; and (2) to delineate factors which may be associated with excess of overweight such as food intake, food habits physical and sedentary activity, family and socio-economic factors. METHODS: In a cross-sectional survey in six kindergartens in the centre of Israel, 204 children (104 boys), mean age 5.5 years were studied. RESULTS: In total, 40% of the children were either at risk for overweight (25%) or overweight (15%). Parents of one-third of all children reported their children ate unbalanced meals; however, caloric intake was not different between the weight groups. Overweight children were reported to eat according to mood status and preferred eating candies. Knowledge of dietary requirements was fairly good and similar in all three weight groups. Screen viewing time was more than twofold greater than the recommended in all weight groups. The rate of parental obesity was not different in the weight groups. CONCLUSIONS: A high rate of overweight was documented among pre-schoolers in the centre of Israel. Poor lifestyle habits were noted in about one-third of all children; however, no association was found between the poor lifestyle habits and overweight but more overweight children eat according to mood status and preferred eating candies as a snack.

Focus on fathers: paternal depression in the perinatal period.

AIMS: This report aims to present a concise overview and synthesis of current research findings regarding paternal depression in the perinatal period. METHODS: A literature search was conducted, primarily via PubMed and PsychNET, for English-language research studies and meta-analyses using combinations of the terms 'perinatal', 'pregnancy', 'postpartum', 'depression' AND 'fathers' OR 'paternal'. Peer-reviewed articles were considered, and a representative sample of literature, with an emphasis on recent publications from a broad range of populations was summarized for each of the following sub-sections: prevalence, risk factors, impact on the infant/child, and healthcare costs. RESULTS: Reported prevalence has ranged from 2.3% to 8.4%, with a significant degree of heterogeneity in rates, due to differences in multiple aspects of the methodology (timing, instruments, etc.). Nevertheless, rates of maternal depression remain higher than paternal depression, and higher rates of one are associated with higher rates of the other. The primary risk factors for paternal depression are maternal depression and the father's history of severe depression, or symptoms of depression or anxiety prenatally. Biological mechanisms may underlie paternal depression, with changes reported in testosterone, cortisol and prolactin levels during this period. Paternal depression has been related to children's behavioral, emotional and social function at 36 months and psychiatric disorders at 7 years, adjusting for maternal depression. Healthcare costs may also be impacted by paternal postpartum depression, with higher father-child dyad costs found after controlling for potential confounders. CONCLUSIONS: Focusing on fathers' emotional well-being in the perinatal period is important in itself, as well as for their wives and children. Programs recommending screening for maternal perinatal mood and anxiety disorders should include inquiry regarding the father's emotional state, and if his distress is reported it should be clarified and followed-up by support and intervention as necessary.

The possible association between IVF and breast cancer incidence.

BACKGROUND: The possible association between ovulation-inducing drugs and breast cancer development has been debated. Our aim was to evaluate the incidence of breast cancer in a cohort of women exposed to in vitro fertilization (IVF). METHODS: A retrospective cohort analysis was performed by linkage of the computerized database of all women treated at the IVF Unit at Assaf Harofeh Medical Center between 1986 and 2003, and the Israeli National Cancer Registry. The standardized incidence ratio (SIR) was computed as the ratio between the observed number of breast cancer cases and the expected cases, adjusted for age and continent of birth, in the general population. Tumor characteristics of the IVF patients were studied by reviewing original medical records. RESULTS: 35 breast carcinomas were diagnosed among 3,375 IVF-treated women, compared to 24.8 cases expected (SIR = 1.4; 95% CI 0.98-1.96). Age >or=40 years at IVF treatment (SIR = 1.9; 95% CI 0.97-3.30), hormonal infertility (SIR = 3.1; 95% CI 0.99-7.22), and >or=4 IVF cycles (SIR = 2.0; 95% CI 1.15-3.27) were found to be risk factors to develop breast cancer compared to the general population. Multivariate analysis revealed that women who underwent >or=4 IVF cycles compared to those with one to three cycles were at risk to develop breast cancer, although not significantly (SIR = 1.9; 95% CI 0.95-3.81). Of IVF-treated women 85% had ER(+) tumors and 29% had positive family history. CONCLUSIONS: A possible association between IVF therapy and breast cancer development was demonstrated, especially in women >or=40 years of age. These preliminary findings need to be replicated in other cohort studies.

Less postnatal steroids, more bronchopulmonary dysplasia: a population-based study in very low birthweight infants.

OBJECTIVE: To study the association between reduced use of postnatal steroids for bronchopulmonary dysplasia (BPD) in very low birthweight (VLBW) infants and oxygen (O(2))-dependency at 28 days of age and at 36 weeks postmenstrual age. DESIGN: Large national database study. SETTING: The Israel National VLBW Neonatal Database. PATIENTS: The sample included infants born between 1997 and 2004, of gestational age 24-32 weeks, who required mechanical ventilation or O(2) therapy. Four time periods were compared: 1997-8 (era 1, peak use), 1999-2000 (era 2, intermediate), 2001-2 (era 3, expected reduction) and 2003-4 (era 4, lowest). The outcome variable "oxygen dependency" was based on clinical criteria. Multivariate regression models were used to account for confounding variables. RESULTS: Steroid use fell significantly from 23.5% in 1997-8 to 11% in 2003-4 (p<0.005). After adjustment for relevant confounding variables, the odds ratio for O(2) therapy at 28 days in era 4 versus era 1 was 1.75, 95% confidence interval (CI) 1.47 to 2.09 and 1.41, 95% CI 1.15 to 1.73 at 36 weeks postmenstrual age. The mean duration of O(2) therapy increased from 25.3 days (95% CI 23.3 to 26.3) in era 1, to 28.0 days (95% CI 26.6 to 29.4) in era 4. Survival increased from 78.5% in era 1 to 81.6% in era 4 (p<0.005). CONCLUSIONS: The use of steroids has fallen considerably since the awareness of the adverse effects of this treatment. This change has been temporally associated with increased O(2) dependency at 28 days of age and at 36 weeks postmenstrual age. The prolongation of O(2) therapy was modest in degree.

Delivery room resuscitation and adverse outcomes among very low birth weight preterm infants.

OBJECTIVE: To evaluate risk factors and impact of delivery room cardiopulmonary resuscitation (DR-CPR) on very low birth weight (VLBW) preterm infants. STUDY DESIGN: A national, population-based, observational study evaluating risk factors and short-term neonatal outcomes associated with DR-CPR among VLBW, extremely preterm infants (EPIs, 24 to 27 weeks' gestation) and very preterm infants (VPI, 28 to 31 weeks' gestation) born in 1995 to 2010. RESULTS: Among 17 564 VLBW infants, 636 (3.6%) required DR-CPR. In the group of 6478 EPI, 412 (6.4%) received DR-CPR compared with 224 of 11 086 infants (2.0%) in the VPI group. EPI who underwent DR-CPR had higher odds ratios (ORs (95% confidence interval)) for mortality compared to EPI not requiring DR-CPR (OR 3.32 (2.58, 4.29)), grades 3 to 4 intraventricular hemorrhage (IVH) (OR 1.59 (1.20, 2.10)) and periventricular leukomalacia (OR 1.81 (1.17, 2.82)). DR-CPR among VPI was associated with higher ORs for mortality (OR 4.99 (3.59, 6.94)), early sepsis (OR 2.07 (1.05, 4.09)), grades 3 to 4 IVH (OR 3.74 (2.55, 5.50)) and grades 3 to 4 retinopathy of prematurity (ROP) (OR 2.53 (1.18, 5.41)) compared to VPI not requiring DR-CPR. Only 11% of infants in the EPI DR-CPR group had favorable outcomes compared with 44% in the VPI DR-CPR group. Significantly higher ORs for mortality, IVH and ROP were found in the VPI compared to the EPI group. CONCLUSION: Preterm VLBW infants requiring DR-CPR were at increased risk of adverse outcomes compared to those not requiring CPR. This effect was more pronounced in the VPI group.

Risk factors associated with post-hemorrhagic hydrocephalus among very low birth weight infants of 24-28 weeks gestation.

OBJECTIVE: Post-hemorrhagic hydrocephalus (PHH) is associated with morbidity and mortality among very low birth weight (VLBW) infants. This study aimed to determine risk factors for PHH among VLBW infants with peri-intraventricular hemorrhage (PIVH). STUDY DESIGN: This is a population-based cohort of VLBW infants of 24 to 28 weeks gestation, born in Israel from 1995 to 2012. Infants in whom a brain ultrasound was not performed before 28 days or with major congenital malformations were excluded. Univariate and multivariable analyses identified risk factors associated with PHH. RESULTS: The final study cohort comprised 2811 infants with grade 2 or higher PIVH, of whom 610 (21.7%) developed PHH. PHH was independently associated with PIVH severity, with bilateral grade 3 PIVH and PIVH grade 3 and contralateral grade 4 having the highest risks (odds ratio (OR) 12.2, 95% confidence interval (CI) 8.56 to 17.4 and OR 13.7, 95% CI 9.4 to 20.1, respectively). Unilateral grade 3 or 4 PIVH's had moderately increased risks of PHH (OR 3.50, 95% CI 2.26 to 5.42 and OR 3.79, 95% CI 2.35 to 6.12, respectively). PHH was independently associated with increasing gestational age (GA) and with neonatal morbidities including patent ductus arteriosus (OR 1.47, 95% CI 1.15 to 1.88 if medically treated and OR 3.01, 95% CI 2.11 to 4.29 if surgically treated), sepsis (OR 1.79, 95% CI 1.44 to 2.22) and necrotizing enterocolitis (OR 1.60, 95% CI 1.18 to 2.17). CONCLUSIONS: Among VLBW infants with PIVH, PHH was independently associated with PIVH severity group, increasing GA and acute neonatal morbidities. Unilateral grade 3 or 4 PIVH was associated with a moderate risk of developing PHH compared with bilateral severe hemorrhages.

Glycemic control and clinic attendance of emerging adults with type 1 diabetes at a transition care clinic.

BACKGROUND: Emerging adulthood is a challenging period for diabetes management. Our aim was to determine whether a dedicated transition clinic for emerging adults with type 1 diabetes can improve glycemic control and visit attendance. METHODS: An observational study of 53 emerging adults (30 males) treated during 2010-2014 in a newly established transition clinic. The clinic was operated jointly by pediatric and adult endocrinologists and included a transition coordinator. Data collected included the source of referral, HbA1c levels, frequency of visit attendance, and acute complications. For 27 patients who had attended the pediatric clinic at the same medical center, data from up to 2 years preceding the transition were also collected. Patients filled the Diabetes Quality of Life-Youth questionnaire at the transition and 1 year later. RESULTS: Mean ± SD age at the transfer to the transition clinic was 22.1 ± 2.7 years; mean disease duration was 8.4 ± 5.0 years. Follow-up duration at the transition clinic was 1.2 ± 1.1 years. Mean HbA1c levels decreased from 67 mmol/mol (95 % CI 63-72) [8.3 % (95 % CI 7.9-8.7)] at transfer to 57 mmol/mol (95 % CI 52-63) [7.4 % (95 % CI 6.9-7.9)] after 1 year (p < 0.001). Thirty-six patients (68 %) attended three or more visits during their first year in the transition clinic. The impact of diabetes on quality of life, disease-related worries, and life satisfaction did not change significantly during 1-year attendance in the transition clinic. CONCLUSIONS: A dedicated transition clinic for emerging adults, with tailored support according to the developmental needs of emerging adulthood, showed improved glycemic control and visit attendance.

Perinatal factors associated with active intensive treatment at the border of viability: a population-based study.

OBJECTIVE: The aim of this national population-based study was to identify perinatal and neonatal factors associated with active intensive treatment (AIT) of infants born at the periviable period of 22 to 24 weeks of gestation. STUDY DESIGN: Data from the Israel national very low-birth weight infant database on 2207 infants born alive in 1995 to 2010 at gestational age (GA) 22 to 24 weeks were evaluated. AIT was defined as endotracheal intubation in the delivery room or mechanical ventilation in the neonatal intensive care unit. Multivariable logistic regression analyses were used to identify the independent effect of demographic and perinatal factors on AIT for each gestational week. RESULT: Of the 2207 infants born at 22 to 24 weeks GA, 1643 (74.4%) received AIT and 564 (25.6%) received comfort care. AIT increased from 25.5% at 22 weeks to 62.7 and 93.5% at 23 and 24 weeks GA, respectively, reflecting a 4.66 (95% confidence interval (CI) 3.32 to 6.54)- and 29.8 (95% CI 19.9 to 44.6)-fold odds for AIT at 23 and 24 weeks GA, respectively, compared with 22-week GA infants. Perinatal treatments associated with AIT included maternal tocolytic therapy (odds ratio (OR) 1.51, 95% CI 1.04 to 2.20), prenatal steroid therapy, both partial (OR 3.30, 95% CI 2.14 to 5.10) and complete (OR 3.17, 95% CI 1.91 to 5.26) and cesarean delivery (OR 2.68, 95% CI 1.88 to 3.83). Each unit increase in birth weight z-score was associated with an OR of 1.58 (95% CI 1.30 to 1.92) for AIT. At 22 weeks GA, maternal tocolytic treatment was associated with higher odds of AIT. In the 23 and 24-week GA infants, maternal infertility treatment, antenatal steroids, cesarean delivery and higher-birth weight z-scores were significantly associated with AIT. Among 23-week GA infants, AIT decreased significantly in the period 2006 to 2010 compared with 1995 to 2000 (OR 0.51, 95% CI 0.34 to 0.77). CONCLUSION: An active approach in obstetric management of pregnancies appears to impact the neonatologists' decision to undertake AIT treatment in infants born at the border of viability. The higher odds for AIT associated with obstetric interventions might contribute to the reported beneficial effect of antenatal steroids and cesarean delivery on the survival of infants born at the border of viability.

Pseudomonas aeruginosa bacteremia in children: analysis of trends in prevalence, antibiotic resistance and prognostic factors.

OBJECTIVE: To determine the factors predisposing to Pseudomonas aeruginosa bacteremia as well as the prevalence, source of infection, outcome and prognostic factors in pediatric patients. METHODS: Retrospective review of pediatric patients with P. aeruginosa bacteremia, at a large tertiary care hospital during a 6.5-year period. RESULTS: Seventy patients with P. aeruginosa bacteremia were identified. The annual rate of P. aeruginosa bacteremia remained unchanged during the study period. Antibiotic susceptibility remained unchanged except for two patients with extensive burns who developed resistant strains. Underlying diseases were malignancy (50%), prematurity (6%), burns (7%) and others (37%). The overall mortality associated with P. aeruginosa bacteremia was 20%. The fatality rate was higher among the young infants (compared with older children) and those who received previous antibiotic therapy (P = 0.02). Mortality rate was higher in nosocomial than in community-acquired infections (25% compared with 11.5%). The mortality rate of low birth weight and burns patients was significantly higher when compared with oncology patients or other patients, 75 and 40% compared with 11 and 19%, P = 0.01. Multiple regression analysis revealed a correlation only between the underlying disease and mortality (P = 0.02). In the oncology patients the only significant risk factor for mortality was absolute neutrophil count < or =0.1 x 10(9)/l (P = 0.06). CONCLUSION: P. aeruginosa bacteremia, although apparently not increasing in incidence and antibiotic resistance, is still a common serious complication in immunocompromised children with a high mortality rate. We conclude that the underlying disease is the main determinant of the clinical outcome.

Expression of topoisomerase II and Ki-67 in cervical carcinoma--clinicopathological study using immunohistochemistry.

AIM: To study the correlation between the expression of topoisomerase II and Ki-67 antigen and disease outcome in cervical squamous cell carcinomas. EXPERIMENTAL DESIGN: Forty-nine cervical carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III) and 5 control cervices were stained by monoclonal antibodies for topoisomerase II and Ki-67 (MIB-1 clone). Nuclear counts were correlated with patient age, tumor stage, histological grade and survival. RESULTS: Thirteen patients died of disease, 35 remained free of disease, and one patient was lost to follow up. Ki-67 counts were higher in CIN lesions, when compared to both invasive carcinomas and control cervices. Topoisomerase II counts were comparable for CIN and invasive tumors. No immunoreactivity for topoisomerase was detected in control cases. Neither stage nor grade was associated with nuclear counts using either marker. In multivariate survival analysis, stage (p=0.001), grade (p=0.03) and older patient age (p=0.02) predicted poor survival. Ki-67 counts predicted survival with borderline significance (p=0.07), while topoisomerase II counts were not related to survival. CONCLUSION: Ki-67 and topoisomerase II counts do not appear to have a significant role in the prediction of survival in cervical squamous cell carcinoma.

Expression of extracellular matrix proteins in cervical squamous cell carcinoma--a clinicopathological study.

AIM: To evaluate the intracellular and peritumoral expression of matrix proteins in squamous cell carcinoma of the uterine cervix using immunohistochemistry. METHODS: 71 squamous cell carcinomas and 10 controls were stained for laminin, fibronectin, and collagen IV. Cytoplasmic staining in tumour cells and peritumoral deposition of matrix proteins were evaluated. The association between staining results and patient age, tumour stage, histological grade, and survival was studied. RESULTS: Positive cytoplasmic staining for laminin, fibronectin, and collagen IV was observed in 17 (23.9%), 27 (38%), and 10 (14.1%) cases, respectively. Staining for laminin was most pronounced in the invasive front of tumour islands, while for fibronectin and collagen IV it appeared to be diffuse. Peritumoral staining for laminin and collagen IV was detected in 12 cases (16.9%). Early stage (Ia1-Ia2) tumours were uniformly negative for all three proteins. Cytoplasmic staining for laminin correlated with positive staining for fibronectin and collagen IV, and with the presence of a peritumoral deposition of collagen IV and laminin. There was no correlation with any of the three markers between staining results and patient age, stage, grade, or survival. CONCLUSIONS: Expression of extracellular matrix proteins in some cervical squamous cell carcinomas might reflect the enhanced ability of these tumours to modify the peritumoral stroma. This ability seems to be absent in early stage tumours. The correlation between intracytoplasmic and peritumoral expression of matrix proteins supports the evidence of their synthesis by tumour cells. However, this property did not correlate with disease outcome in this study.

Autoimmunity and reproduction.

OBJECTIVE: To review the association between autoimmunity and reproductive failure. DESIGN: A MEDLINE search done from 1965 to 1996. More than 300 original and review articles were evaluated, from which the most relevant were selected. RESULT(S): Autoimmune processes now are accepted widely as one of the possible mechanisms of many human diseases. The presence of autoimmune disorders has been associated repeatedly with reproductive failure. On the other hand, reproductive failure may be the first manifestation of autoimmune disorders. CONCLUSION(S): When abnormal autoantibody levels are present in women with reproductive failure, the reproductive failure alone should be considered as one of the possible clinical expressions of autoimmune disorders. Two relevant questions of whether these patients should be treated for autoimmunity remain unsolved. A prospective, placebo-controlled trial is necessary to evaluate the importance of any treatment.

Intrauterine insemination before transfer of frozen-thawed embryos may improve the pregnancy rate for couples with unexplained infertility: preliminary results of a randomized prospective study.

OBJECTIVE: To evaluate whether a combination of IUI and frozen-thawed embryo transfer (FT-ET) with ovulation induction would improve the PR in couples with unexplained infertility. DESIGN: Prospective, randomized study. SETTING: In Vitro Fertilization Unit, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. PATIENT(S): Sixty-two patients with unexplained infertility were assigned into two groups. The study group was composed of 32 women (38 cycles) who received ovulation induction followed by IUI and FT-ET. The control group was composed of 30 women (33 cycles) who received ovulation induction followed by FT-ET. INTERVENTION(S): Clomiphene citrate (CC) and hCG, IUI, and FT-ET. MAIN OUTCOME MEASURE(S): Pregnancy rate (PR) per cycle, PR per ET. RESULT(S): In the study group, the PR per cycle and per ET were 36.8% (14 of 38) and 40.6% (13 of 32), respectively. In the control group, the PR per cycle and per ET were 12.1% (4 of 33) and 14.3% (4 of 28), respectively. Statistically significant differences were found between the two groups in the PR per cycle (P=.02) and PR per ET (P=.03). No statistically significant difference was found between the groups for the stage in which the embryos were cryopreserved, the survival cleavage rates after thawing, grading of thawed embryos, and number of embryos transferred. CONCLUSION(S): In couples with unexplained infertility, the PR may be improved by combining IUI and FT-ET with ovulation induction. Performing IUI before thawing may prevent treatment cancellation in cycles with no surviving embryos.

Elevated levels of interleukin-6 in the follicular fluid at the time of oocyte retrieval for in vitro fertilization may predict the development of early-form ovarian hyperstimulation syndrome.

OBJECTIVE: To determine the possible predictive role of interleukin-2 (IL-2), IL-6, and tumor necrosis factor (TNF-alpha) in the development of early-form ovarian hyperstimulation syndrome (OHSS). DESIGN: Nested, case-control study. SETTING: An IVF unit, university-based program. PATIENT(S): Follicular fluid (FF) was obtained from 322 high responders. The study group and control group comprised 10 patients who developed early, severe OHSS and 10 who did not develop OHSS, respectively. An additional control group included 10 low-responder patients who did not develop OHSS. INTERVENTION(S): Ovulation induction with hMG combined with GnRH analogue. MAIN OUTCOME MEASURE(S): All FF samples were tested for IL-2, IL-6, and TNF-alpha. The patient's serum was tested for mean E2 and P concentrations. RESULT(S): Interleukin-6 levels in the FF were significantly higher in the OHSS group than in the two control groups, whereas no differences were found in IL-2 and TNF-alpha. No correlation was found between the FF concentrations of IL-2, IL-6, and TNF-alpha and the mean serum E2 levels or the number of oocytes retrieved. CONCLUSION(S): Elevated levels of IL-6 in the preovulatory FF at the time of oocyte retrieval for IVF may predict the development of early-form OHSS in high responders.

Patients with stages III and IV endometriosis have a poorer outcome of in vitro fertilization-embryo transfer than patients with tubal infertility.

OBJECTIVE: To evaluate the outcome of IVF in patients with stages III and IV endometriosis. DESIGN: Retrospective study. SETTING: The Sara Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Israel. PATIENT(S): Fifty-eight patients with stages III and IV endometriosis and 60 patients with tubal infertility. INTERVENTION(S): IVF-ET for all couples. MAIN OUTCOME MEASURE(S): Fertilization, pregnancy, and birth rates. RESULT(S): The comparison between patients with endometriosis and those with tubal infertility indicated that the former had a poor IVF outcome in terms of reduced fertilization rate (40% vs. 70%), reduced pregnancy rate per cycle (10.6% vs. 22.4%), and reduced birth rate per cycle (6.7% vs. 16.6%). The differences were statistically significant. CONCLUSION(S): The results show an unfavorable outcome of IVF-ET in patients with endometriosis when compared with those who have tubal infertility.

The ratio between carcinoma antigen-125 levels in the seminal plasma and serum may be a marker for fertilization in intracytoplasmic sperm injection.

OBJECTIVE: To assess the relationship between tumor marker carcinoma antigen-125 levels in seminal plasma and serum and fertilization rates in an IVF program, using intracytoplasmic sperm injection (ICSI). DESIGN: A prospective study. SETTING: IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. PATIENT(S): Twenty-five infertile patients with severe oligo-terato-asthenospermia syndrome and 25 fertile male donors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Serum and seminal plasma carcinoma antigen-125 concentrations and fertilization rate per cycle. RESULT(S): In the infertile group, the seminal plasma carcinoma antigen-125 levels ranged from 22.0 to 1,284.0 U/mL (mean level +/- SD, 229.9 +/- 274.2 U/mL). In the normospermic fertile male donors, the seminal plasma carcinoma antigen-125 concentrations ranged from 12.2 to 336.7 U/mL (mean level +/- SD, 110.1 +/- 91.6 U/mL). This difference was statistically significant. The mean +/- SD ratio between the seminal plasma/serum carcinoma antigen-125 levels differed significantly between the infertile group (47.9 +/- 61.3) and the fertile male donors (5.7 +/- 3.5). In the infertile group, the ratio between the seminal plasma/serum carcinoma antigen-125 levels was found to be negatively correlated with the oocyte fertilization rate. CONCLUSION(S): The ratio between carcinoma antigen-125 levels in the seminal plasma and serum may be an indirect marker for male infertility and fertilization rate in IVF treatment using ICSI.