Ofer Lehavi

First Trimester Maternal Serum Free Human Chorionic Gonadotropin as a Predictor of Adverse Pregnancy Outcome

Objective: The purpose of this study was to evaluate whether abnormal levels of first trimester maternal serum free human chorionic gonadotropin (β-hCG) are predictive of adverse pregnancy outcomes. Methods: The study included 1,622 consecutive patients with singleton pregnancies who underwent first trimester Down syndrome screening using nuchal translucency, and maternal serum free β-hCG and pregnancy-associated plasma protein-A. Patients with fetal anomalies or chromosome aberrations were excluded from the study. The incidences of various adverse pregnancy outcomes were evaluated according to maternal serum free β-hCG levels. Outcome variables included spontaneous miscarriage, proteinuric and non-proteinuric pregnancy-induced hypertension, fetal growth restriction, intrauterine fetal demise, spontaneous preterm delivery, oligohydramnios and placental abruption. Results: No significant differences were noted between groups for any of the demographic variables. The only statistically significant result was an increase in the relative risk for spontaneous miscarriage (RR = 6.33) at free β-hCG <0.2 multiples of the medians. No other statistically significant result was noted for the other adverse outcomes or for the overall complication rate. Conclusion: Low free β-hCG is associated with a higher incidence of spontaneous miscarriage but is a poor predictor of other pregnancy complications.

Virtual Azoospermia and Cryptozoospermia—Fresh/Frozen Testicular or Ejaculate Sperm for Better IVF Outcome?

Men diagnosed as having azoospermia occasionally have a few mature sperm cells in other ejaculates. Other men may have constant, yet very low quality and quantity of sperm cells in their ejaculates, resulting in poor intracytoplasmic sperm injection (ICSI) outcome. It has not been conclusively established which source of sperm cells is preferable for ICSI when both ejaculate and testicular (fresh or frozen) sperm cells are available. It is also unclear whether there is any advantage of fresh over frozen sperm if testicular sperm is to be used. We used ejaculate, testicular (fresh or frozen) sperm cells, or both for ICSI in 13 couples. Five of these couples initially underwent ICSI by testicular sperm extraction, because the males had total azoospermia, and in later cycles with ejaculate sperm cells. Ejaculate sperm cells were initially used for ICSI in the other 8 patients, and later with testicular sperm cells. The fertilization rate was significantly higher when fresh or frozen-thawed testicular sperm cells were used than when ejaculated sperm cells were used. Likewise, the quality of the embryos from testicular (fresh and frozen) sperm was higher than from ejaculated sperm (65.3% vs 53.2%, respectively, P < .05). The use of fresh testicular sperm yielded better implantation rates than both frozen testicular sperm and ejaculate. Therefore, fresh testicular sperm should be considered first for ICSI in patients with virtual azoospermia or cryptozoospermia because of their superior fertility.

Mass casualty incident management, triage, injury distribution of casualties and rate of arrival of casualties at the hospitals: lessons from a suicide bomber attack in downtown Tel Aviv

Background: Terrorist attacks in Israel cause mass events with varying numbers of casualties. A study was undertaken to analyse the medical response to an event which occurred on 17 April 2006 near the central bus station, Tel Aviv, Israel. Lessons are drawn concerning the management of the event, primary triage, evacuation priorities and the rate and characteristics of casualty arrival at the nearby hospitals. Methods: Data were collected both during and after the event in formal debriefings. Their analysis refers to medical response components, interactions and main outcomes. The event is described according to the DISAST-CIR methodology (Disastrous Incidents Systematic AnalysiS Through – Components, Interactions and Results). Results: 91 casualties were reported in this event; 85 were evacuated from the scene including 3 already dead on arrival, 9 severely injured, 14 moderately injured and 59 mildly injured. Six were declared dead at the scene. Emergency medical service (EMS) vehicle accumulation was rapid. The casualties were distributed between five hospitals (three level 1 and two level 2 trauma centres). The first evacuated casualty arrived at the hospital within 20 min of the explosion and the last urgent victim was evacuated from the scene after 1 h 14 min. Evacuation occurred in two phases: the first, lasting 1 h 20 min, in which most of the patients with evident trauma were evacuated and the second, lasting 8 h 15 min, in which most patients presented with tinnitus and symptoms of somatisation. The most common injuries were upper and lower limb injuries, diagnosed in 37% of the total injuries, and stress-related disturbances (anxiety, tinnitus, somatisation) diagnosed in 41%. Conclusion: Rapid accumulation of EMS vehicles, effective primary triage between urgent and non-urgent casualties and primary distribution between five hospitals enabled rapid conclusion of the event, both at the scene and at the receiving hospitals.

Screening for familial dysautonomia in Israel: evidence for higher carrier rate among Polish Ashkenazi Jews.

Familial dysautonomia (FD) is an autosomal recessive disorder characterized by hereditary sensory and autonomic neuropathies. Although extremely rare in most populations, FD is common among Ashkenazi Jews (AJ), with a calculated carrier frequency of 1 in 30, based on disease prevalence. The gene for FD was recently identified as IKBKAP. One major mutation (IVS2 + 6T --> C) is responsible in >99.5% of cases among AJ. The purpose of this study was to determine the actual frequency of FD carriers in the AJ population in Israel and to determine whether carriers are more frequent among a subpopulation of AJ from Poland. The study group included 1267 Jews of Ashkenazi origin who were referred for routine DNA screening tests. These included 1100 individuals who were full AJ and 167 who were part AJ. None had a family history of FD. Mutation analysis for (IVS2 + 6T --> C) was performed by PCR amplification followed by restriction enzyme analysis. All positive cases were confirmed by DHPLC WAVE( trade mark ). Among the 1100 full AJ tested, 34 were found to be FD carriers (1:32). The incidence of mutation carriers was significantly higher in AJ of Polish descent (1:18) compared to AJ of non-Polish descent (1:99). Among the 167 individuals who were part AJ, there were 3 carriers (1:56). The incidence of FD among AJ, particularly those of Polish background, warrants population screening. Population screening may be performed by denaturing high-performance liquid chromatography.

USP26 gene variations in fertile and infertile men.

BACKGROUND The human X chromosome is enriched with testis-specific genes that may be crucial for male fertility. One is the ubiquitin-specific protease 26 (USP26). Five frequent mutations have been identified: 1737G>A, 1090C > T, 370-371insACA, 494T > C and 1423C>T (with the latter three usually detected in a cluster). Their role in infertility is still controversial. This study assesses the association of the most frequent USP26 mutations with male infertility and male infertility etiology factors. METHODS The study included 300 infertile and 287 fertile men. Data were collected on ethnicity (according to maternal origin) and family history of reproduction. Clinical records from 235 infertile and 62 fertile (sperm bank donors) men were available and summarized. The five mutations were investigated by bioinformatic tools and their frequencies were assessed by restriction analysis. The results were correlated with clinical findings. Segregation of the mutations in four families was analyzed. RESULTS The five analyzed mutations were detected in 44 men from both fertile and infertile groups. The cluster and the 1090C>T mutations showed the highest frequency among Arabs and Sephardic Jews of the infertile group, respectively. Inheritance studies showed that mutations were not always associated with the infertility trait. Mutations 1090C>T and 1737G>A were significantly associated with a history of inguinal hernia (P = 0.007 and P = 0.043, respectively). The prevalence of inguinal hernia among men with the 1090C > T mutation was 33.3% (5/15 men), higher than that reported in infertile men (6.7%). CONCLUSIONS Mutation 1090C > T may be a new genetic risk factor for developing inguinal hernia which may be associated with impaired male fertility.

Preservation of sperm of cancer patients: extent of use and pregnancy outcome in a tertiary infertility center

Sperm cryopreservation is the best modality to ensure future fertility for males diagnosed with cancer. The extent to which cryopreserved sperm is actually used for impregnation, the fertility treatment options that are available and the success rates of these treatments have not been investigated in depth. The medical records of 682 patients who cryopreserved sperm cells due to cancer treatment were analyzed. Seventy of these patients withdrew their frozen sperm for fertility treatments over a 20-year period (most within the first 4 years after cryopreservation). Sperm quality of different malignancies and outcomes of assisted reproduction treatment (ART) for pregnancy achievement in relation to the type of treatment and the type of malignancy were evaluated. The results showed that the rate of using cryo-thawed sperm from cancer patients for fertility treatments in our unit was 10.3%. Sperm quality indices differed between different types of malignancies, with the poorest quality measured in testicular cancer. Conception was achieved in 46 of the 184 ART cycles (25%), and resulted in 36 deliveries. The use of intracytoplasmic sperm injection (ICSI) methodology yielded a significantly higher pregnancy rate (37.4%) than intrauterine insemination (IUI; 11.5%) and was similar to other groups of infertile couples using these modalities. In vitro fertilization (IVF) failed to produce pregnancies. In conclusion, the rate of use of cryopresseved sperm in cancer patients is relatively low (10.3%). Achievement of pregnancies by ICSI presents the best option but when there are enough stored sperm samples and adequate quality, IUI can be employed. Cryopreservation is nevertheless the best option to preserve future fertility potential and hope for cancer patients.

Screening for partial AZFa microdeletions in the Y chromosome of infertile men: is it of clinical relevance?

OBJECTIVE To evaluate the frequency of complete and partial AZFa Y-chromosome microdeletions among infertile Israeli men. To review the published frequencies and histologic findings of AZFa deletions. DESIGN Retrospective study. SETTING Academic medical center. PATIENT(S) A total of 1,260 infertile Israeli men. Literature review (2000-2010) of reports on men with AZFa deletions and their testicular findings. INTERVENTION(S) The DNA of 1,260 infertile men was evaluated for AZF microdeletions. The DNA of 657 of them with undetected microdeletions was analyzed for partial AZFa deletion in the USP9Y and DDX3Y genes using sequence-tagged sites beyond EAA/EMQN recommendations. MAIN OUTCOME MEASURE(S) The frequency of complete and partial AZFa microdeletions. Availability of sperm cells for intracytoplasmic sperm injection in men with complete/partial microdeletions. RESULT(S) Two men had complete AZFa deletion (a frequency of 0.28% among nonobstructive azoospermic men). None had partial AZFa deletions. CONCLUSION(S) The likelihood of finding sperm cells in men with complete AZFa deletions is negligible. Complete AZFa deletion is rare and usually associated with azoospermia and absence of sperm cells in testicular tissue. The low frequency of partial AZFa deletions and the inconsistent prospects for spermatogenesis reported in the literature question the need for routine assessment of microdeletions in genes, such as USP9Y or DDX3Y.

The likelihood of finding mature sperm cells in men with AZFb or AZFb-c deletions: six new cases and a review of the literature (1994–2010)

OBJECTIVE To reassess the predictive value of detecting sperm cells in men with AZFb or AZFb-c deletions. DESIGN Retrospective analysis of previously reported men with AZFb or AZFb-c deletions and the addition of six new cases. SETTING Fertility institution. PATIENT(S) Men with both sequence tagged site marker identification and testicular cytology/histology findings. INTERVENTION(S) Systematic review of reported men with microdeletions that included eligibility, data extraction and analysis. MAIN OUTCOME MEASURE(S) Availability of sperm cells for intracytoplasmic sperm injection (ICSI) in men with AZFb/AZFb-c microdeletions. RESULT(S) The average prevalences reported for AZFb, AZFb-c, partial AZFb, and partial AZFb-c in azoospermic men were 0.9%±0.07%, 2.7%±0.93%, 1.23%±0.9%, and 1%±0.6%, respectively. Sperm cells were identified in 7% and 3% of the 28 and 71 men with complete AZFb and AZFb-c and in 57% and 43% of the 14 and 7 men with partial AZFb and AZFb-c deletions, respectively. The likelihood of finding sperm cells in men with complete versus partial AZFb and AZFb-c deletions was significantly lower. As yet, no clinical or chemical pregnancy after ICSI in cases with complete AZFb/b-c microdeletions has been reported. CONCLUSION(S) Determining the extent of AZFb or AZFb-c deletions is critical considering the frequency and the reasonable prospect of finding sperm cells in partial AZFb/AZFb-c deletions. Referring men with complete AZFb/b-c microdeletions to testicular sperm extraction/ICSI programs should be revaluated.

2nd-Trimester Maternal Serum Human Chorionic Gonadotropin and α-Fetoprotein Levels in Male and Female Fetuses with Down Syndrome

Background/Objective: Several studies have shown that the 2nd-trimester maternal serum α-fetoprotein (AFP) level is significantly lower and that the maternal serum human chorionic gonadotropin (hCG) level is significantly higher in the presence of a female fetus. This may potentially affect Down syndrome (DS) screening such that a higher false-positive rate may occur in women carrying a female fetus, whereas a lower detection rate may result in those carrying males. The purpose of this study was to evaluate the gender impact on marker levels in DS pregnancies and its effect on DS screening. Methods: The study included 62 DS pregnancies with a single fetus of known gender (31 male and 31 female). Only pregnancies with chromosomal analysis showing trisomy 21 were included. The maternal serum levels of hCG, AFP, and unconjugated estriol were measured at 16–20 weeks of pregnancy. These levels were expressed as gestational-age-corrected multiples of the median. Results: No statistically significant differences were noted in maternal serum levels of hCG or AFP in DS pregnancies between women carrying a female and those carrying a male DS fetus. No statistically significant differences in ‘screen-negative’ rates were noted among male and female fetuses. Conclusions: In normal pregnancies, the maternal serum hCG level is higher, and the AFP level is lower in the presence of a female fetus. However, this gender-related difference is not apparent in DS pregnancies. Therefore, the gender-related differences in serum marker levels would not result in a lower detection rate of DS in male fetuses.

Primary Triage, Evacuation Priorities, and Rapid Primary Distribution between Adjacent Hospitals—Lessons Learned from a Suicide Bomber Attack in Downtown Tel-Aviv

INTRODUCTION Terrorist attacks have occurred in Tel-Aviv that have caused mass-casualties. The objective of this study was to draw lessons from the medical response to an event that occurred on 19 January 2006, near the central bus station, Tel-Aviv, Israel. The lessons pertain to the management of primary triage, evacuation priorities, and rapid primary distribution between adjacent hospitals and the operational mode of the participating hospitals during the event. METHODS Data were collected in formal debriefings both during and after the event. Data were analyzed to learn about medical response components, interactions, and main outcomes. The event is described according to Disastrous Incidents Systematic AnalysiS Through-Components, Interactions and Results (DISAST-CIR) methodology. RESULTS A total of 38 wounded were evacuated from the scene, including one severely injured, two moderately injured, and 35 mildly injured. The severe casualty was the first to be evacuated 14 minutes after the explosion. All of the casualties were evacuated from the scene within 29 minutes. Patients were distributed between three adjacent hospitals including one non-Level-1 Trauma Center that received mild casualties. Twenty were evacuated to the nearby, Level-1 Sourasky Medical Center, including the only severely injured patient. Nine mildly injured patients were evacuated to the Sheba Medical Center and nine to Wolfson Hospital, a non-Level-1 Trauma Center hospital. All the receiving hospitals were operated according to the mass-casualty incident doctrine. CONCLUSIONS When a mass-casualty incident occurs in the vicinity of more than one hospital, primary triage, evacuation priority decision-making, and rapid distribution of casualties between all of the adjacent hospitals enables efficient and effective containment of the event.