Victor Y. Fujimoto

Fibroids and reproductive outcomes: a systematic literature review from conception to delivery

We examined the published relationship between uterine fibroids and reproductive outcomes. Submucosal fibroids had the strongest association with lower ongoing pregnancy rates, odds ratio, 0.5; 95% confidence interval, 0.3-0.8, primarily through decreased implantation. Cumulative pregnancy rates appeared slightly lower in patients with intramural fibroids 36.9% vs 41.1%, which may reflect biases in the literature; however, patients with intramural fibroids also experienced more miscarriages, 20.4% vs 12.9%. Adverse obstetric outcomes are rare and may reflect age or other differences in fibroid populations. Increased risk of malpresentation (odds ratio, 2.9; 2.6-3.2), cesarean (odds ratio, 3.7; 3.5-3.9), and preterm delivery (odds ratio, 1.5; 1.3-1.7) are reported; however, the incidence of labor dystocia was low (7.5%). There was no conclusive evidence that intramural or subserosal fibroids adversely affect fecundity. More prospective, controlled trials are needed to assess the effects of myomectomy. Good maternal and neonatal outcomes are expected in pregnancies with uterine fibroids.

Ultrasound therapy head configured to couple to an ultrasound imaging probe to facilitate contemporaneous imaging using low intensity ultrasound and treatment using high intensity focused ultrasound

Method and apparatus for the simultaneous use of ultrasound on a probe for imaging and therapeutic purposes. The probe limits the effects of undesirable interference noise in a display by synchronizing high intensity focused ultrasound (HIFU) waves with an imaging transducer to cause the noise to be displayed in an area of the image that does not overlap the treatment site. In one embodiment, the HIFU is first energized at a low power level that does not cause tissue damage, so that the focal point of the HIFU can be identified by a change in the echogenicity of the tissue caused by the HIFU. Once the focal point is properly targeted on a desired treatment site, the power level is increased to a therapeutic level. The location of each treatment site is stored and displayed to the user to enable a plurality of spaced-apart treatment sites to be achieved. As the treatment progresses, any changes in the treatment site can be seen in the real time, noise-free image. A preferred application of the HIFU waves is to cause lesions in blood vessels, so that the supply of nutrients and oxygen to a region, such as a tumor, is interrupted. The tumor will thus eventually be destroyed. In a preferred embodiment, the HIFU is used to treat disorders of the female reproductive system, such as uterine fibroids. The HIFU treatment can be repeated at spaced-apart intervals, until any remaining fibroid tissue is destroyed.

Female obesity adversely affects assisted reproductive technology (ART) pregnancy and live birth rates

BACKGROUND Obesity has risen among women in the USA, including those seeking infertility treatments. In 2007, height and weight were added to the Society for Assisted Reproductive Technology Clinic Online Reporting System (SART CORS), permitting calculation of BMI (weight/height(2)) for the first time using this national dataset. METHODS The SART CORS was used to evaluate the odds of failure to achieve a clinical intrauterine pregnancy and failure to achieve a live birth by the womans age, BMI and oocyte source (autologous versus donor), controlling for race and ethnicity, day of embryo transfer, number of embryos transferred and infertility diagnoses. The reference population was women with normal BMI. RESULTS There were 45 163 ART embryo transfers where maternal height and weight were recorded. Increasing obesity was associated with a significant rise in failure to achieve a clinical pregnancy with the use of autologous oocytes (P< 0.0001), but no difference with the use of donor oocytes. Among women using autologous oocytes who did conceive, failure to achieve a live birth increased with increasing obesity, to a greater extent among women <35 years of age. CONCLUSIONS Higher BMI is associated with an increased failure to achieve a clinical intrauterine gestation; this risk was overcome with the use of donor oocytes. Failure to achieve a live birth increases with higher BMI, significantly with the use of autologous oocytes (P< 0.0001), and to a greater extent among women <35 years of age (P< 0.0001).

Racial and ethnic disparities in assisted reproductive technology outcomes in the United States

OBJECTIVE To evaluate ethnic differences in assisted reproductive technology (ART) outcomes in the United States. DESIGN Historical cohort study. SETTING Clinic-based data. PATIENT(S) A total of 139,027 ART cycles from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System online database for 2004-2006, limited to white, Asian, black, and Hispanic women. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Logistic regression was used to model the odds of pregnancy and live birth; among singletons and twins, the odds of preterm birth and fetal growth restriction. Results are presented as adjusted odds ratios, with white women as the reference group. RESULT(S) The odds of pregnancy were reduced for Asians (0.86), and the odds of live birth were reduced for all groups: Asian (0.90), black (0.62), and Hispanic (0.87) women. Among singletons, moderate and severe growth restriction were increased for all infants in all three minority groups (Asians [1.78, 2.05]; blacks [1.81, 2.17]; Hispanics [1.36, 1.64]), and preterm birth was increased among black (1.79) and Hispanic women (1.22). Among twins, the odds for moderate growth restriction were increased for infants of Asian (1.30) and black women (1.97), and severe growth restriction was increased among black women (3.21). The odds of preterm birth were increased for blacks (1.64) and decreased for Asians (0.70). CONCLUSION(S) There are significant disparities in ART outcomes according to ethnicity.

DNA methylation changes in whole blood is associated with exposure to the environmental contaminants, mercury, lead, cadmium and bisphenol A, in women undergoing ovarian stimulation for IVF

BACKGROUND Changes in DNA methylation may play an important role in the deleterious reproductive effects reported in association with exposure to environmental pollutants. In this pilot study, we identify candidate methylation changes associated with exposure to pollutants in women undergoing in vitro fertilization (IVF). METHODS Blood and urine were collected from women on the day of oocyte retrieval. Whole blood was analyzed for mercury and lead, and urine for cadmium using inductively coupled plasma mass spectrometry. Unconjugated bisphenol A (BPA) was analyzed in serum using high-performance liquid chromatography with Coularray detection. Participants were dichotomized as higher or lower exposure groups by median concentrations. Using the Illumina GoldenGate Methylation Cancer Panel I, DNA methylation in whole blood from 43 women was assessed at 1505 CpG sites for association with exposure levels of each pollutant. Candidate CpG sites were identified using a Diff Score >|13| (P< 0.05) and an absolute difference >10% which were confirmed using bisulfite pyrosequencing. RESULTS Methylation of the GSTM1/5 promoter was increased for women with higher mercury exposure (P= 0.04); however, no correlation was observed (r= 0.17, P= 0.27). Reduced methylation was detected in the COL1A2 promoter in women with higher exposure to lead (P= 0.004), and an inverse correlation was observed (r = - 0.45, P= 0.03). Lower methylation of a promoter CpG site at the TSP50 gene was detected in women with higher BPA exposure (P= 0.005), and again an inverse correlation was identified (r = - 0.51, P= 0.001). CONCLUSIONS Altered DNA methylation at various CpG sites was associated with exposure to mercury, lead or BPA, providing candidates to be investigated using a larger study sample, as the results may reflect an independently associated predictor (e.g. socioeconomic status, diet, genetic variants, altered blood cell composition). Further studies accommodating variations in these factors will be needed to confirm these associations and identify their underlying causes.

Racial and ethnic disparities in benign gynecologic conditions and associated surgeries.

Common gynecologic conditions and surgeries may vary significantly by race or ethnicity. Uterine fibroid tumors are more prevalent in black women, and black women may have larger, more numerous fibroid tumors that cause worse symptoms and greater myomectomy complications. Some, but not all, studies have found a higher prevalence of endometriosis among Asian women. Race and ethnicity are also associated with hysterectomy rate, route, and complications. Overall, the current literature has significant deficits in the identification of racial and ethnic disparities in the incidence of fibroid tumors, endometriosis, and hysterectomy. Further research is needed to better define racial and ethnic differences in these conditions and to examine the complex mechanisms that may result in associated health disparities.

An image‐guided high intensity focused ultrasound device for uterine fibroids treatment

A high intensity focused ultrasound (HIFU) device was developed for treating uterine fibroid tumors. This prototype device enables image-guided therapy by aligning a commercially available abdominal ultrasound image probe to a vaginal HIFU transducer so the HIFU focus is in the image plane. The device was designed based on anatomical constraints of the female pelvic structures. HIFU was generated using a 3.5 MHz PZT-8 crystal, 25.4 mm in diameter, bonded to an aluminum lens. Computer simulations were performed to ensure that effective focusing was achievable at a fixed focal depth of 40 mm. Transducer efficiency was empirically determined to be 58%, and the half pressure maximum focal dimensions were 11 mm in length and 1.2 mm in width. A water-filled latex condom surrounding the transducer provided acoustic coupling, a stand-off, and allowed water circulation for transducer cooling. In vitro experiments in a tissue-mimicking gel phantom and in turkey breast demonstrated ultrasound image-guided lesion formation, or tissue necrosis, at the focus due to HIFU induced thermal and cavitation effects. The HIFU treatment site appeared as a hyperechoic spot on the ultrasound image at intensities above 1250 W/cm2. The results of in vitro experiments and in vivo ergonomic testing in six human volunteers indicated that the device has the potential of providing a nonsurgical approach for uterine fibroid treatment. Future in vivo studies in large animal models and fibroids patients are planned.

Bisphenol-A (BPA), BPA glucuronide, and BPA sulfate in midgestation umbilical cord serum in a northern and central California population.

Bisphenol-A (BPA) is an endocrine disrupting chemical used in numerous consumer products, resulting in universal exposure in the United States. Prenatal exposure to BPA is associated with numerous reproductive and developmental effects in animals. However, little is known about human fetal exposure or metabolism of BPA during midgestation. In the present study, we present a new liquid chromatography-tandem mass spectrometry method to directly measure concentrations of BPA and two predominant metabolic conjugates-BPA glucuronide and BPA sulfate-in umbilical cord serum collected from elective second trimester pregnancy terminations. We detected at least one form of BPA in all umbilical cord serum samples: BPA (GM 0.16, range <LOD-52.26 ng/mL), BPA glucuronide (GM 0.14, range <LOD-5.41 ng/mL) and BPA sulfate (GM 0.32, range <LOD-12.65 ng/mL). Levels of BPA ranged from less than 1/100th to over 400 times higher than levels of BPA in conjugated form. Although levels of BPA in conjugated form exceeded BPA levels in about 3/4 of the samples, BPA levels were higher in samples with total BPA above the median. Our findings suggest universal fetal exposure to BPA in our study population, with some at relatively high levels, and we provide the first evidence of detectable BPA sulfate in midgestation fetuses.

Meiotic recombination in human oocytes.

Studies of human trisomies indicate a remarkable relationship between abnormal meiotic recombination and subsequent nondisjunction at maternal meiosis I or II. Specifically, failure to recombine or recombination events located either too near to or too far from the centromere have been linked to the origin of human trisomies. It should be possible to identify these abnormal crossover configurations by using immunofluorescence methodology to directly examine the meiotic recombination process in the human female. Accordingly, we initiated studies of crossover-associated proteins (e.g., MLH1) in human fetal oocytes to analyze their number and distribution on nondisjunction-prone human chromosomes and, more generally, to characterize genome-wide levels of recombination in the human female. Our analyses indicate that the number of MLH1 foci is lower than predicted from genetic linkage analysis, but its localization pattern conforms to that expected for a crossover-associated protein. In studies of individual chromosomes, our observations provide evidence for the presence of “vulnerable” crossover configurations in the fetal oocyte, consistent with the idea that these are subsequently translated into nondisjunctional events in the adult oocyte.

Serum unconjugated bisphenol A concentrations in women may adversely influence oocyte quality during in vitro fertilization

Bisphenol A (BPA) is an endocrine disruptor with estrogenic properties that can adversely affect meiotic spindle assemblies. Our data indicate that BPA exposure in female patients may interfere with oocyte quality during IVF, as suggested by the inverse association between serum unconjugated BPA concentration and normal fertilization.