Journal Articles by Dr. Sills

Below are links to representative publications by Dr. Sills and colleagues. A full list of indexed papers can be accessed here . For reprint requests, please contact Dr. Sills at drsills@CAGivf.com. Happy reading!

 

MolCytogenet. 2014 Oct 25;7(1):68.
Determining parental origin of embryo aneuploidy: analysis of genetic error observed in 305 embryos derived from anonymous donor oocyte IVF cycles.
Sills ES1, Li X2, Frederick JL3, Khoury CD3, Potter DA3.

Abstract

BACKGROUND: Since oocyte donors are typically young and believed to be a source of highly competent gametes, donor oocyte IVF is considered to be an effective treatment for diminished ovarian reserve. However, the aneuploidy rate for embryos originating from anonymously donated oocytes remains incompletely characterized. Here, comprehensive chromosomal screening results were reviewed from embryos obtained from anonymous donor-egg IVF cycles to determine both the aneuploidy rate and parental source of the genetic error. To measure this, preimplantation genetic screening (PGS) data on embryos were retrospectively collated with parental DNA obtained before IVF for chromosome-specific assessments. This approach permitted mitotic and meiotic copy errors to be differentiated for each chromosome among all embryos tested, thus providing information on the parental source of embryo aneuploidy (i.e., from the anonymous egg donor vs. sperm source). RESULTS: 305 embryos generated for 24 patients who began IVF treatment in 2013. For oocyte donors (n = 24), mean (±SD) age was 24.0 ± 2.7 years (range = 20-29). For embryos with full chromosomal reporting (n = 284), euploidy was present in only 133 (46.8%). Considering all embryo chromosomes, the average error rate was 18%. 133 of 151 observed embryo aneuploidies (88.1%) were attributable to an oocyte donor source. Among all aneuploid embryos (n = 151), chromosomal errors from both genetic parents (i.e., oocyte donor and sperm source) were present in 57%. The average correlation coefficient across all pairs of chromosomal abnormalities (r = 0.60) suggests that chromosomes tend to have multiple and simultaneous errors (complex aneuploidy) even when oocytes from young donors are used. CONCLUSION: These data show that even when young donors provide oocytes for IVF, the probability of embryo aneuploidy remains high. The oocyte donor appears to make an important contribution to embryo aneuploidy even when her age is

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ClinExpObstet Gynecol. 2014;41(2):219-22.
Can laparoscopic removal of Essure device before embryo transfer correct poor reproductive outcome pattern in IVF? A case report.
Salem SA, Peck AC, Salem RD, Sills ES.

Abstract

OBJECTIVE: This report describes a successful surgical approach to multiple in vitro fertilization (IVF) failures in the setting of hydrosalpinges, which had been previously treated with Essure inserts. MATERIALS AND METHODS: A non-smoking 33-year-old Caucasian G2 P0020 (body mass index: BMI = 22) attended for second opinion. Her history was significant for bilateral hydrosalpinges having been noted on hysterosalpingogram two years earlier. This was managed by hysteroscopic placement of Essure inserts bilaterally. One year later, and now with Essure in situ, the patient completed three IVF cycles elsewhere. Her first and third IVF attempts resulted in biochemical pregnancy, while human chorionic gonadotropin (hCG) was negative after the second cycle. Upon presentation at the authors’ center and before beginning a fourth IVF cycle, further testing and surgical removal of the Essure devices was recommended. RESULTS: Repeat hysteroscopy was unremarkable; laparoscopic bilateral salpingectomy and extirpation of Essure implants was accomplished without difficulty. Following menses, the patient initiated IVF with three embryos transferred. At day 60, a single intrauterine pregnancy was identified with positive cardiac activity (rate > 100/min). Her obstetrical course was uneventful; a healthy 4,195 gram male infant was delivered (breech) by Cesarean at 40 weeks’ gestation. CONCLUSION: Essure inserts comprise inner fibers of polyethylene terephthalate, a stainless steel coil, and a nickel-titanium coil. The product received FDA approval as a contraceptive in 2002 although its use for hydrosalpinx remains off-label. While successful outcomes with IVF following Essure placement have been reported, this is the first description of pregnancy and delivery from IVF after Essure removal. Essure may be considered for sterilization when laparoscopy is contraindicated, but experience with its use specifically for treating hydrosalpinges before IVF is limited. This observed association between prior poor IVF outcomes and Essure with subsequent delivery after surgical Essure removal is the first of its kind to be reported, and warrants further investigation.
ClinExpReprod Med. 2013 Dec;40(4):169-73.
Irish public opinion on assisted human reproduction services: Contemporary assessments from a national sample.
Walsh DJ1, Sills ES2, Collins GS3, Hawrylyshyn CA1, Sokol P1, Walsh AP1.

Abstract

OBJECTIVE: To measure Irish opinion on a range of assisted human reproduction (AHR) treatments.METHODS: A nationally representative sample of Irish adults (n=1,003) were anonymously sampled by telephone survey.RESULTS: Most participants (77%) agreed that any fertility services offered internationally should also be available in Ireland, although only a small minority of the general Irish population had personal familiarity with AHR or infertility. This sample finds substantial agreement (63%) that the Government of Ireland should introduce legislation covering AHR. The range of support for gamete donation in Ireland ranged from 53% to 83%, depending on how donor privacy and disclosure policies are presented. For example, donation where the donor agrees to be contacted by the child born following donation, and anonymous donation where donor privacy is completely protected by law were supported by 68% and 66%, respectively. The least popular (53%) donor gamete treatment type appeared to be donation where the donor consents to be involved in the future life of any child born as a result of donor fertility treatment. Respondents in social class ABC1 (58%), age 18 to 24 (62%), age 25 to 34 (60%), or without children (61%) were more likely to favour this donor treatment policy in our sample.CONCLUSION: This is the first nationwide assessment of Irish public opinion on the advanced reproductive technologies since 2005. Access to a wide range of AHR treatment was supported by all subgroups studied. Public opinion concerning specific types of AHR treatment varied, yet general support for the need for national AHR legislation was reported by 63% of this national sample. Contemporary views on AHR remain largely consistent with the Commission for Assisted Human Reproduction recommendations from 2005, although further research is needed to clarify exactly how popular opinion on these issues has changed. It appears that legislation allowing for the full range of donation options (and not mandating disclosure of donor identity at a stipulated age) would better align with current Irish public opinion.

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Ulster Med J. 2013 Sep;82(3):150-6.
Contrasting selected reproductive challenges of today with those of antiquity–the past is prologue.
Jones CA1, Sills ES2.

Abstract

Viewing human history through a medical lens provides a renewed appreciation for today’s vexing reproductive challenges, as some modern dilemmas are actually continuations of similar challenges experienced long ago. Certainly there are many examples of assisted fertility therapy that were entirely theoretical only a generation ago, but have become commonplace in modern practice and society. In particular posthumous birth and infertility have, over time, been the focus of compelling social interest, occasionally even impacting national security and dynastic succession. While the concepts have remained static, the tools available to extend and improve reproductive success have changed radically. Appropriately regarded as confidential and private, an individual’s reproductive details are typically impervious to formal study. Yet, archival sources including ancient literature and formal court records can occasionally provide evidence of otherwise deeply personal concerns of a different era. Our assessment finds the issues, worries, and desires of patients of antiquity to align closely with contemporary reproductive challenges. Because children and family have always been central to the human experience, the consequences of reproduction (or the lack thereof) can make substantial imprints upon the cultural, economic, and political landscape-irrespective of civilization or century. In this article, selected motifs are described in a broad historical context to illustrate how challenges of human reproduction have remained essentially unchanged, despite a vast accumulation of knowledge made possible by gains in reproductive science and technology. Plus ça change, plus c’est la même chose. -Jean-Baptiste Alphonse Karr (1808-1890).
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Neuro Endocrinol Lett. 2013;34(3):177-83.
Gonadotropin releasing hormone in the primitive vertebrate family Myxinidae: reproductive neuroanatomy and evolutionary aspects.
Sills ES1, Palermo GD.

Abstract

The family Myxinidae embraces all hagfish species, and occupies an evolutionary niche intermediate between ancestral vertebrates and the gnathostomes (jawed vertebrates). Gonadotropin releasing hormone (GnRH) modulates neuroendocrine activity in vertebrates and works in the context of the hypothalamic-pituitary (H-P) axis. The appearance of this neuroendocrine axis marks one of the most crucial developmental achievements in vertebrate evolution, because it enabled further diversification in general growth, metabolism, osmoregulation and reproduction as jawed vertebrates evolved. GnRH studies in hagfish draw attention because such work may be considered as providing proxy data for similar investigations conducted upon long extinct species. Indeed, the fossil record reveals little anatomical difference between those hagfish living 300 million years ago and their modern descendants. Accordingly, the hagfish can offer important evolutionary lessons as they have some highly unusual characteristics not seen in any other vertebrate; they retain many representative features of an ancestral state from which all vertebrates originated. Indeed, because central control of reproduction is perhaps the most basic function of the vertebrate H-P axis, and given the importance of GnRH in this network, research on GnRH in hagfish can help elucidate the early evolution of the H-P system itself. Like all vertebrates, hagfish have a functional hypothalamic area and a pituitary gland, constituting a basic H-P axis. But what role does GnRH play in the reproductive system of this “living fossil”? How can understanding GnRH in hagfish help advance the knowledge of vertebrate neuroendocrinology? Here, information on neuroendocrine function and the role of GnRH specifically in this very basal vertebrate is reviewed.
Clinicoecon Outcomes Res. 2013;5:119-24.
Follow-up analysis of federal process of care data reported from three acute care hospitals in rural Appalachia.
Sills ES1, Chiriac L, Vaughan D, Jones CA, Salem SA.

Abstract

BACKGROUND: This investigation evaluated standardized process of care data collected on selected hospitals serving a remote rural section of westernmost North Carolina.METHODS: Centers for Medicare and Medicaid Services data were analyzed retrospectively for multiple clinical parameters at Fannin Regional Hospital, Murphy Medical Center, and Union General Hospital. Data were analyzed by paired t-test for individual comparisons among the three study hospitals to compare the three facilities with each other, as well as with state and national average for each parameter.RESULTS: Centers for Medicare and Medicaid Services “Hospital Compare” data from 2011 showed Fannin Regional Hospital to have significantly higher composite scores on standardized clinical process of care measures relative to the national average, compared with Murphy Medical Center (P = 0.01) and Union General Hospital (P = 0.01). This difference was noted to persist when Fannin Regional Hospital was compared with Union General Hospital using common state reference data (P = 0.02). When compared with national averages, mean process of care scores reported from Murphy Medical Center and Union General Hospital were both lower but not significantly different (-3.44 versus -6.07, respectively, P = 0.54).CONCLUSION: The range of process of care scores submitted by acute care hospitals in western North Carolina is considerable. Centers for Medicare and Medicaid Services “Hospital Compare” information suggests that process of care measurements at Fannin Regional Hospital are significantly higher than at either Murphy Medical Center or Union General Hospital, relative to state and national benchmarks. Further investigation is needed to determine what impact these differences in process of care may have on hospital volume and/or market share in this region. Additional research is planned to identify process of care trends in this demographic and geographically rural area.

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ReprodBiolEndocrinol. 2012 Aug 30;10:67.
Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients.
Sills ES1, Collins GS, Salem SA, Jones CA, Peck AC, Salem RD.

Abstract

BACKGROUND: During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF. METHODS: Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH-agonist [A] and GnRH-antagonist [B] protocols in IVF was studied. RESULTS: Completed questionnaires (n = 71) revealed a mean +/- SD patient age of 34 +/- 4.1 yrs. Most (83.1%) had no prior IVF experience; 2.8% reported another medical condition requiring self-administration of subcutaneous medication(s). When out-of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7% patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/- 11.75 and $654.55 +/- 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased. CONCLUSIONS: This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level.

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Arch Gynecol Obstet. 2012 Sep;286(3):755-61.
Comprehensive genetic assessment of the human embryo: can empiric application of microarray comparative genomic hybridization reduce multiple gestation rate by single fresh blastocyst transfer?
Sills ES1, Yang Z, Walsh DJ, Salem SA.

Abstract

PURPOSE: The unacceptable multiple gestation rate currently associated with in vitro fertilization (IVF) would be substantially alleviated if the routine practice of transferring more than one embryo were reconsidered. While transferring a single embryo is an effective method to reduce the clinical problem of multiple gestation, rigid adherence to this approach has been criticized for negatively impacting clinical pregnancy success in IVF. In general, single embryo transfer is viewed cautiously by IVF patients although greater acceptance would result from a more effective embryo selection method.METHODS: Selection of one embryo for fresh transfer on the basis of chromosomal normalcy should achieve the dual objective of maintaining satisfactory clinical pregnancy rates and minimizing the multiple gestation problem, because embryo aneuploidy is a major contributing factor in implantation failure and miscarriage in IVF. The initial techniques for preimplantation genetic screening unfortunately lacked sufficient sensitivity and did not yield the expected results in IVF. However, newer molecular genetic methods could be incorporated with standard IVF to bring the goal of single embryo transfer within reach.RESULTS: Aiming to make multiple embryo transfers obsolete and unnecessary, and recognizing that array comparative genomic hybridization (aCGH) will typically require an additional 12 h of laboratory time to complete, we propose adopting aCGH for mainstream use in clinical IVF practice.CONCLUSION: As aCGH technology continues to develop and becomes increasingly available at lower cost, it may soon be considered unusual for IVF laboratories to select a single embryo for fresh transfer without regard to its chromosomal competency. In this report, we provide a rationale supporting aCGH as the preferred methodology to provide a comprehensive genetic assessment of the single embryo before fresh transfer in IVF. The logistics and cost of integrating aCGH with IVF to enable fresh embryo transfer are also discussed.
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MolCytogenet. 2012 May 2;5(1):24.
Selection of single blastocysts for fresh transfer via standard morphology assessment alone and with array CGH for good prognosis IVF patients: results from a randomized pilot study.
Yang Z1, Liu J, Collins GS, Salem SA, Liu X, Lyle SS, Peck AC, Sills ES, Salem RD.

Abstract

 
BACKGROUND: Single embryo transfer (SET) remains underutilized as a strategy to reduce multiple gestation risk in IVF, and its overall lower pregnancy rate underscores the need for improved techniques to select one embryo for fresh transfer. This study explored use of comprehensive chromosomal screening by array CGH (aCGH) to provide this advantage and improve pregnancy rate from SET.METHODS: First-time IVF patients with a good prognosis (age <35, no prior miscarriage) and normal karyotype seeking elective SET were prospectively randomized into two groups: In Group A, embryos were selected on the basis of morphology and comprehensive chromosomal screening via aCGH (from d5 trophectoderm biopsy) while Group B embryos were assessed by morphology only. All patients had a single fresh blastocyst transferred on d6. Laboratory parameters and clinical pregnancy rates were compared between the two groups.RESULTS: For patients in Group A (n = 55), 425 blastocysts were biopsied and analyzed via aCGH (7.7 blastocysts/patient). Aneuploidy was detected in 191/425 (44.9%) of blastocysts in this group. For patients in Group B (n = 48), 389 blastocysts were microscopically examined (8.1 blastocysts/patient). Clinical pregnancy rate was significantly higher in the morphology + aCGH group compared to the morphology-only group (70.9 and 45.8%, respectively; p = 0.017); ongoing pregnancy rate for Groups A and B were 69.1 vs. 41.7%, respectively (p = 0.009). There were no twin pregnancies.CONCLUSION: Although aCGH followed by frozen embryo transfer has been used to screen at risk embryos (e.g., known parental chromosomal translocation or history of recurrent pregnancy loss), this is the first description of aCGH fully integrated with a clinical IVF program to select single blastocysts for fresh SET in good prognosis patients. The observed aneuploidy rate (44.9%) among biopsied blastocysts highlights the inherent imprecision of SET when conventional morphology is used alone. Embryos randomized to the aCGH group implanted with greater efficiency, resulted in clinical pregnancy more often, and yielded a lower miscarriage rate than those selected without aCGH. Additional studies are needed to verify our pilot data and confirm a role for on-site, rapid aCGH for IVF patients contemplating fresh SET.
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ReprodBiolEndocrinol. 2011 Dec 2;9:153.
Bivariate analysis of basal serum anti-Müllerian hormone measurements and human blastocyst development after IVF.
Sills ES1, Collins GS, Brady AC, Walsh DJ, Marron KD, Peck AC, Walsh AP, Salem RD.

Abstract

 
BACKGROUND: To report on relationships among baseline serum anti-Müllerian hormone (AMH) measurements, blastocyst development and other selected embryology parameters observed in non-donor oocyte IVF cycles.METHODS: Pre-treatment AMH was measured in patients undergoing IVF (n = 79) and retrospectively correlated to in vitro embryo development noted during culture.RESULTS: Mean (+/- SD) age for study patients in this study group was 36.3 ± 4.0 (range = 28-45) yrs, and mean (+/- SD) terminal serum estradiol during IVF was 5929 +/- 4056 pmol/l. A moderate positive correlation (0.49; 95% CI 0.31 to 0.65) was noted between basal serum AMH and number of MII oocytes retrieved. Similarly, a moderate positive correlation (0.44) was observed between serum AMH and number of early cleavage-stage embryos (95% CI 0.24 to 0.61), suggesting a relationship between serum AMH and embryo development in IVF. Of note, serum AMH levels at baseline were significantly different for patients who did and did not undergo blastocyst transfer (15.6 vs. 10.9 pmol/l; p = 0.029).CONCLUSIONS: While serum AMH has found increasing application as a predictor of ovarian reserve for patients prior to IVF, its roles to estimate in vitro embryo morphology and potential to advance to blastocyst stage have not been extensively investigated. These data suggest that baseline serum AMH determinations can help forecast blastocyst developmental during IVF. Serum AMH measured before treatment may assist patients, clinicians and embryologists as scheduling of embryo transfer is outlined. Additional studies are needed to confirm these correlations and to better define the role of baseline serum AMH level in the prediction of blastocyst formation.
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J ExpClin Assist Reprod. 2011;8:3.
Prediction of individual probabilities of livebirth and multiple birth events following in vitro fertilization (IVF): a new outcomes counselling tool for IVF providers and patients using HFEA metrics.
Jones CA1, Christensen AL, Salihu H, Carpenter W, Petrozzino J, Abrams E, Sills ES, Keith LG.

Abstract

In vitro fertilization (IVF) has become a standard treatment for subfertility after it was demonstrated to be of value to humans in 1978. However, the introduction of IVF into mainstream clinical practice has been accompanied by concerns regarding the number of multiple gestations that it can produce, as multiple births present significant medical consequences to mothers and offspring. When considering IVF as a treatment modality, a balance must be set between the chance of having a live birth and the risk of having a multiple birth. As IVF is often a costly decision for patients-financially, medically, and emotionally-there is benefit from estimating a patient’s specific chance that IVF could result in a birth as fertility treatment options are contemplated. Historically, a patient’s “chance of success” with IVF has been approximated from institution-based statistics, rather than on the basis of any particular clinical parameter (except age). Furthermore, the likelihood of IVF resulting in a twin or triplet outcome must be acknowledged for each patient, given the known increased complications of multiple gestation and consequent increased risk of poor birth outcomes. In this research, we describe a multivariate risk assessment model that incorporates metrics adapted from a national 7.5-year sampling of the Human Fertilisation& Embryology Authority (HFEA) dataset (1991-1998) to predict reproductive outcome (including estimation of multiple birth) after IVF. To our knowledge, http://www.formyodds.com is the first Software-as-a-Service (SaaS) application to predict IVF outcome. The approach also includes a confirmation functionality, where clinicians can agree or disagree with the computer-generated outcome predictions. It is anticipated that the emergence of predictive tools will augment the reproductive endocrinology consultation, improve the medical informed consent process by tailoring the outcome assessment to each patient, and reduce the potential for adverse outcomes with IVF.
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Mol Med Rep. 2012 Jan;5(1):29-31.
Ovarian dysgenesis associated with an unbalanced X;6 translocation: first characterisation of reproductive anatomy and cytogenetic evaluation in partial trisomy 6 with breakpoints at Xq22 and 6p23.
Sills ES1, Cotter PD, Marron KD, Shkrobot LV, Walsh HM, Salem RD.

Abstract

The aim of this study was to describe the clinical and laboratory findings associated with a previously unreported unbalanced X;6 translocation. Physical examination, reproductive history and cytogenetic techniques were used to characterise a novel chromosomal anomaly associated with gonadal dysgenesis. A healthy non-dysmorphic 23 year-old phenotypic female with primary amenorrhea and infertility presented for reproductive endocrinology evaluation. No discrete ovarian tissue was identified on transvaginal ultrasound, although the uterus appeared essentially normal. BMI was 19 kg/m2. Serum FSH and oestradiol were 111 mIU/ml and 15 pmol/l, respectively. TSH, prolactin and all infectious serologies were all normal. The karyotype of 46,X,der(X)t(X;6)(q22;p23) was determined following cytogenetic analysis of peripheral blood lymphocytes via fluorescence in situ hybridisation (FISH) with whole chromosome paint for chromosome 6, and a separate FISH analysis using a 6p subtelomeric probe. The patient was continued on hormone replacement therapy and underwent genetic counselling; the patient subsequently enrolled as a recipient in an anonymous donor oocyte IVF treatment. Translocations involving autosomes and chromosome X are rare. While female carriers of balanced X;autosome translocations are generally phenotypically normal, the impact of unbalanced X;autosome translocations can be severe. This is the first known report of an unbalanced translocation involving X;6. This abnormality was associated with ovarian dysgenesis, but an otherwise normal female phenotype. From this investigation, the observed developmental impact of the unbalanced translocation with breakpoints at Xq22 and 6p23 appears to be limited to ovarian failure.
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Health Res Policy Syst. 2011 Jun 24;9:28.
The evolution of health policy guidelines for assisted reproduction in the Republic of Ireland, 2004-2009.
Walsh DJ1, Ma ML, Sills ES.

Abstract

This analysis reports on Irish regulatory policies for in vitro fertilisation (IVF) from 2004-2009, in the context of membership changes within the Medical Council of Ireland. To achieve this, the current (2009) edition of the Guide to Professional Conduct & Ethics was compared with the immediately preceding version (2004). The statutory composition of the Medical Council from 2004-2009 was also studied. Content analysis of the two editions identified the following differences: 1) The 2004 guide states that IVF “should only be used after thorough investigation has failed to reveal a treatable cause of the infertility”, while the 2009 guide indicates IVF “should only be used after thorough investigation has shown that no other treatment is likely to be effective”; 2) The 2004 stipulation stating that fertilized ovum (embryo) “must be used for normal implantation and must not be deliberately destroyed” is absent from the 2009 guidelines; 3) The option to donate “unused fertilised ova” (embryos) is omitted from the 2009 guidelines; 4) The 2009 guidelines state that ART should be offered only by “suitably qualified professionals, in appropriate facilities, and according to the international best practice”; 5) The 2009 guidelines introduce criteria that donations as part of a donor programme should be “altruistic and non-commercial”. These last two points represent original regulatory efforts not appearing in the 2004 edition. The Medical Practitioners Act 2007 reduced the number of physicians on the Medical Council to 6 (of 25) members. The ethical guidelines from 2004 preceded this change, while the reconstituted Medical Council published the 2009 version. Between 2004 and 2009, substantial modifications in reproductive health policy were incorporated into the Medical Council’s ethical guidelines. The absence of controlling Irish legislation means that patients and IVF providers in Ireland must rely upon these guidelines by default. Our critique traces the evolution of public policy on IVF during a time when the membership of the Medical Council changed radically; reduced physician contribution to decision-making was associated with diminished protection for IVF-derived embryos in Ireland. Considerable uncertainty on IVF practice in Ireland remains.
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J Investig Med. 2011 Aug;59(6):912-6.
Simvastatin effects on androgens, inflammatory mediators, and endogenous pituitary gonadotropins among patients with PCOS undergoing IVF: results from a prospective, randomized, placebo-controlled clinical trial.
Rashidi B1, Abediasl J, Tehraninejad E, Rahmanpour H, Sills ES.

Abstract

OBJECTIVE: To evaluate effects of simvastatin on selected biochemical parameters and reproductive outcome among patients with polycystic ovary syndrome (PCOS) who undergo in vitro fertilization (IVF).METHODS: Patients with PCOS were randomized to receive either oral simvastatin, 20 mg/d (n = 32), or placebo (n = 32) in a prospective, double-blind, randomized clinical trial (NCT 005-75601) in parallel with controlled ovarian hyperstimulation for IVF. All patients were determined to be at average risk for cardiovascular disease, based on high-sensitivity C-reactive protein (hsCRP) measurement at entry. After an 8-week treatment interval concluding at periovulatory human chorionic gonadotropin administration, selected clinical and laboratory parameters were measured.RESULTS: Mean serum total testosterone level decreased by 25% in the simvastatin group, compared to a 10% reduction in the placebo group (P < 0.001). A trend of lower serum luteinizing hormone levels was noted in experimental and control groups (29% vs 22%, respectively), although this difference was not significant (P > 0.05). Neither fasting insulin nor quantitative insulin sensitivity check index were significantly impacted by simvastatin (P > 0.05). As expected, total cholesterol was not modified among placebo patients but was significantly reduced after simvastatin (P = 0.001). In addition, hsCRP and vascular cell adhesion protein-1 were both significantly lower after simvastatin therapy compared to controls (P ≤ 0.005 for both). At study completion, no important change in body mass index was observed in either group (P ≥ 0.60). Although oocyte maturation, fertilization, and clinical pregnancy rates were all higher after simvastatin, none of these improvements were statistically significant.CONCLUSIONS: This report presents data from the first prospective, randomized, placebo-controlled clinical investigation of simvastatin in the setting of PCOS and IVF. Simvastatin seems to be compatible with gonadotropin therapy for IVF and can offer beneficial endocrine and cardiovascular effects for patients with PCOS who undergo embryo transfer. Although the observed improvements in reproductive function were mild, the reductions in hsCRP and vascular cell adhesion protein-1 after simvastatin treatment were significant, suggesting the need for further clinical trials to clarify simvastatin’s impact on reproductive physiology.
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Reprod Health. 2011 Apr 20;8:8.
Recipient screening in IVF: first data from women undergoing anonymous oocyte donation in Dublin.
Walsh AP1, Omar AB, Marron KD, Walsh DJ, Salma U, Sills ES.

Abstract

BACKGROUND: Guidelines for safe gamete donation have emphasised donor screening, although none exist specifically for testing oocyte recipients. Pre-treatment assessment of anonymous donor oocyte IVF treatment in Ireland must comply with the European Union Tissues and Cells Directive (Directive 2004/23/EC). To determine the effectiveness of this Directive when applied to anonymous oocyte recipients in IVF, we reviewed data derived from selected screening tests performed in this clinical setting. METHODS: Data from tests conducted at baseline for all women enrolling as recipients (n = 225) in the anonymous oocyte donor IVF programme at an urban IVF referral centre during a 24-month period were analysed. Patient age at programme entry and clinical pregnancy rate were also tabulated. All recipients had at least one prior negative test for HIV, Hepatitis B/C, chlamydia, gonorrhoea and syphilis performed by her GP or other primary care provider before reproductive endocrinology consultation.RESULTS: Mean (±SD) age for donor egg IVF recipients was 40.7 ± 4.2 yrs. No baseline positive chlamydia, gonorrhoea or syphilis screening results were identified among recipients for anonymous oocyte donation IVF during the assessment interval. Mean pregnancy rate (per embryo transfer) in this group was 50.5%. CONCLUSION: When tests for HIV, Hepatitis B/C, chlamydia, gonorrhoea and syphilis already have been confirmed to be negative before starting the anonymous donor oocyte IVF sequence, additional (repeat) testing on the recipient contributes no new clinical information that would influence treatment in this setting. Patient safety does not appear to be enhanced by application of Directive 2004/23/EC to recipients of anonymous donor oocyte IVF treatment. Given the absence of evidence to quantify risk, this practice is difficult to justify when applied to this low-risk population.
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Mol Med Rep. 2010 Mar-Apr;3(2):223-6.
Novel ETHE1 mutation in a carrier couple having prior offspring affected with ethylmalonic encephalopathy: Genetic analysis, clinical management and reproductive outcome.
Walsh DJ1, Sills ES, Lambert DM, Gregersen N, Malone FD, Walsh AP.

Abstract

Ethylmalonic encephalopathy (EE) is an autosomally recessive inherited disorder with a relentlessly progressive decline in neurological function, usually fatal by the age of ten. It is characterised by generalisedhypotonia, psychomotor regression, spastic tetraparesis, dystonia, seizures and, eventually, global neurological failure. Approximately 50 reports have been published worldwide describing this devastating disease, most involving patients of Mediterranean or Arab origin. The fundamental defect in EE likely involves the impairment of a mitochondrial sulphur dioxygenase coded by the ETHE1 gene responsible for the catabolism of sulphide, which subsequently accumulates to toxic levels. A diagnosis of EE should initiate careful genetic evaluation and counselling, particularly if the parents intend to have additional offspring. The present report describes the diagnosis of EE in a reproductive endocrinology context, where both members of a non-consanguineous couple were confirmed to be carriers of an identical A↷G mutation. This previously unknown mutation at nucleotide position c.494 resulted in an amino acid substitution, p.Asp165Gly. Although consideration was given to in vitro fertilisation, embryo biopsy and single gene pre-implantation genetic diagnosis, the couple decided to first utilise a less aggressive therapeutic approach with donor sperm insemination. Pregnancy with a low risk of EE was indeed achieved; however, the infant was affected with a different anomaly (hypoplastic left heart). As this case demonstrates, prior to the initiation of fertility therapy, genetic analysis may be used to provide a confirmatory diagnosis when EE is suspected.

Ir J Med Sci. 2011 Mar;180(1):251-3.
First reported deliveries in Ireland using surgically retrieved sperm for non-obstructive azoospermia.
Walsh AP1, Yokota TT, Walsh DJ, Jones BJ, Coull GD, Sills ES.

Abstract

Couples presenting with male factor infertility comprise an important proportion of clinical reproductive endocrinology consultations. Indeed, a problem with the male is the only cause, or a contributing cause, of infertility in ~40% of infertility evaluations. Here we present the first published deliveries obtained from IVF utilising surgically retrieved sperm in Ireland; pregnancy and delivery are also described following transfer of cryopreserved/thawed embryos derived from such sperm. Finding no sperm from a semen analysis in a man without a vasectomy can be a devastating event, and substantially influences the scope of the reproductive endocrinology consultation. Successful treatment of non-obstructive azoospermia is possible without reliance on anonymous donor sperm.

Rom J MorpholEmbryol. 2010;51(3):441-5.
Human blastocyst culture in IVF: current laboratory applications in reproductive medicine practice.
Sills ES1, Palermo GD.

Abstract

For fertility patients undergoing in vitro fertilization (IVF), blastocyst culture brings a number of potential advantages over laboratory techniques leading to traditional cleavage-stage embryo transfer. Because day 2-3 embryos normally should transit the oviduct only, their direct exposure to an intrauterine microenvironment is physiologically inappropriate. This mismatch is obviated by blastocyst transfer. Moreover, the nutritional milieu inside the fallopian tube is not the same as within the endometrial compartment, a feature possibly antagonistic to implantation when a day 2-3 embryo is placed directly within the uterus. Delaying transfer to day 5-6 may also improve reproductive outcome by reducing risk of embryo expulsion, given increased myometrialpulsatility measured at day 2-3. However, rigid reliance on a blastocyst culture approach will more often result in treatment cancellation due to embryo loss (no transfer), or having fewer embryos for cryopreservation. The development of sequential media to support embryos in extended in vitro culture was a significant laboratory refinement, since it enabled direct observation of embryos to improve transfer selection bias. This approach, in tandem with blastocyst cryopreservation, leads to fewer embryos being transferred and reducing multiple gestation rate. This review discusses key features of human blastocyst culture and its application in clinical reproductive medicine practice.

Hum Fertil (Camb). 2010;13(2):98-104.
A descriptive study of selected oocyte, blood and organ/tissue donation features among fertility patients in Ireland.
Sills ES1, Collins GS, Walsh DJ, Omar AB, Salma U, Walsh AP.

Abstract

OBJECTIVE: Anonymous oocyte donation and participation in organ and blood/tissue donation programmes were studied specifically among Irish fertility patients. METHODS: An anonymous questionnaire measured patient perceptions of, and participation in, blood/organ/tissue donor programmes, and to record opinion on anonymous donor oocyte compensation. RESULTS: A total of 337 patents were sampled; 56.7% had no children. None had participated in a donor oocyte programme either as donor or recipient. At baseline, 19.6% had previous in vitro fertilisation experience, more than one-third (35.9%) had donated blood anonymously, 19.9% were organ/tissue donors and 52.2% indicated that anonymous oocyte donors should receive some compensation. We found patients with infertility for extended periods were more likely to view oocyte donation favourably, compared to those with infertility of shorter durations (p = 0.022, by Krusksal-Wallis Rank Sum test). Average recommended compensation for anonymous oocyte donor was euro 2177 (range euro 200-euro 9500), and most (77.2%) favoured confidential protections for recipient and donor identity. CONCLUSION: This is the first investigation of blood and organ/tissue donation features among fertility patients in Ireland; the rate of blood donation in this group was more than 10 times higher than in the general Irish population. Protection of anonymity for both donors and recipients was supported by most patients, even opponents of compensated anonymous donation. Further studies should clarify patient perceptions about oocyte donation as a function of involvement in organ/tissue procurement programmes and blood banks.

Reprod Health. 2010 Aug 11;7:20.
The long path to pregnancy: early experience with dual anonymous gamete donation in a European in vitro fertilisation referral centre.
Sills ES1, Mykhaylyshyn LO, Dorofeyeva US, Walsh DJ, Salma U, Omar AB, Coull GD, David IA, Brickell KM, Tsar OM, Walsh AP.

Abstract

BACKGROUND: This investigation describes features of patients undergoing in vitro fertilisation (IVF) and embryo transfer (ET) where both gametes were obtained from anonymous donors. METHODS: Gamete unsuitability or loss was confirmed in both members of seven otherwise healthy couples presenting for reproductive endocrinology consultation over a 12-month interval in Ireland. IVF was undertaken with fresh oocytes provided by anonymous donors in Ukraine; frozen sperm (anonymous donor) was obtained from a licensed tissue establishment. For recipients, saline-enhanced sonography was used to assess intrauterine contour with endometrial preparation via transdermal estrogen. RESULTS: Among commissioning couples, mean+/-SD female and male age was 41.9 +/- 3.7 and 44.6 +/- 3.5 yrs, respectively. During this period, female age for non dual anonymous gamete donation IVF patients was 37.9 +/- 3 yrs (p < 0.001). Infertility duration was >/=3 yrs for couples enrolling in dual gamete donation, and each had >/=2 prior failed fertility treatments using native oocytes. All seven recipient couples proceeded to embryo transfer, although one patient had two transfers. Clinical pregnancy was achieved for 5/7 (71.4%) patients. Non-transferred cryopreserved embryos were available for all seven couples. CONCLUSIONS: Mean age of females undergoing dual anonymous donor gamete donation with IVF is significantly higher than the background IVF patient population. Even when neither partner is able to contribute any gametes for IVF, the clinical pregnancy rate per transfer can be satisfactory if both anonymous egg and sperm donation are used concurrently. Our report emphasises the role of pre-treatment counselling in dual anonymous gamete donation, and presents a coordinated screening and treatment approach in IVF where this option may be contemplated.

J ObstetGynaecol. 2010;30(6):613-6.
Application of EU tissue and cell directive screening protocols to anonymous oocyte donors in western Ukraine: data from an Irish IVF programme.
Walsh AP1, Omar AB, Collins GS, Murray GU, Walsh DJ, Salma U, Sills ES.

Abstract

Anonymous oocyte donation in the EU proceeds only after rigorous screening designed to ensure gamete safety. If anonymous donor gametes originating from outside EU territory are used by EU patients, donor testing must conform to the same standards as if gamete procurement had occurred in the EU. In Ireland, IVF recipients can be matched to anonymous donors in the Ukraine (a non-EU country). This investigation describes the evolution of anonymous oocyte donor screening methods during this period and associated results. Data were reviewed for all participants in an anonymous donor oocyte IVF programme from 2006 to 2009, when testing consistent with contemporary EU screening requirements was performed on all Ukrainian oocyte donors. HIV and hepatitis tests were aggregated from 314 anonymous oocyte donors and 265 recipients. The results included 5,524 Ukrainian women who were interviewed and 314 of these entered the programme (5.7% accession rate). Mean age of anonymous oocyte donors was 27.9 years; all had achieved at least one delivery. No case of hepatitis or HIV was detected at initial screening or at oocyte procurement. This is the first study of HIV and hepatitis incidence specifically among Ukrainian oocyte donors. We find anonymous oocyte donors to be a low-risk group, despite a high background HIV rate. Following full disclosure of the donation process, most Ukrainian women wishing to volunteer as anonymous oocyte donors do not participate. Current EU screening requirements appear adequate to maintain patient safety in the context of anonymous donor oocyte IVF.

Ir Med J. 2010 Apr;103(4):107-10.
Who abandons embryos after IVF?
Walsh AP1, Tsar OM, Walsh DJ, Baldwin PM, Shkrobot LV, Sills ES.

Abstract

This investigation describes features of in vitro fertilisation (IVF) patients who never returned to claim their embryos following cryopreservation. Frozen embryo data were reviewed to establish communication patterns between patient and clinic; embryos were considered abandoned when 1) an IVF patient with frozen embryo/s stored at our facility failed to make contact with our clinic for > 2 yrs and 2) the patient could not be located after a multi-modal outreach effort was undertaken. For these patients, telephone numbers had been disconnected and no forwarding address was available. Patient, spouse and emergency family contact/s all escaped detection efforts despite an exhaustive public database search including death records and Internet directory portals. From 3244 IVF cycles completed from 2000 to 2008, > or = 1 embryo was frozen in 1159 cases (35.7%). Those without correspondence for > 2 yrs accounted for 292 (25.2%) patients with frozen embryos; 281 were contacted by methods including registered (signature involving abandoned embryos did not differ substantially from other patients. The goal of having a baby was achieved by 10/11 patients either by spontaneous conception, adoption or IVF. One patient moved away with conception status unconfirmed. The overall rate of embryo abandonment was 11/1159 (< 1%) in this IVF population. Pre-IVF counselling minimises, but does not totally eliminate, the problem of abandoned embryos. As the number of abandoned embryos from IVF accumulates, their fate urgently requires clarification. We propose that clinicians develop a policy consistent with relevant Irish Constitutional provisions to address this medical dilemma.
Arch Gynecol Obstet. 2010 Aug;282(2):221-4.
National birth rate, IVF utilisation and multiple gestation trends: findings from a 6-year analysis in the Republic of Ireland.
Sills ES1, Walsh DJ, Omar AB, Salma U, Walsh AP.

Abstract

PURPOSE: The impact of the advanced reproductive technologies on multiple gestation has been well documented in several large populations, but only infrequently in smaller countries, where its effects may be different. This study estimated domestic in vitro fertilisation (IVF) use and multiple gestation rate in Ireland based on two data-reporting platforms. METHODS: The number of IVF cycles completed in Ireland was extrapolated from statistics reported to the central European fertility registry (ESHRE) between 1999 and 2004. Multiple gestation data during this period were obtained from the National Perinatal Reporting System (NPRS). These datasets were interlocked to offer a method to track the impact of IVF activity on background multiple gestation rate in Ireland. RESULTS: Total Irish births registered increased from 54,307 in 1999 to 62,406 in 2004, and multiple gestation rate (per 1,000) fluctuated non-linearly from 27.2 to 31.4 during this time. Reported IVF activity increased from 972 in 1999 to 1,705 in 2004. Annual incidence of multiple gestation appeared strongly correlated with annual number of ETs although statistical significance was not reached (unadjusted Spearman correlation coefficient = 0.6; p = 0.21). CONCLUSION: Although IVF providers must continue to reduce multiple births by limiting the number of embryos transferred, this study places national IVF activity in the context of multiple gestations recorded in the general Irish population. These datasets suggest the number of patients undergoing IVF increased steadily in Ireland from 1999 to 2004, but a similar increase in multiple gestation was not observed in the overall Irish population during our study interval. While it is reassuring that increased use of IVF in Ireland did not significantly influence the multiple gestation rate, the absence of a formal data collection method hampers direct and comprehensive monitoring of this phenomenon here.

ReprodBiolEndocrinol. 2010 Mar 25;8:31.
IVF for premature ovarian failure: first reported births using oocytes donated from a twin sister.
Sills ES1, Brady AC, Omar AB, Walsh DJ, Salma U, Walsh AP.

Abstract

BACKGROUND: Premature ovarian failure (POF) remains a clinically challenging entity because in vitro fertilisation (IVF) with donor oocytes is currently the only treatment known to be effective. METHODS: A 33 year-old nulligravid patient with a normal karyotype was diagnosed with POF; she had a history of failed fertility treatments and had an elevated serum FSH (42 mIU/ml). Oocytes donated by her dizygotic twin sister were used for IVF. The donor had already completed a successful pregnancy herself and subsequently produced a total of 10 oocytes after a combined FSH/LH superovulation regime. These eggs were fertilised with sperm from the recipient’s husband via intracytoplasmic injection and two fresh embryos were transferred to the recipient on day three. RESULTS: A healthy twin pregnancy resulted from IVF; two boys were delivered by caesarean section at 39 weeks’ gestation. Additionally, four embryos were cryopreserved for the recipient’s future use. The sister-donor achieved another natural pregnancy six months after oocyte retrieval, resulting in a healthy singleton delivery.CONCLUSION: POF is believed to affect approximately 1% of reproductive age females, and POF patients with a sister who can be an oocyte donor for IVF are rare. Most such IVF patients will conceive from treatment using oocytes from an anonymous oocyte donor. This is the first report of births following sister-donor oocyte IVF in Ireland. Indeed, while sister-donor IVF has been successfully undertaken by IVF units elsewhere, this is the only known case where oocyte donation involved twin sisters. As with all types of donor gamete therapy, pre-treatment counselling is important in the circumstance of sister oocyte donation.

Reprod Health. 2009 Dec 17;6:21.
Pre-treatment preferences and characteristics among patients seeking in vitro fertilisation.
Walsh AP1, Collins GS, Le Du M, Walsh DJ, Sills ES.

Abstract

BACKGROUND: This study sought to describe patient features before beginning fertility treatment, and to ascertain their perceptions relative to risk of twin pregnancy outcomes associated with such therapy. METHODS: Data on readiness for twin pregnancy outcome from in vitro fertilisation (IVF) was gathered from men and women before initiating fertility treatment by anonymous questionnaire. RESULTS: A total of 206 women and 204 men were sampled. Mean (+/- SD) age for women and men being 35.5 +/- 5 and 37.3 +/- 7 yrs, respectively. At least one IVF cycle had been attempted by 27.2% of patients and 33.9% of this subgroup had initiated >/=3 cycles, reflecting an increase in previous failed cycles over five years. Good agreement was noted between husbands and wives with respect to readiness for twins from IVF (77% agreement; Cohen’s K = 0.61; 95% CI 0.53 to 0.70). CONCLUSION: Most patients contemplating IVF already have ideas about particular outcomes even before treatment begins, and suggests that husbands & wives are in general agreement on their readiness for twin pregnancy from IVF. However, fertility patients now may represent a more refractory population and therefore carry a more guarded prognosis. Patient preferences identified before IVF remain important, but further studies comparing pre- and post-treatment perceptions are needed.

Ir Med J. 2009 Oct;102(9):282-5.
Blastocyst transfer for multiple prior IVF failure: a five year descriptive study.
Walsh AP1, Shkrobot LV, Coull GD, Peirce KL, Walsh DJ, Salma U, Sills ES.

Abstract

Patients with recurrent IVF failure are generally regarded as having a poor prognosis, and when female age exceeds 35 yrs such patients face a particularly bleak outlook. This study reported on blastocyst transfer (BT) performed over a five-year interval in patients seeking “second opinion” after multiple failed IVF cycles. Clinical features and reproductive outcomes were compared between two sets of poor-prognosis IVF patients undergoing BT for the first time, the initial group underwent treatment in 2002 (n=66) and a second group presented five years later (n=392). The two clinical sets had no patients in common. The 2002 group had an average of 3.5 (+/- 1.1) prior failed IVF cycles at baseline, and mean (+/- SD) patient age was 36.4 (+/- 3.9) yrs. Average number of oocytes retrieved in this group was 10.4 (+/- 5.3) with a fertilisation rate of 58.8%. Although embryo arrest resulted in no transfer for 19 patients (28.8%), clinical pregnancy was achieved for 59.6% of transfers. Five years later, 392 patients underwent BT, but this group had an average of 4.5 (+/- 2.3) prior failed IVF cycles. Mean (+/- SD) female age was 36.0 (+/- 3.9) yrs, and the average number of oocytes retrieved in this group was 9.1 (+/- 5.4); the fertilisation rate was 59.5%. No blastocysts were available for transfer in 99 cases (25.3%); clinical pregnancy was achieved for 50.0% of transfers. The number of blastocysts transferred was similar in the two groups (1.6 vs. 1.3; p=0.06); the twinning rate rose slightly from 8.2% to 15.1% (p=0.12) despite an increased utilisation of single embryo transfer in 2007 (19.7% vs. 22.2%; p=0.40). Comparisons from 2002 and 2007 found no important differences between the two patient groups, except for a significantly higher rate of prior failed cycles in the 2007 group (p<0.001). This refractoriness was accompanied by a somewhat reduced blastocyst cryopreservation rate in 2007, compared to 2002 (27.6% vs. 29.5%; p=0.44). Clinical pregnancy rates are not adversely affected by application of BT in patients with multiple prior unsuccessful IVF cycles. For these patients, our data suggest that extended embryo culture and BT should be considered. Further controlled studies are needed to document more precisely the role of BT in this sub-set of refractory IVF patients.
ClinExpObstet Gynecol. 2009;36(3):160-2.
Analysis of federal process of care data reported from hospitals in rural westernmost North Carolina.
Sills ES1, Lotto BA, Bremer WS, Bacchi AJ, Walsh AP.

Abstract

OBJECTIVE: To evaluate standardized process of care data collected on selected hospitals serving a remote, rural section of westernmost North Carolina.MATERIALS & METHODS: Centers for Medicare & Medicaid Services (CMS) data were retrospectively analyzed for 21 clinical parameters at Fannin Regional Hospital (FRH), Murphy Medical Center (MMC), and Union General Hospital (UGH). A binomial test was used to compare each study site to state (NC) and national (U.S.A.) average. RESULTS: Summary data showed FRH to have higher scores on a significant number of standardized clinical process of care measures compared to state (p < 0.05) and national (p < 0.005) averages. Too few process of care measures at UGH were significantly higher than state and national averages to conclude that differences were not due to Type I error. Similarly, at MMC too few process of care measures were significantly higher than national averages to conclude that observed differences were not attributable to Type I error. MMC did not achieve a significantly higher score on any process of care measure when compared to state averages. CONCLUSION: Despite limitations associated with summary data analysis, the CMS “Hospitals Compare” information suggests that process of care scores at FRH are significantly higher than the state and national average. As these hospital quality data are freely available to patients, it remains to be determined what impact this may have on hospital volume and/or market share in this region. Additional research is planned to identify process of care trends in this geographical area.
Ir J Med Sci. 2012 Sep;181(3):349-51.
First Irish delivery following sequential, two-stage embryo and blastocyst transfer.
Hayrinen LH1, Sills ES, Fogarty AO, Walsh DJ, Lutsyk AD, Walsh AP.

Abstract

BACKGROUND: The timing of embryo transfer (ET) after in vitro fertilisation (IVF) remains controversial, and there are no reliable guidelines available to prospectively identify which patients would benefit from either day-3 or blastocyst transfer. While blastocyst transfer is generally favoured over day-3 transfers, very few IVF patients get both in the same treatment cycle. CASE DESCRIPTION: We report on a 35.5-year-old female with tubal factor infertility who underwent IVF, which included transfer of a fresh day-3 embryo and a thawed blastocyst frozen at day 6. Transfer occurred on two separate days (days 3 and 6) in a two-stage/dual catheter fashion and resulted in a healthy term singleton livebirth. CONCLUSIONS: While combined day-3 and day-5 ET has been available elsewhere for several years, this is the first description of its successful application in Ireland and confirms the effectiveness of coordinated two-stage transfer in a single IVF treatment cycle.

Int Arch Med. 2009 Aug 3;2(1):24.
Fertility patients and their prescriptions: a two-year audit of patient-pharmacist interactions in a reproductive endocrinology practice.
Sills ES1, Shurpyak SA, Gorman DJ, Shkrobot LV, Murray GU, O’Connor BM, Rapple UE, Fogarty AO, Sarkova P, Brickell KM, Walsh DJ.

Abstract

BACKGROUND: This study assessed pharmacy performance and satisfaction as reported by patients during ovulation induction therapy. MATERIALS AND METHODS: Patients (n = 1269) receiving gonadotropin prescriptions for intrauterine insemination or in vitro fertilisation-embryo transfer in 2007-2008 were prospectively interviewed by nurses and/or completed a structured questionnaire to evaluate pharmacy performance. “Community” (n = 12) and “specialty” (n = 2) pharmacy status (C vs. S) was defined by each pharmacy, and all pharmacies were selected by patients before cycle start. Patient comments about their pharmacy were classified into five types: i) Dispensing error-gonadotropin, ii) Dispensing error-non gonadotropin, iii) Mistake in prescribed medical equipment/supplies, iv) Counselling/communication inaccuracy, and v) Inventory problem or other. RESULTS: 391 pharmacy concerns were reported from 150 fertility patients during the study period. The majority (75.9%) of patients selected a S pharmacy to fill their prescriptions, and this pharmacy type was identified in 2.8% of adverse pharmacy encounters (p < 0.0001). Non-gonadotropin prescriptions filled at C pharmacies accounted for 40.2% of all complaints, followed by problems with prescriptions for supplies (20.2%) and gonadotropins (18.7%) at C pharmacies. Patient conflict involving S pharmacies was limited (n = 11), and related to operating hours and medication delivery logistics. CONCLUSION: Fertility patients reported a disproportionate and significantly higher number of adverse pharmacy encounters from C pharmacies compared to S pharmacies. Although no licensing mechanism in Ireland currently recognises special training or certification in any area of pharmacy practice, informal self-designations by pharmacies remain a useful discriminator. Level of familiarity with fertility medicines and availability of inventory are important characteristics to be considered when counselling fertility patients about pharmacy choice. Those who select a C pharmacy should be advised to allow extra time for inventory verification, order confirmation, and additional counselling. Additional study is needed to determine if a minimum volume of fertility-related prescriptions is necessary to assure competence in this particular field of pharmacy practice.

Philos Ethics Humanit Med. 2009 Jul 9;4:8.
Determining the status of non-transferred embryos in Ireland: a conspectus of case law and implications for clinical IVF practice.
Sills ES1, Murphy SE.

Abstract

The development of in vitro fertilisation (IVF) as a treatment for human infertilty was among the most controversial medical achievements of the modern era. In Ireland, the fate and status of supranumary (non-transferred) embryos derived from IVF brings challenges both for clinical practice and public health policy because there is no judicial or legislative framework in place to address the medical, scientific, or ethical uncertainties. Complex legal issues exist regarding informed consent and ownership of embryos, particularly the use of non-transferred embryos if a couple separates or divorces. But since case law is only beginning to emerge from outside Ireland and because legislation on IVF and human embryo status is entirely absent here, this matter is poised to raise contractual, constitutional and property law issues at the highest level. Our analysis examines this medico-legal challenge in an Irish context, and summarises key decisions on this issue rendered from other jurisdictions. The contractual issues raised by the Roche case regarding informed consent and the implications the initial judgment may have for future disputes over embryos are also discussed. Our research also considers a putative Constitutional ‘right to procreate’ and the implications EU law may have for an Irish case concerning the fate of frozen embryos. Since current Medical Council guidelines are insufficient to ensure appropriate regulation of the advanced reproductive technologies in Ireland, the report of the Commission on Assisted Human Reproduction is most likely to influence embryo custody disputes. Public policy requires the establishment and implementation of a more comprehensive legislative framework within which assisted reproductive medical services are offered.

Eur J ObstetGynecolReprod Biol. 2009 Sep;146(1):30-6.
Ovarian reserve screening in infertility: practical applications and theoretical directions for research.
Sills ES1, Alper MM, Walsh AP.

Abstract

The concept of ovarian reserve describes the natural oocyte endowment and is closely associated with female age, which is the single most important factor influencing reproductive outcome. Fertility potential first declines after the age of 30 and moves downward rapidly thereafter, essentially reaching zero by the mid-40s. Conceptions beyond this age are exceedingly rare, unless oocytes obtained from a younger donor are utilised. How best to estimate ovarian reserve clinically remains controversial. Passive assessments of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), oestradiol (E(2)), anti-Müllerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are provocative methods that have been used to assess ovarian reserve. Importantly, a patient’s prior response to gonadotropins also provides highly valuable information about ovarian function. Regarding prediction of reproductive outcome, in vitro fertilisation (IVF) experience at our centres and elsewhere has shown that some assessments of ovarian reserve perform better than others. In this report, these tests are discussed and compared; we also present practical strategies to organise screening as presently used at our institutions. Experimental challenges to the long-held tenet of irreversible ovarian ageing are also introduced and explored. While pregnancy rates after IVF are influenced by multiple (non-ovarian) factors including in vitro laboratory conditions, semen parameters, psychological stress and technique of embryo transfer, predicting response to gonadotropin treatment nevertheless remains an important aim in the evaluation of the couple struggling with infertility.

World J SurgOncol. 2009 May 14;7:46.
Ovarian serous adenocarcinoma identified during IVF: diagnostic approach, surgical management, and reproductive outcome.
Walsh DJ1, Sills ES, Shkrobot LV, Gleeson NC, Sheppard MN, Walsh AP.

Abstract

BACKGROUND: To present a diagnostic evaluation and treatment strategy for serous adenocarcinoma of the ovary discovered during an in vitro fertilisation (IVF) sequence, and report on reproductive outcome after tumour resection and embryo transfer. CASE PRESENTATION: Cycle monitoring in IVF identified an abnormal ovarian lesion which was subjected to ultrasound-guided needle aspiration. Cytology suggested malignancy, and unilateral oophorectomy was performed after formal staging. After surgery, the patient underwent an anonymous donor oocyte IVF cycle which established a viable twin intrauterine pregnancy. No recurrence of cancer has been detected in the >72 month follow-up interval; mother and twin daughters continue to do well. CONCLUSION: Suspicious adnexal structures noted during controlled ovarian hyperstimulation for IVF warrant assessment, and this report confirms the role of aspiration cytology in such cases. If uterine conservation is possible, successful livebirth can be achieved from IVF if donor oocyes are utilised, as described here.

Ir Med J. 2009 Feb;102(2):56-8.
First Irish pregnancies after IVF with gestational carrier.
Sills ES1, Shkrobot L, Coull GD, Salma U, Walsh DJ, Walsh AP.

Abstract

In this report, our early experience with screening, monitoring and coordinating IVF utilising gestational carrier treatment is described. Although congenital and iatrogenic etiologies for uterine factor infertility manifest distinctly different reasons for considering a gestational carrier approach, we outline a unified management strategy for both conditions. One patient had congenital absence of the uterus and proximal vagina (Mayer-Rokitansky-Kuster-Hauser syndrome variant), while another patient presented post-hysterectomy and adjuvant brachytherapy for invasive squamous cervical carcinoma. Conception was established for both patients, the first pregnancies to be achieved using an IVF/gestational carrier technique in Ireland. As demonstrated here, selected patients with at least one intact ovary who suffer from uterine factor infertility can be excellent candidates for IVF with embryo transfer to a carefully screened gestational carrier. The role of individual and group counselling is reviewed; professional legal advice is prudent in complex cases.
Ulster Med J. 2009 Jan;78(1):57-8.
Clinical experience with intravenous immunoglobulin and tnf-a inhibitor therapies for recurrent pregnancy loss.
Sills ES, Walsh DJ, Shkrobot LV, Palermo GD, Walsh AP.

Arch Gynecol Obstet. 2009 May;279(5):771-4.
Who’s asking? Patients may under-report postoperative pain scores to nurses (or over-report to surgeons) following surgery of the female reproductive tract.
Sills ES1, Genton MG, Walsh AP, Wehbe SA.

Abstract

OBJECTIVE: To determine if postoperative pain reporting via standardised visual analogue scale (VAS) is affected by which member of the healthcare team collects the information. MATERIALS AND METHODS: A standardised ten-point VAS measured postsurgical pain level among patients (n = 60) undergoing laparotomy via Pfannenstiel incision. All study patients received the same patient-controlled analgesia and uniform post-operative orders were used. VAS data were gathered from patients by surgeons (MD) and nurses (RN) 6 h and 24 h after surgery; RNs and MDs independently recorded patients’ VAS pain scores in variable order. RESULTS: When assessed 6 h after surgery, the average pain level reported by patients to RNs was significantly lower than that reported to MDs (3.3 +/- 2.8 vs. 4.0 +/- 2.4; P = 0.02). Average patient pain levels remained lower when reported to RNs 24 h post-operatively compared to that reported to MDs, although this difference was not significant (1.9 +/- 2.1 vs. 2.1 +/- 2.1; P = 0.39). Whenever post-surgical patients provided different VAS scores for pain level to RNs and MDs, the higher pain reading was always reported to the MD.CONCLUSION: This study identified important variances in subjective pain reporting by patients that appeared to be influenced by who sampled the data. We found patients gave lower VAS pain scores to RNs compared to MDs; the reverse pattern was never observed. Post-surgical patients may communicate pain information differently depending on who asks them, particularly in the early post-operative period. Accordingly, patient pain data gathered over time by a care team with a heterogeneous composition (i.e., RNs, MDs) may not be fully interchangeable. Patient projections of pain severity and/or intensity appear to vary as a function of who evaluates the patient.

J ExpClin Assist Reprod. 2009 Jun 10;6:3.
Ovarian hyperstimulation syndrome: current views on pathophysiology, risk factors, prevention, and management.
Alper MM, Smith LP, Sills ES.

Abstract

OBJECTIVE: To summarize current views on the pathophysiology, risk factors, prevention, clinical features, and management of Ovarian Hyperstimulation Syndrome (OHSS).DESIGN: Literature reviewRESULTS: OHSS is a condition characterized by increased capillary permeability, and experimental evidence has identified a provocative link to pathologic vasoactive cytokine actions. Although the ultimate physiologic mechanism of OHSS is not yet known, there are well-known risk factors that must be considered during the administration of medications to treat infertility. Clinical features are consequences of third-spaced intravascular fluid, and OHSS may become life-threatening secondary to thromboembolism or compromised pulmonary or cardiovascular function. Cornerstones of prevention have historically included cycle cancellation, coasting, decreased dosing of human chorionic gonadotropin (hCG) trigger, use of an agonist trigger, and cryopreservation of all embryos. Newer methods of prevention include the administration of a dopamine agonist medication. Management options for OHSS include outpatient transvaginalparacentesis, outpatient transabdominalparacentesis, and inpatient hospitalization with or without paracentesis.CONCLUSIONS: OHSS continues to be a serious complication of assisted reproductive therapy (ART), with no universally agreed upon best method of prevention. Coasting and cryopreservation of all embryos are the most commonly used approaches in the literature, but cycle cancellation is the only method that can completely prevent the development of OHSS. Dopamine agonists are currently being investigated to both prevent and improve the clinical course in OHSS. Recent publications suggest that outpatient paracentesis both prevents the need for inpatient hospitalization and is a cost-effective strategy.

Neuro Endocrinol Lett. 2008 Dec;29(6):846-51.
The GPR54-Kisspeptin complex in reproductive biology: neuroendocrine significance and implications for ovulation induction and contraception.
Sills ES1, Walsh AP.

Abstract

KISS1 encodes the kisspeptin (KP) family of peptides which were originally characterised as potent antimetastatic agents in breast cancer and malignant melanoma cells. One member of this family of arginine-phenylalanine amide peptides, KP-54, was subsequently identified as the natural ligand for the G-protein coupled receptor-54 (GPR54). In addition to its importance as a metastatic suppressor, KP has been found to play a major neuroregulatory role in governing endogenous gonadotropin release by its modulation of the hypothalamic-pituitary-gonadal (HPG) axis. In humans, KISS1 mRNA has been localised to the hypothalamic anteroventral periventricular nucleus and arcuate nucleus. Although GPR54 is expressed in human pituitary cells, it is not presently known if gonadotrope cells themselves are targets for significant KP activity. It was recently shown that full disruption of the KP/GPR54 complex resulted in hypogonadotropic hypogonadism. Indeed, evidence now suggests that KP/GPR54 signalling during gestation is necessary for sexual differentiation and implicates activation of the KP/GPR54 complex as the single most important upstream event regulating GnRH release. Several compelling studies have placed KP as the leading candidate molecule responsible for initiating puberty, making this receptor-ligand complex of fundamental importance to the neuroendocrinology of reproduction. Here, we discuss key KP/GPR54 discovery events and present an evolution of KP biology in the context of recent animal and human experimental work. With evidence pointing to proper KP/GPR54 signalling as the principal trigger for activation of GnRH neurons and subsequent ovulation, elucidation of how this pathway is modulated is likely to bring novel pharmacologic strategies for fertility treatment (and contraception) within reach. Because the physiological significance KP is now acknowledged to extend well beyond cancer biology (and may also contribute to the pathophysiology of pre-eclampsia), KP represents an exciting research theme in human reproductive biology and neuroendocrinology.
J Ovarian Res. 2008 Nov 6;1(1):7.
Ovarian hyperstimulation syndrome and prophylactic human embryo cryopreservation: analysis of reproductive outcome following thawed embryo transfer.
Sills ES1, McLoughlin LJ, Genton MG, Walsh DJ, Coull GD, Walsh AP.

Abstract

OBJECTIVE:
To review utilisation of elective embryo cryopreservation in the expectant management of patients at risk for developing ovarian hyperstimulation syndrome (OHSS), and report on reproductive outcome following transfer of thawed embryos.MATERIALS AND METHODS: Medical records were reviewed for patients undergoing IVF from 2000-2008 to identify cases at risk for OHSS where cryopreservation was electively performed on all embryos at the 2 pn stage. Patient age, total number of oocytes retrieved, number of 2 pn embryos cryopreserved, interval between retrieval and thaw/transfer, number (and developmental stage) of embryos transferred (ET), and delivery rate after IVF were recorded for all patients.RESULTS: From a total of 2892 IVF cycles undertaken during the study period, 51 IVF cases (1.8%) were noted where follicle number exceeded 20 and pelvic fluid collection was present. Elective embryo freeze was performed as OHSS prophylaxis in each instance. Mean (+/- SD) age of these patients was 32 +/- 3.8 yrs. Average number of oocytes retrieved in this group was 23 +/- 8.7, which after fertilisation yielded an average of 14 +/- 5.7 embryos cryopreserved per patient. Thaw and ET was performed an average of 115 +/- 65 d (range 30-377 d) after oocyte retrieval with a mean of 2 +/- 0.6 embryos transferred. Grow-out to blastocyst stage was achieved in 88.2% of cases. Delivery/livebirth rate was 33.3% per initiated cycle and 43.6% per transfer. Non-transferred blastocysts remained in cryostorage for 24 of 51 patients (46.1%) after ET, with an average of 3 +/- 3 blastocysts refrozen per patient.CONCLUSION: OHSS prophylaxis was used in 1.8% of IVF cycles at this institution; no serious OHSS complications were encountered during the study period. Management based on elective 2 pn embryo cryopreservation with subsequent thaw and grow-out to blastocyst stage for transfer did not appear to compromise embryo viability or overall reproductive outcome. For these patients, immediate elective embryo cryopreservation and delay of ET by as little as 30 d allowed for satisfactory conclusion of the IVF sequence, yielding a livebirth-delivery rate (per ET) >40%.

Reprod Health. 2008 Nov 4;5:9.
Building Irish families through surrogacy: medical and judicial issues for the advanced reproductive technologies.
Sills ES1, Healy CM.

Abstract

Surrogacy involves one woman (surrogate mother) carrying a child for another person/s (commissioning person/couple), based on a mutual agreement requiring the child to be handed over to the commissioning person/couple following birth. Reasons for seeking surrogacy include situations where a woman has non-functional or absent reproductive organs, or as a remedy for recurrent pregnancy loss. Additionally, surrogacy may find application in any medical context where pregnancy is contraindicated, or where a couple consisting of two males seek to become parents through oocyte donation. Gestational surrogacy is one of the main issues at the forefront of bioethics and the advanced reproductive technologies, representing an important challenge to medical law. This analysis reviews the history of surrogacy and clinical and legal issues pertaining to this branch of reproductive medicine. Interestingly, the Medical Council of Ireland does not acknowledge surrogacy in its current practice guidelines, nor is there specific legislation addressing surrogacy in Ireland at present. We therefore have developed a contract-based model for surrogacy in which, courts in Ireland may consider when confronted with a surrogacy dispute, and formulated a system to resolve any potential dispute arising from a surrogacy arrangement. While the 2005 report by the Commission on Assisted Human Reproduction (CAHR) is an expert opinion guiding the Oireachtas’ development of specific legislation governing assisted human reproduction and surrogacy, our report represents independent scholarship on the contractual elements of surrogacy with particular focus on how Irish courts might decide on surrogacy matters in a modern day Ireland. This joint medico-legal collaborative also reviews the contract for services arrangement between the commissioning person/s and the surrogate, and the extent to which the contract may be enforced.

FertilSteril. 2009 Apr;91(4 Suppl):1568-70.
Clinical features and reproductive outcomes for embryos undergoing dual freeze-thaw sequences followed by blastocyst transfer: critique of 14 consecutive cases in IVF.
Sills ES1, Murray GU, Genton MG, Walsh DJ, Coull GD, Walsh AP.

Abstract

These data suggest that the physiologic stress associated with two consecutive freeze-thaw processes is likely minor. Dual freeze-thaw of embryos does not appear to adversely impact delivery rate in IVF; a livebirth delivery rate of 35.7% per transfer was observed in our population.

Copyright © 2015 CAG.All rights reserved.
E. Scott Sills, MD PhD and the Center for Advanced Genetics (CAG) is a reproductive medicine clinic located in Carlsbad, California USA, in North San Diego County, and serves the cities of Carlsbad, Oceanside, Vista, San Marcos, Encinitas, Escondido, Fallbrook, Bonsall, and Camp Pendleton. The fertility clinic specializes in in-vitro fertilization (IVF), frozen embryo transfer (FET), blastocyst transfer, pre-implantation genetic diagnosis/screening/testing of embryos (PGD, PGS) for possible genetic abnormalities and gender selection, Next Generation Sequencing (NGS), intra-uterine insemination (IUI), surrogacy, donor cycles, male-factor infertility, Essure® removal, treatment for recurrent pregnancy loss, and fertility preservation (egg freezing, sperm banking). Dr. Sills is published over 100 times in peer-reviewed publications and just published his book “Fighting at the Fertility Front,” a book that covers infertility, treatments, and issues that are unique to military personnel. CAG is committed to building families, including assisting those of the LGBT community. We offer low-interest fertility treatment financing to make having a baby a reality for virtually everyone.
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