Is there evidence to support serum antinuclear antibodies testing in women with recurrent implantation failure undergoing in vitro fertilization?

One of the most challenging aspects of reproductive medicine is the management of recurrent implantation failure. Various investigations, including antinuclear antibodies testing, are performed to seek an explanation and guide treatment. However, is there sufficient evidence or available therapeutic options to support antinuclear antibodies testing? We present a short review on the current literature and an attempt at a systematic review evaluating the association between antinuclear antibodies and recurrent implantation failure to address this question.

What exactly do we mean by 'recurrent implantation failure'? A systematic review and opinion.

Recurrent implantation failure (RIF) is an iatrogenic condition, being the result of repetitive unsuccessful cycles of IVF or intracytoplasmic sperm injection (ICSI) treatment. The aim of this review was to assess the definitions of RIF used in literature as well as suggest a uniform definition of this condition. A systematic search of MEDLINE, Embase and Cochrane Library was conducted. The most commonly stated definitions described RIF as 'three or more failed treatment cycles' or 'two or more failed cycles'. Other identified definitions were based solely on the number of embryos transferred in previous cycles or combined the number of previously failed cycles with the number of transferred embryos. Several other definitions were also identified. This review highlights the lack of uniformity of the definition of RIF. Based on the available literature and the expert opinion of the authors, RIF should be defined as the absence of implantation after two consecutive cycles of IVF, ICSI or frozen embryo replacement cycles where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, with all embryos being of good quality and of appropriate developmental stage.

Assessment of endometrial and subendometrial blood flow in women undergoing frozen embryo transfer cycles.

This study evaluated whether 3D power Doppler (3DPD) indices from endometrium and subendometrium can identify increases in endometrial volume/vascularity induced by exogenous oestradiol and subsequent introduction of progestogens in women undergoing frozen-thawed embryo transfer (FET). Oral oestradiol was administered at increasing doses after down-regulation to prepare the endometrium and progestogens were used for luteal support. 3DPD data sets were acquired at down-regulation, on days 5, 10 and 15 of oestradiol administration and at the time of FET. Endometrial thickness was measured using the multiplanar method and endometrial volume and blood flow from the endometrium and subendometrium were estimated using virtual organ computer-aided analysis and shell-imaging. This study evaluated 45 women at least once: 19 achieved clinical pregnancy (CP); 21 were evaluated at down-regulation (eight CP), 26 at day 5 (10 CP), 31 at day 10 (12 CP), 31 at day 15 (13 CP) and 16 at FET (seven CP). Changes were observed in all parameters between the examinations; however, differences between women who achieved CP and those who did not were not significant. 3DPD angiography is not a sufficiently sensitive tool to predict the outcome of FET. We evaluate whether 3D ultrasound using power Doppler (3DPD) indices from endometrium and subendometrium can identify predictable increases in endometrial volume and vascularity induced by serial increments in exogenous oestradiol and the subsequent introduction of progestogens in women undergoing frozen-thawed embryo transfer (FET) using hormone replacement therapy to prepare the endometrium. Oral oestradiol was administered at increasing doses after down-regulation to prepare the endometrium and progestogens were used for luteal support. 3DPD data sets of the uterus were acquired at down-regulation, on days 5, 10, and 15 of oestradiol administration, and at the time of FET. Endometrial thickness was measured. Endometrial volume and blood flow from the endometrium and subendometrium were measured using virtual organ computer-aided analysis (VOCAL) and shell imaging. This study evaluated 45 women at least once: 19 achieved clinical pregnancy (CP); 21 were evaluated at down-regulation (eight CP), 26 at day 5 (10 CP), 31 at day 10 (12 CP), 31 at day 15 (13 CP) and 16 at FET (seven CP). Changes were observed in all the parameters between the examinations; however, differences between women who achieved CP and those who did not were not significant, suggesting that quantitative 3D power Doppler angiography is not a sufficiently sensitive tool to predict the outcome of FET treatment.

Influence of gain adjustment on 3-dimensional power Doppler indices and on spatiotemporal image correlation volumetric pulsatility indices using a flow phantom.

Spatiotemporal image correlation can be used to acquire 3-dimensional power Doppler information across a single cardiac cycle. Assessment and comparison of the systolic and diastolic components of the data sets allow measurement of the recently introduced "volumetric pulsatility index" (vPI) through algorithms comparable with those used in 2-dimensional Doppler waveform analysis. The vPI could potentially overcome the dependency on certain machine settings, such as power, color gain, pulse repetition frequency, and attenuation, since these factors would affect the power Doppler signal equally throughout the cardiac cycle. The objective of this study was to compare the effect of color gain on the vascularization index (VI), vascularization-flow index (VFI), and vPI using an in vitro flow phantom model. We separated gains into 3 bands: -8 to -1 (no noise), -1 to +5 (low noise), and +5 to +8 (obvious noise). The vPI was determined from the 3-dimensional VI or VFI using the formula vPI = (maximum - minimum)/mean. Using no-noise gains, we observed that although the VI and VFI increased linearly with gain, the vPI was substantially less dependent on this adjustment. The VI and VFI continued to increase linearly with gain, whereas the vPI decreased slightly using low-noise gains. When gain was increased above the lower limit of obvious noise (+5), the VI and VFI increased noticeably, and there were marked reductions in both vPI values. We conclude that the vPI is less affected by changes in color gain than the VI and VFI at no-noise gains.

Difficult embryo transfers or blood on catheter and assisted reproductive outcomes: a systematic review and meta-analysis.

We performed a systematic review and meta-analysis to examine whether a difficult embryo transfer or the presence of blood on the transfer catheter affects assisted reproduction outcomes. We searched the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), MEDLINE, Embase, PsycINFO, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS). We aimed to determine the risk ratio (RR) associated with difficult embryo transfer or the presence of blood on the transfer catheter for the following outcomes: live birth, clinical pregnancy, and miscarriage. We identified 3066 papers, of which 194 were reviewed and nine were included. The outcome of live birth was not reported in any of the included studies and the effect on miscarriage was too imprecise for any conclusions. Pooled analysis of five studies demonstrated lower clinical pregnancy rates following a non-easy embryo transfer (RR=0.75; 95% CI=0.66-0.86). This included three studies showing subjectively difficult transfers reducing clinical pregnancies (RR=0.67; 95% CI=0.51-0.87) and two studies in which the need for additional manoeuvers reduced clinical pregnancies (RR=0.78; 95% CI=0.67-0.91). The presence of blood on the transfer catheter did not affect clinical pregnancy rates (RR=0.96; 95% CI=0.82-1.14) in five studies. We concluded that low quality evidence suggests that a difficult embryo transfer but not a bloody catheter reduces the chance of achieving a clinical pregnancy. More good quality studies are needed to evaluate the effect of difficult embryo transfer and the presence of blood on the catheter on the main outcomes of assisted reproduction.

The "volumetric" pulsatility index as evaluated by spatiotemporal imaging correlation (STIC): a preliminary description of a novel technique, its application to the endometrium and an evaluation of its reproducibility.

We propose new volumetric indices derived from three-dimensional (3-D) power Doppler (PD) using spatiotemporal imaging correlation (STIC) to overcome the influence of machine settings and attenuation. In this study, we describe these indices and evaluate their interobserver reliability: two static-3-D and two STIC PD datasets were acquired from 60 women and two observers (blinded analysis) evaluated vascularization index (VI), the flow index (FI) and the vascularization flow index (VFI) of standardized spherical samples of endometrium. Three new indices were determined based on maximum, minimum and mean values (vPI, vRI(max-min), vS/D(max-min)) and two indices from frames subjectively defined as systole and diastole (vRI(sys-dia), vS/D(sys-dia)). Highest intraclass coefficient correlations (ICCs) were obtained from vPI derived from VI or VFI (0.77-0.76), followed by vRI(max-min) (0.72-0.72) and vS/D(max-min) (0.52-0.49). ICCs from indices based on subjectively systole and diastole or FI were consistently lower (<0.40). We conclude that the subjective choice of systolic and diastolic frames only lacks reliability but indices based on complete evaluation may reliably be used.

The interovarian variation in three-dimensional ultrasound markers of ovarian reserve in women undergoing baseline investigation for subfertility.

OBJECTIVE: To evaluate differences in the three-dimensional (3D) ultrasound markers of ovarian reserve between the ovaries within an individual undergoing investigation for subfertility. DESIGN: Prospective observational study. SETTING: University-based assisted conception unit. PATIENT(S): Two hundred seventy women undergoing baseline early follicular phase ultrasound as an investigation for subfertility. INTERVENTION(S): Three-dimensional ultrasound scan in early follicular phase between days 2 and 5 of the menstrual cycle. MAIN OUTCOME MEASURE(S): Variations in 3D ultrasound markers of ovarian reserve between the two ovaries within same individual. RESULT(S): Two hundred fifteen subjects were analyzed for ovarian volume and antral follicle count, and 205 subjects for 3D power Doppler indices. Significant differences were noted (median, range) in the number of antral follicles measuring >6.0 mm and ovarian volume. Significant correlation was noted between the two ovaries in antral follicles measuring 6.0 mm or less, ovarian volume, and 3D power Doppler indices. On stratifying the antral follicles according to size using sonography-based automated volume calculation with postprocessing, maximum variation was seen in follicles measuring more than 6.0 mm as measured using limits of agreement. CONCLUSION(S): There are significant differences in the antral follicles measuring >6.0 mm and ovarian volume, as measured using 3D ultrasound, that require consideration when comparing the two ovaries within an individual.

A novel technique for the semi-automated measurement of embryo volume: an intraobserver reliability study.

The aim was to assess intraobserver reliability of a new semi-automated technique of embryo volumetry. Power calculations suggested 46 subjects with viable, singleton pregnancies were required for reliability analysis. Crown rump length (CRL) of each embryo was analyzed using 2-D and a 3-D dataset acquired using transvaginal ultrasound. Virtual organ computer-aided analysis (VOCAL) was used to calculate volume of gestation sac (GSV) and yolk sac (YSV) and SonoAVC (sonography-based automated volume count) was used to quantify fluid volume (FV). Embryo volume was calculated by subtracting FV and YSV from GSV. Each dataset was measured twice. Reliability was assessed using Bland-Altman plots and intraclass correlation coefficients (ICCs). Fifty-two datasets were analyzed. Median embryo volume was 1.8 cm(3) (0.1 to 8.1 cm(3)); median gestational age 7 + 4 weeks; median CRL 13 mm (2 to 29 mm). Mean difference of embryo volume measurements was 0.1cm(3) (limits of agreement [LOA] -0.3 to 0.4 cm(3)); multiples of mean (MoM) 0.38; mean difference of CRL measurements 0.3 mm (LOA -1.4 to 2.0 mm), MoM = 0.26. ICC for embryo volume was 0.999 (95%CI 0.998 to 0.999), confirming excellent intraobserver agreement. ICC for CRL was 0.996 (95%CI 0.991 to 0.998). Regression analysis showed good correlation between embryo volume and CRL (R(2) = 0.60). The new semi-automated 3-D technique provides reliable measures of embryo volume. Further work is required to assess the validity of this technique.

The management of miscarriage.

Women diagnosed with incomplete and delayed miscarriage are faced with three options for their subsequent management: expectant, medical or surgical. Health-care practitioners must empower patients to make educated decisions about their own management by providing them with sufficient information in a readily understandable format. This can be difficult both for the patient and the staff in what is often an understandably, highly emotional situation. Detailed counselling is an essential part of the process as psychological outcomes have been shown to be improved when women feel in control of the decision-making process. In this article, we discuss each of the treatment options in detail, and explore how the type of miscarriage influences their relative success rates. We also consider the comparative risks of bleeding, infection, side effects of drugs, pain scores and quality-of-life scores associated with each method through evidence derived from systematic reviews, meta-analyses and randomised controlled trials.

Defining endometrial growth during the menstrual cycle with three-dimensional ultrasound.

OBJECTIVE: To define the changes in endometrial morphometry that occur during the normal menstrual cycle and to examine the discriminatory power of volumetric analysis over conventional two-dimensional measurements in quantifying the effect of compounding factors on endometrial growth. DESIGN: The design was that of a longitudinal observational study. Subjects were seen on an alternate-day basis until ovulation and then every four days until the next menstrual period. SETTING: A University teaching hospital. POPULATION: Thirty women with regular cycles and acceptable "normal", menstrual patterns. METHODS: Three-dimensional ultrasound data were acquired and subsequently analysed by a single observer. MAIN OUTCOME MEASURES: Endometrial thickness and volume. RESULTS: Both endometrial volume and thickness increased significantly during the follicular phase (P < 0.001), reaching a plateau around the time of ovulation and remaining relatively stable throughout the luteal phase. These changes in endometrial thickness and volume were highly correlated (R(2)= 0.767; P < 0.001). Parity was associated with a significantly greater endometrial volume than nulliparity (4.159 vs 2.234 cm(3); P < 0.05). CONCLUSIONS: This study has defined the relative and absolute changes in endometrial growth, both in terms of thickness and volume, throughout the normal menstrual cycle. These data provide a reference for future three-dimensional studies investigating menstrual disorders, pathophysiological change and subfertility.

Skin aging and menopause : implications for treatment.

The skin is one of the largest organs of the body, which is significantly affected by the aging process and menopause. The significant changes sustained by the skin during the menopause are due to the effect sustained on the skin's individual components. The estrogen receptor has been detected on the cellular components of the skin. Accordingly, dermal cellular metabolism is influenced by the hypoestrogenoemic state of menopause leading to changes in the collagen content, alterations in the concentration of glycoaminoglycans and most importantly the water content. Consequently changes in these basic components leads to an alteration in function compatible with skin aging. Changes in the skin collagen leads to diminished elasticity and skin strength. Collagen content may be measured by various methods such as direct skin biopsy, skin blister assessment for collagen markers and skin thickness measurement. All these variables indicate a reduction in collagen content following menopause. This may be reversed with the administration of estrogen given both topically and systemically.A reduction in hydrophilic glycoaminglycans leads to a direct reduction in water content, which influences the skin turgor. These effects on glycoaminoglycans, due to the hypoestrogenia, have been clearly shown in animal studies and appeared to be rapidly reversed with the application of estrogens. The sum total of these basic effects on the skin leads to wrinkles, the skin condition typifying skin aging.Structures resident in the skin are likewise influenced by menopause. Changes to the cutaneous vascular reactivity are noted following menopause. Capillary blood flow velocity decreases significantly in postmenopausal women. Postmenopausal flushing is due to profound vasodilatation in the dermal papillae. Hair growth is also influenced by the hormonal milieu and consequently hair loss has been associated with the beginning of menopause. Treatments administered for menopause, in particular hormone replacement therapy, appear to alter its effects on the basic components of the skin as well as the more complex structures residing in the skin, consequently retarding the skin aging process.