Antiphospholipid antibodies in women having in-vitro fertilization

Antiphospholipid antibodies have an established associationwith pregnancy complications such as recurrent miscarriage,growth retardation, placental abruption and stillbirth but theirmechanism of action is unclear. We have investigated whetherantiphospholipid antibodies occur more frequently in women havingin-vitro fertilization (IVF) and whether their presence is associatedwith the likelihood of failed implantation. We studied 240 womenundergoing IVF treatment who were <38 years and had attemptedfewer than three previous IVF cycles. Antiphos-pholipid antibodies(anticardiolipin and antiphosphatidyl serine immunoglobulinG and immunoglobulin M) were present in 36 out of 240 (15%)of the study population and were not associated with a failedIVF cycle or miscarriage. There was no association between thecause of infertility and the presence of antiphospholipid antibodies.Antiphos-pholipid antibodies were not detected more frequentlyin women with previous attempts at IVF compared with women havingtheir first cycle, indicating that the high incidence of theseantibodies is not due to the IVF treatment. There was a strongassociation between the presence of antiphospholipid antibodiesand intrauterine growth retardation in singleton pregnancies(P<0.005). We recommend routine screening for the presenceof antiphos-pholipid antibodies in women having IVF in orderto identify those pregnancies at increased risk of intrauterinegrowth retardation.     

Influence of antiphospholipid antibodies on pregnancy outcome in women undergoing in vitro fertilization and embryo transfer

PROBLEM: Antiphospholipid antibodies (APA) are thought to be involved in recurrent pregnancy loss. Therefore, we investigated the impact of APA on pregnancy outcome in women undergoing in vitro fertilization and embryo transfer (IVF-ET). METHOD OF STUDY: Blood samples taken from 54 Korean women referred for IVF were tested for the presence of APA, anticardiolipin antibody IgG and IgM and lupus anticoagulant. The standard gonadotropin-releasing hormone agonist long protocol was used for ovarian stimulation. RESULTS: Nine patients (16.7%) were positive and 45 (83.3%) were negative for APA. There were no significant differences between the two groups in clinical characteristics such as age, infertility duration, and response to controlled ovarian hyperstimulation. However, pregnancy outcome significantly differed between the two groups (p < 0.05). The APA positive group and APA negative group had abortion rates of 62.5% and 20.0%, respectively and delivery rates of 37.5% and 80.0%, respectively. CONCLUSION: The presence of APA in women undergoing IVF-ET was associated with a poor pregnancy outcome.     

Management of patients with antiphospholipid antibodies undergoing in vitro fertilization

Infertility affects 10-15% of all married couples of reproductive age in the United States and results in substantial emotional distress and medical investment. Though it is uncertain whether antiphospholipid syndrome (APS) is a cause of infertility, inevitably there is a small proportion of women who have both APS and infertility. In turn, some of these patients are candidates for ovulation induction, with or without assisted reproductive technologies, such as in vitro fertilization and embryo transfer, in an attempt to achieve successful pregnancy. The medications used for ovulation induction cause an increase in ovarian estrogen production beyond that typical of a normal menstrual cycle. Clinicians are appropriately concerned about the potential adverse effects of this estrogen surge on the clinical status of women with autoimmune disease. For APS, a primary concern would be that of thrombosis or embolism.     

Immunology: High fecundity rates following in- vitro fertilization and embryo transfer in antiphospholipid antibody seropositive women treated with heparin and aspirin

This study was undertaken to explore whether intervention withheparin and aspirin (H/A) in selected patients undergoing in-vitrofertilization (TVF) and embryo transfer could improve fecundityrates. Specifically, it explored the possibility that womendiagnosed with organic pelvic disease who demonstrated antiphospholipidantibodies (APA) could benefit from H/A administration in asimilar manner to that used in patients with recurrent pregnancyloss. We used an enzyme–linked immunosorbent assay forsix different phospholipids to identify patients who expressedAPA before they underwent IVF/embryo transfer. This study wasconfined to the first IVF/embryo transfer cycle that followedassessment of APA status and accordingly, the number of IVF/embryotransfer cycles corresponds with the number of patients treated.APA seropositive patients were treated with aspirin, 81 mg orallyq.d., and heparin 5000 IU s.c. b.i.d., beginning on day 1 ofcontrolled ovarian stimulation. The endpoint for success wasa live birth or an ultrasound confirming fetal cardiac activity(a viable pregnancy). The prevalence of APA in patients diagnosedwith organic pelvic disease (53%) was much higher than in thosewithout female pathology (14%). The administration of H/A toAPA seropositive patients significantly (P < 0.05) improvedthe viable pregnancy rate (49%) compared to the untreated APAseropositive group (16%). The viable pregnancy rate for APAseropositive women treated with H/A was also significantly (P< 0.001) higher than for untreated APA seronegative patients(27%). We conclude that all women undergoing IVF/embryo transfershould be tested for APA prior to initiating ovarian stimulation,and those with APA seropositivity should be treated with H/A.     

Immunology: Serum markers of immune activation in women undergoing in-vitro fertilization and embryo transfer

We evaluated serum concentrations of two early and sensitivemarkers of immune activation, interleukin-2 receptor (sIL-2R)and intercellular adhesion molecule-1 (ICAM-1) in two age-matchedgroups of in-vitro fertilization (IVF)-embryo transfer women,group I (n = 26) without and group II (n = 40) with methylprednisolone(MPD) supplementation of the luteal phase, on the days of oocyteretrieval (sample A) and embryo transfer (B), and second (C)and 13th (D) days post-transfer and in 20 normally cycling women(controls) on the day of luteinizing hormone (LH) peak. No differencein the outcome of the IVF-embryo transfer was observed betweengroups I and II. In sample A, both immunomarker concentrationsshowed no significant difference between the two groups of IVFwomen, while they were significantly higher (P < 0.01) thanvalues in controls. In cycles in which conception occurred,significantly higher immunomarker concentrations were observedin sample A of both groups I and II compared with those in unsuccessfulcycles of the same group. A significant decrease of both sIL-2Rand ICAM-1 was noticed in sample B only in group II (P <0.0001 and P < 0.001 respectively; paired t-test) that continuedfurther in the late luteal phase only hi the case of conception,independently of MPD supplementation. These data suggest that(i) due to multiple ovulations, IVF-embryo transfer women showelevated concentrations of sIL-2R and ICAM-1 at oocyte retrieval;(ii) since, even at oocyte retrieval stage, high concentrationsof immunomarkers are associated with IVF-embryo transfer success,sEL-2R and ICAM-1 could be used as early indicators for conceptioncycles; (iii) transient suppression of T cell activity by MPDsupplementation following IVF-embryo transfer does not improvepregnancy rate.     

Infertility: Altered responses to stress in women undergoing in-vitro fertilization and recipients of oocyte donation

Clinical impressions suggest the presence of considerable anxietyand depression in infertile couples. We utilized a psychologicalstress test to assess adaptations to provoked stress to improvethe psychological profile of infertile women. A psychologicalstress test was administered to four groups: normal menstruatingfemales (controls, n = 13); oocyte donors (n = 13); recipientsof oocyte donation (n = 7); and women undergoing standard in-vitrofertilization (IVF; mean age 38.0 years; n = 8). The psychologicalstress test consisted of three active coping tasks: (i) serialsubtraction, (ii) Stroop colour test, (iii) speech task and(iv) one passive coping task, the cold-pressor test. Haemo-dynamicresponses (HD) were monitored before, during and after the psychologicalstress test, and serum samples were drawn for catecholaminesand cortisol. Baseline blood pressures were similar among groups.The psychological stress test elicited different biophysicalresponses in controls compared with the other groups (P <0.001). Oocyte donors had different speech task responses frombaseline, although these and the other parameters of the psychologicalstress test were not different from either the recipient orIVF groups. Blood pressure responses from baseline were bluntedin both recipients and standard IVF patients following provokedstress. Baseline cortisol and norepi-nephrine were similar amongall groups, yet provoked stress elicited a significant increasein controls (142.0 ± 25.2%, P < 0.001) compared withoocyte donors (17.1 ± 19.7%), recipients and standardIVF patients (mean –15.5 ± 17.3% respectively).Norepinephrine responses were apparently greater in controls(60.1 ± 13.1%) compared with oocyte donors (41.8 ±27%) and recipient and IVF groups combined (21.7 ± 12.4%)but this result was not significant. These data suggest thatinfertile women have blunted biophysical and biochemical reactionsto provoked behavioural stressors. Oocyte donors demonstrateblunted passive coping responses similar to those of infertilewomen, yet still respond to active coping stressors in a mannersimilar to that of normal controls. Our data suggest that infertilitytherapy combined with the anticipation of success or failureresults in blunted patterns of response to passive coping stressors.However, blunted active coping responses are unique to infertilewomen.     

Effect of prednisolone on serum and follicular fluid androgen concentrations in women with polycystic ovary syndrome undergoing in-vitro fertilization.

Increased androgen concentrations are thought to be detrimental to oocyte quality and reproductive potential. Adjuvant treatment with glucocorticoids has been tried to suppress androgens in women undergoing infertility treatment. In the present study 20 infertile women with polycystic ovary syndrome were prospectively randomized in a placebo-controlled study to receive either placebo or prednisolone 10 mg at night, during standard in-vitro fertilization (IVF) treatment. Serum samples for assays of gonadotrophins, steroids and sex hormone-binding globulin (SHBG) were collected before treatment, at down-regulation, and at oocyte retrieval. Up to five follicles in each ovary were analysed separately regarding follicular fluid and oocytes, the rest according to the clinic's routines. In the placebo group, serum dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEA-S) did not change between down-regulation and oocyte retrieval, whereas adjuvant prednisolone resulted in a significant decrease. In follicular fluid, adjuvant prednisolone resulted in significantly lower concentrations of DHEA-S as compared to placebo, no other significant differences were found. No significant differences were found in embryo characteristics or pregnancy rates between the groups.     

Cumulative pregnancy and live birth rates in women with antiphospholipid antibodies undergoing assisted reproduction.

The aims of this study were to investigate the influence of antiphospholipid antibodies (APA) on cumulative pregnancy and live-birth rates in patients undergoing assisted reproductive treatment. Serum samples from 173 patients were collected prior to initiation treatment cycle and tested by enzyme-linked immunosorbent assay (ELISA) for the presence of immunoglobulin (Ig)G, IgM and IgA against cardiolipin, phosphoserine, phosphoethanolamine, phosphoinositol, phosphatidic acid, and phosphoglycerol. Fifty-six samples from patients who had at least two failed cycles by assisted reproductive treatment were also tested by a bioassay for the presence of lupus anticoagulants. Both cumulative pregnancy and live birth rates were not affected by the presence of any specific or any number of seropositive APA. There was no association between multiple assisted reproductive treatment failures and APA seropositivity. Neither the serum concentration of any of the 18 APA, nor the number of positive APA was correlated with the number of assisted reproductive treatment failed cycles or affected the probability of pregnancy. No patient was found to be positive for lupus anticoagulants. Using life table analyses, which has been recognized as the most appropriate method available to analyse assisted reproductive treatment results, we conclude that there is no relationship between circulating APA and assisted reproductive treatment outcome. APA do not affect the early process of implantation or maintenance of pregnancy among assisted reproductive treatment patients.     

Increased prevalence of thyroid antibodies in euthyroid women with a history of recurrent in-vitro fertilization failure

This study was undertaken to evaluate whether the presence of thyroid antibodies in euthyroid women is associated with an adverse outcome in an in-vitro fertilization (IVF)-embryo transfer programme. In 24 women (study group: mean age +/- SD: 31.5 +/- 4.4 years) who failed to conceive after having three or more cycles of IVF and embryo transfer, serum concentrations of thyroglobulin (TG), thyroid peroxidase antibodies (TPO) and anticardiolipin antibodies (IgG and IgM) were measured using commercially available kits. The control group comprised 24 consecutive patients without endocrine dysfunction (mean age +/- SD: 30.3 +/- 4.1 years) seeking infertility treatment in our department of assisted reproduction. All patients in both the study and the control groups were determined to be euthyroid by demonstrating normal concentrations of thyroid-stimulating hormone (TSH). In the study and control groups respectively, 13 and two patients demonstrated positive titres of TG, TPO or both thyroid antibodies (Fisher's exact test: P = 0.002). Mean serum concentrations of TG were significantly increased in the study group compared to the control subjects (156 +/- 167 IU/ml versus 33.5 +/- 32.0 IU/ml; U-test: P = 0.009). Serum concentrations of TPO and anticardiolipin antibodies were similar in both groups. Our investigations revealed that thyroid antibodies might be independent markers for reproductive failure in an IVF-embryo transfer programme.     

Attitudes about genetic risk of couples undergoing in-vitro fertilization

Many couples undergoing in-vitro fertilization (IVF) are at a higher risk of having a child with a genetic abnormality. In a sample of 55 consecutive couples starting IVF, only 33% had no genetic risk factor. The most common genetic risks were advanced maternal age and possible abnormalities associated with severe male infertility. Despite education on these risks, 71% of couples had no interest in receiving formal genetic counselling. Only 14% of couples at risk would consider using a gamete donor to avoid transmitting a genetic disorder to a child. The triple test to screen for fetal abnormalities was acceptable to 82% of couples, but only 47% planned to have amniocentesis or chorionic villi sampling. Couples were significantly more likely to opt for prenatal testing if they would consider terminating a pregnancy should the fetus have a severe genetic abnormality (P < 0.01). Roman Catholic couples tended to have more conservative attitudes about pregnancy termination. Socio-economic status and whether the infertility factor was male or female were not predictors of a couple's attitudes.      

The role of oocyte donation in women who are unsuccessful with in-vitro fertilization treatment.

Oocyte donation improves the chances of becoming pregnant in some women who are unsuccessful with in-vitro fertilization (IVF) treatment. A total of 119 IVF cycles achieved a pregnancy rate per cycle of 2.5% whereas the same women, when treated with 45 cycles of oocyte donation, achieved a 24.5% pregnancy rate per cycle. To ascertain which women may be helped by oocyte donation, IVF data were analysed according to the outcome of oocyte donation. There was a difference in the number of previous natural conceptions and live births, and in the IVF fertilization rate. There was no difference in the age of the women and the numbers of oocytes collected per cycle of IVF. New criteria are therefore suggested for recommending oocyte donation to women who have previously failed to become pregnant with IVF treatment.     

Management of pregnant women with antiphospholipid antibodies

Introduction: Important advancements in pregnancy outcome have been reported in women with antiphospholipid antibodies (aPL), despite the fact that the treatment of aPL related pregnancy morbidity is not guided by consistent findings from well-designed trials.

Areas covered: The current study draws a picture of the studies in the literature by performing a Medline search of relevant English language articles and reports our experience in managing different subsets of obstetric antiphospholipid syndrome (APS), defined on the basis of their clinical and laboratory characteristics. The management of pregnant women with non-criteria APS manifestations and that of aPL carriers during their first pregnancy is also examined.

Expert commentary: A heparin/aspirin combination constitutes conventional treatment for APS affected pregnant women. As this strategy fails in approximately 20–30% of cases, uncovering other options for women refractory to conventional treatment or at high risk of pregnancy complications has become an urgent undertaking. Some attempts have been made to prescribe additional treatments in the effort to improve live birth rates and/or reduce pregnancy complications, which often occur even in patients treated conventionally. The evidence from some studies and an individual risk/benefit assessment should instead guide treatment decisions for pregnant patients with non-criteria APS manifestations and aPL carriers.     

Uterus and endometrium: Endometrial pattern in diethylstilboestrol-exposed women undergoing in-vitro fertilization may be the most significant predictor of pregnancy outcome

The objective of this study was to compare prospectively pregnancyoutcome as it is related to ultrasonic endometrial echo patternin women exposed to diethylstilboestrol (DES) in utero by theirmother's consumption with women not exposed to DES, all of whomwere undergoing in-vitro fertilization (TVF). Pregnancy outcomerelative to endometrial thickness and pattern was evaluatedin 540 cycles of IVF including DES (n = 50) and non-DES-exposed(n = 490) women. Endometrial patterns were designated as p1= solid; p2 = ring; and p3 = intermediate. DES patients exhibitedp1 more often than the majority of the non-DES-exposed group.There was no significant difference in endometrial thicknessamong the cycles where p1 was noted when comparing the DES (103mm) with the non-DES-exposed (10.7 mm) groups. Notably, withinthe group exhibiting p1, no pregnancies occurred in the 18 cyclesof DES-exposed women compared with a 39.2% clinical pregnancyand 36.5% delivery rate in the non-DES-exposed controls (P 0.0001 and P = 0.008 respectively). Pregnancy rates were notsignificantly different in the cycles where the other endometrialpatterns were found when comparing the two groups. The impactof uterine shape on pregnancy outcome was also investigated.A T-shaped uterine configuration was noted in 11 out of 18 (61.1%)cycles of DES-exposed women with pattern p1 compared with nineout of 23 (39.1%) with pattern p2. Of cycles where a T-shapeduterus was demonstrated, none out of 11 (0%) with pattern p1compared with four out of nine (44.4%) with pattern p2 resultedin pregnancy (P = 0.026). These data suggest that endometrialpattern is one of the most significant variables for pregnancyoutcome in DES-exposed women undergoing IVF.     

Responses in post-menopausal women: Counselling post-menopausal women for donor in-vitro fertilization and hormone replacement therapy

Oocyte donation was applied initially to women with hypergonadotrophichypogonadism or ‘premature menopause’. Later, therapywas extended to recipients >40 years old and to post-menopausalwomen. In all cases, enhanced implantation and pregnancy rateswere obtained by many investigators. Post-menopausal women mustbe informed about in-vitro fertilization results, obstetricrisks for themselves and their newborn babies. They must bescreened and investigated as accurately as possible for anyexisting medical contraindication. Results are encouraging becausethese patients become pregnant as easily as young donors, withpregnancy rates of 58, 34.6 and 37.9% per patient, per synchronizationcycle and per transfer respectively. Abortion rates (5%) arevery low considering the women are >45 years old. The post-menopausaluterus can sustain implantation, grow and carry pregnancy toterm and reduce adequately after labour. The incidence of maternalmorbidity during pregnancy is less encouraging. A higher incidenceof pregnancy-related diseases, e.g. gestational diabetes, hypertension,moderate and severe pre-eclampsia have been reported.     

Distress level in men undergoing intracytoplasmic sperm injection versus in-vitro fertilization

The purpose of this study was to compare the psychological reactions of men undergoing intracytoplasmic sperm injection (ICSI) (n=18) or in- vitro fertilization (IVF) (n=22). Men monitored their psychological reactions daily for one complete treatment cycle from the first day of down-regulation until the outcome of treatment was known (approximately 52 days). The results showed that ICSI patients reported marginally more distress on the days prior to retrieval than the IVF patients. Other than this difference the pattern of results indicated that the psychological reactions of men undergoing ICSI or IVF were similar and that there was no need to manage these patients differently during treatment. However, ICSI patients may benefit from some reassuring comments on the days prior to retrieval when they showed more anticipatory anxiety.      

Counselling: An evaluation of counselling for couples undergoing treatment for in-vitro fertilization

Fertility difficulties, along with their investigation and treatment,are widely believed to cause significant psychological problems.This study was designed to investigate the efficacy of a non-directivecounselling intervention with couples undertaking their firstcycle of in-vitro fertilization treatment. Couples were randomlyassigned to either a control group, given information aboutthe treatment programme, or to an experimental group, giventhe same information plus three sessions of counselling before,during and on conclusion of the first treatment cycle. Psychologicalassessments were made at three points in the treatment process.Ratings were also obtained from the couples on the stress engenderedby different parts of the treatment, the effects on their relationshipand satisfaction with counselling. The results showed the patientsto be generally well adjusted and anxiety levels dropped overthe course of treatment. Counselling compared to informationalone did not lead to any enhanced reduction in levels of anxietyor depression. The implications of the findings for serviceprovision are discussed.     

Subcutaneous low dose leuprolide acetate depot versus leuprolide acetate for women undergoing ovarian stimulation for in-vitro fertilization

A total of 100 women undergoing ovarian stimulation with gonadotrophin-releasinghormone agonist (GnRHa) and a human menopausal gonadotrophin(HMG) for in-vitro fertilization (IVF) participated in thisrandomized comparative study. Leuprolide acetate at a dose of0.5 mg/day s.c. (n = 52, group I), or low-dose leuprolide acetatedepot at a dose of 1.88 nig s.c. (n = 48, group II), was startedon days 21–23 of the cycle. Stimulation with 225 IU/dayHMG was started after pituitary desensitization had been achieved.The luteal phase was supported by human chorionic gonadotrophin(HCG) i.m. injection. There were nostatistical differences inbaseline oestradiol (24.5 ± 4.8 versus 21.9 ±4.5 pg/ml) and follicle stimulating hormone (FSH) concentrations(3.9 ± 1.9 versus 3.2 $ 1.8 mlU/ml), and concentrationson the day of HCG administration of oestradiol (1657 ±245 versus 1512$165 pg/ml), luteinizing hormone (LH; 6.2 ±4.8 versus 5.6 ± 4.3 mlU/ml) and FSH (10.6 ± 2.8versus 10.8 ± 3.6 mIU/ml). There were also no statisticaldifferences in the HMG dosage (26.8 ± 1.8 versus 28.5± 1.5), the number of oocytes retrieved (7.6 ±3.0 versus 8.1 ± 4.3), the number of oocytes fertilized(5.3 ± 2.1 versus 5.6 ± 3.0) and the number ofembryos transferred (3.5 ± 1.3 versus 3.4 ± 1.6).There was no evidence of a premature LH surge in either group,but two patients appeared to have a poor response in the leuprolideacetate group (group I). There were 11 pregnancies (21.2%) afterthe use of leuprolide acetate and 12 pregnancies (25.0%) inthose given leuprolide acetate depot; no statistical differenceexisted between these two groups. Thus, an s.c. low-dose leuprolideacetate depot injection may offer a useful alternative for pituitarysuppression in ovarian stimulation for IVF.     

The emerging role of multiple antiphospholipid antibodies positivity in patients with antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by clinical symptoms of vascular thrombosis and/or pregnancy morbidity in the presence of autoimmune antiphospholipid antibodies (aPL). Current laboratory APS criteria include the presence of at least one of the three relevant aPL: lupus anticoagulant, anticardiolipin antibodies and anti-β₂ glycoprotein I antibodies. Therefore, patients could have a single aPL pattern or combinations of aPL. Evidence arising from clinical experience indicates that patients having the highest aPL titer and simultaneous aPL detected by different tests have a worse prognosis and a higher probability of recurrence of the APS clinical features. In recent years, an emerging role of multiple aPL positivity in the identification of high-risk patients with aPL/APS is evident. This paper will review the current knowledge on the clinical relevance of having single or multiple aPL positivity.     

体外受精-胚胎移植妇女的焦虑、抑郁情绪

目的:了解体外受精-胚胎移植(IVF-ET)妇女的焦虑、抑郁情绪及相关因素。方法:2009年4月-2010年3月,在湖南省妇幼保健院生殖中心选取来自全国各地符合本研究筛选标准的妇女连续入组,共入组IVF-ET妇女538例,采取现场询问的方式,在胚胎移植术后2小时内进行问卷调查,内容包括社会人口学特征、生育情况、治疗情况、社会心理因素及情绪症状的评定。结果:焦虑评分(39.6±3.1)分,焦虑症状检出率38.5%;抑郁评分(35.8±4.5)分,抑郁症状检出率12.3%。居住在城市(OR=1.66)、不孕年限长(OR=1.34)、夫妻交流少(OR=2.25)、积极应对评分低(OR=4.30)、生理健康(OR=3.24)评分低、心理健康(OR=5.36)评分低的IVF-ET妇女焦虑倾向危险比高;既往治疗费用多(OR=3.02),取卵个数少(OR=2.24)及性生活(OR=1.13)、积极应对(OR=6.08)评分低,应激性生活事件评分高(OR=1.83)的IVF-ET妇女抑郁倾向危险比高。结论:体外受精-胚胎移植妇女存在不同程度的焦虑、抑郁情绪,社会心理变量是其主要相关因素。