Recurrent IVF failure: other factors

Alan S. Penzias, M.D.

Boston IVF, Beth Israel Deaconess Medical Center, Harvard Medical School, Waltham, Massachusetts

IVF failure is a problem for a couple in the singular but can be a tragedy in the plural. Recurrent IVF failure has multiple known causes butmanywhich arenot routinely considered as part of the posttreatment analysis. The reason is there are several causes associated with lifestyle and other causes related topre-existing conditions that have only a tenuous or no apparent connection to fertility. This article examines the impact of obesity, cigarette smoke,uterine anatomy, body mass index, thyroid dysfunction, immune factors, the hereditary and acquired thrombophilias, and embryo transfer techniqueon recurrent IVF failure. (Fertil Steril� 2012;97:1033–8. �2012 by American Society for Reproductive Medicine.)Key Words: Recurrent IVF failure, ART, obesity, fibroids, cigarette smoke

PROBABILITY,METEOROLOGY, AND IVFWhenever I quote statistics to an indi-vidual patient regarding her likelihoodof having a baby, I have at my disposaldirect knowledge of her medical his-tory, past successes or failures and in-formation about other patients I'vetreated and their outcomes. I talk abouther personal odds in the setting ofpopulation statistics. There are manyquotes about statistics, what they hideand what they reveal, and many timesgambling analogies are invoked asa comparator. Howmany times a tossedcoin will land heads or tails; the odds ofred or black at the Roulette table, etc.None of these analogies seems to im-press, amuse, or otherwise satisfy a pa-tient looking to me for answers whenshe has completed an IVF cycle thathas not resulted in a baby.

I've now turned to meteorology forsome answers. Much like IVF wherea positive or negative outcome hasa cause, so does the weather. Weatheris not random; there are forces, condi-tions and factors that determine whererain will fall and when, whether it willbe warm or cool, sunny or cloudy,windy or still. Meteorologists use so-phisticated models of past history andcurrent circumstances to predict the

Received January 16, 2012; revised and accepted MaA.S.P. has nothing to disclose.Reprint requests: Alan S. Penzias, M.D., Boston IVF, B

Avenue, Waltham, MA 02451 (E-mail: alan.pen

Fertility and Sterility® Vol. 97, No. 5, May 2012 0015Copyright ©2012 American Society for Reproductivedoi:10.1016/j.fertnstert.2012.03.017

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future. Often, they provide the publicwith the odds of an event occurring,much like I do when meeting with a pa-tient at the time of embryo transfer.

If the meteorologist tells me thatthere is a 65% chance of rain, Ishouldn't be surprised when the cloudsroll in and the raindrops fall. However, Iknow that I will be pleased if the 35%chance of sunshine rules the day. That'sa single day and just about everyonecan accept whichever outcome occurs.If my weeklong holiday is punctuatedby 7 consecutive days of rain despitethe 35% chance of sun forecast daily,I begin to doubt their forecasting abil-ity. The lack of sun in any of 7 daysseems improbable despite the forecastodds of only 1 chance in 3 each day.

My ability to accept the weatheroutcome on a single day but my rejec-tion of a string of 7 such days is proba-bly attributable to human nature. Whywas the weather forecaster unable totell me that there would be 7 consecu-tive days of rain? Clearly, the modelwas lacking data on an important fac-tor or factors that shifted the trueodds beyond the 65:35 split churnedout by the existing formula.

When it comes to predicting IVFoutcomes, we know that oocytebiology, embryonic development andendometrial receptivity contribute

rch 14, 2012; published online March 28, 2012.

eth Israel Deaconess Medical Center, 130 Secondzias@bostonivf.com).

-0282/$36.00Medicine, Published by Elsevier Inc.

significantly to predictive models ofoutcome. The list of other factors con-tained herein is incomplete but grow-ing. When this elusive list is finallycomplete, perhaps then we will be ableto forecast the outcome with 100%certainty.

OBESITYThe World Health Organization (WHO)defines overweight as a body mass in-dex (BMI) equal to or more than 25,and obesity as a BMI equal to or morethan 30. According to the WHO, onebillion adults are overweight andmore than 300 million are obese. Onceassociated with high-income countries,obesity is now also prevalent in low-and middle-income countries (1). Ap-proximately one third of U.S. adultsare obese and in 2010, 12 states hadan obesity prevalence of 30% or more(2). The lay press has devoted many pa-ges to the negative health conse-quences of obesity but with regard tofertility, most press coverage regardingfemale obesity focuses on disorders ofovulation and polycystic ovary syn-drome. One of the earliest studies onthe subject of BMI and IVF outcomefound no difference when 76 patientswith a BMI >27.9 were compared to152 normal controls; or 35 under-weight patients (BMI <19) were com-pared to 70 normal controls (3). In2003 a study by Doody et al. (4), the in-vestigators stratified 822 women overfour WHO BMI categories with meanage range of 33.1 to 33.7 years anddemonstrated lower pregnancy and

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FIGURE 1

Implantation, pregnancy, and live birth rates in IVF-ICSI cyclesaccording to the women's BMI. Each point represents percentagesand 95% CI.Penzias. Recurrent IVF failure. Fertil Steril 2012.

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implantation rates in women with BMI >35. Ryley et al. (5)confirmed these findings the following year in a study of6,827 cycles in women whose ages averaged 35.2–36.6 years(Table 1).

Bellver et al. (6) evaluated 6500 cycles in which only 6.4%(419) were conducted in women with a BMI>30 (mean 33.6).An additional comorbidity in the study population was ciga-rette smoking among roughly one-third of the group. The au-thors demonstrated a similar number of oocytes retrieved, andno differences in the fertilization rate, day of embryo transfer(ET), or mean number of embryos transfered or cryopreserved.In addition, there was similar embryo quality in all the BMIgroups. However, the implantation rate, pregnancy rate andlive birth rate were clearly and adversely affected by elevatedBMI (Fig. 1).

In 2007, the first U.S. national data set study was con-ducted by the Society for Assisted Reproductive Technology(SART) (7). In that year, height and weight fields were addedto the Clinic Online Reporting System, permitting calculationof BMI. The 345 member clinics comprised more than 90% ofall centers performing ART in the U.S. The authors limitedanalysis to cycles where one or more embryos were trans-fered, and both height and weight were recorded. A total of45,163 cycles were analyzed. The investigators found thathigher BMI was associated with lower clinical pregnancyrates, especially in women under age 35 using their own oo-cytes. The adverse effects of high BMI were mitigated by theuse of donor oocytes.

While all of the aforementioned studies focused exclu-sively on female obesity, the largest study to date by Kupkaet al. (8) included men. The investigators analyzed 12 yearsof data (1997–2008) from the national German IVF Registry.A total of 706,360 cycles from as many as 120 centers wereincluded, from which 650,452 cycles where information con-cerning weight was given were analyzed. Obesity, defined asBMI >30, was assigned to four groups: none, female, male orboth. Compared to non-obese couples (28.15%), the highestclinical pregnancy rate in fresh IVF cycles was found in cou-ples with an obese male partner (30.38%, P¼ .0028). In thegroup of obese women, the pregnancy rate decreased to27.2%. There was no statistically significant difference in out-

TABLE 1

IVF outcome stratified by BMI.

Characteristic All cycles BMI <20 BMI 20–24

n (total) 6827 466 3605Age (y), mean 36.5 36.3 36.6BMI, mean 24.9 18.9 22.1Cycles/patient 2.7 2.6 2.6Peak estradiol 1290 1424 1333No. of mature follicles 6.1 6.0 6.1No. of oocytes retrieved 9.4 9.5 9.4No. of mature oocytes 7.7 7.7 7.8No. of embryos transfered 2.6 2.5 2.6Implantation rate (%) 18 20 19Clinical pregnancy rate (%) 28.3 32.9 31.4a BMI >35 group vs. all other groups.b BMI >35 group vs. all groups with BMI 25 and higher.

Penzias. Recurrent IVF failure. Fertil Steril 2012.

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comes between groups when thawed cryopreserved embryoswere transfered. The authors offer an explanation for the cu-rious success of obese men and normal weight females andcite a study by the Robert Koch Institute (9), which associatesthe combination with couples of higher social status. The au-thors postulate ‘‘the increased pregnancy rate in this groupmight as well be related to other lifestyle factors associatedwith higher social status.’’

Overall, while some smaller studies have not found an as-sociation between elevated BMI and pregnancy outcome, thepreponderance of data including two national data setsclearly demonstrates the negative impact of elevated BMIon achievement of pregnancy through ART. An important fi-nal distinction to be made about obesity is that while it isknown to be associated with lower per cycle pregnancy anddelivery rates, it is not, by itself, a cause of recurrent implan-tation failure.

.9 BMI 25–29.9 BMI 30–34.9 BMI >35 P value

1632 724 40036.6 36.2 35.2 < .0001a

26.8 31.8 37.4 N/A2.7 2.7 2.6 .14

1222 1233 1135 < .0001b

6.0 6.2 6.2 .349.4 9.4 8.7 .187.7 7.8 7.2 .352.6 2.6 2.5 .56

20 18 13 < .0001a

27.6 27.9 21.8 < .0001a

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FIGURE 2

Pregnancy rate and implantation rate following IVF for controlswithout fibroids and subjects with fibroids stratified by their uterineposition. SS ¼ subserosal; IM ¼ intramural; SM ¼ submucosal.*P<.05 for IM vs. controls or SS; **P<.005 for IM vs. controls.Penzias. Recurrent IVF failure. Fertil Steril 2012.

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CIGARETTE SMOKEThe incidence of cigarette smoking in the U.S. populationdropped by half between 1965 and 2006; 42% to 20.8% ofadults (10). Unfortunately this decrease is not uniform world-wide. Though male smokers outnumber female 5:1, the 20.8%in the U.S. population still represents a very large number ofindividuals, many of who are trying to become pregnant.

In their meta-analysis, Waylen et al. (11) evaluated 17studies and showed in aggregate significantly lower odds oflive birth per cycle (OR 0.54, 95% CI 0.30–0.99), and signifi-cantly higher odds of spontaneous miscarriage (OR 2.65,95% CI 1.33–5.30) in women who smoked. This is very power-ful data that demonstrate an entirely preventable cause of IVFfailure. Women who smoke cigarettes should be stronglycounseled that smoking cuts their odds of live birth nearlyin half and increases their odds of miscarriage by 265%.

The effects of cigarette smoking are felt not just by thesmokers themselves, but to women trying to become pregnantwho suffer from secondhand tobacco smoke (STS) exposure.Benedict et al. (12) measured cotinine, a nicotine metabolite,in follicular fluid collected during 3270 IVF treatment cyclesfrom 1909 non-smoking women between 1994 and 2003 toexamine the relationship between secondhand tobacco smokeexposure and implantation failure. They reported a 52% in-crease in the risk of implantation failure among women ex-posed to STS compared with those unexposed. They alsofound a 25% decrease in the odds for a live birth amongSTS-exposed women.

The summary point is that women trying to get pregnantshould stop smoking, but non-smoking women, too, shouldremove themselves from chronic exposure to secondhandsmoke.

UTERINE FIBROIDSLeiomyomata have long been a source of gynecological prob-lems for women. A number of studies have been performedlooking at the impact of uterine fibroids on ART outcomes.Farhi et al. (13) studied 46 patients with uterine fibroidswho underwent 172 IVF cycles (range 1–9 attempts) between1986 and 1992. Themean� SD age of the patients was 34.0�4.5 years (range 23–40) with a mean duration of infertility of6.1� 4.5 years (range 1–17). They concluded that fibroids im-paired implantation and successful pregnancy only when theuterine cavity was distorted. A subsequent study by Eldar-Geva et al. (14) (Fig. 2) compared the location of uterine fi-broids—subserosal, intramural and submucosal—to controlpatients without fibroids undergoing IVF. In their series of88 patients undergoing 106 IVF cycles, they found that preg-nancy and implantation rates were significantly lower in the46 patients with intramural fibroids and no cavity distortionand the 9 patients with submucosal fibroids.

In an effort to determine whether intramural fibroids areassociated with lower pregnancy and live birth rates than isobserved in women without fibroids, Sunkara et al. (15)(Fig. 3) performed a meta-analysis. The authors' searchyielded 19 studies that met inclusion criteria, 11 of whichused live birth as an endpoint. There were 1626 cycles withnon-cavity distorting intramural fibroids compared with

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2355 control cycles. The comparison showed a statisticallysignificant 21% relative reduction in live birth rate in womenwith non-cavity-distorting intramural fibroids comparedwith women without fibroids (RR ¼ 0.79, 95% CI: 0.70–0.88; P¼ .0001).

Somigliana et al. (16) performed a prospective study of119 cases of women with intramural (n¼ 80) or subserosal fi-broids (n ¼ 39) under 50 mm and 119 controls and found nodifferences in embryo implantation or delivery. The smallsample size and the two locations of fibroids under consider-ation may explain the variance from the findings of Sunkaraet al. (15).

What is most striking is the paucity of literature followingsurgery to demonstrate improved IVF outcomes followingmyomectomy. The practitioner whose patient has uterine fi-broids that distort or enter the endometrial cavity may rea-sonably conclude that surgical restoration of the uterineanatomy is rational given the data of negative outcomes.The mixed data on intramural fibroids allow room for clinicaljudgment prior to a first attempt at IVF. In cases of recurrentimplantation failure with no other attributable factors, surgi-cal removal becomes a very reasonable choice. The questionthat remains unresolved is how large an intramural fibroidhas to be in order to exert its negative influence.

UTERINE ANOMALIESThe uterine septum has been implicated as a cause of recurrentpregnancy loss and its resection touted to improve outcomesin those affected by them. Whether infertility is caused by thepresence of a uterine septum is the subject of much specula-tion. Most published works on the topic are small, uncon-trolled trials; case studies of experiences. Mollo et al.recently published a controlled trial on the subject (17). Theauthors compared 44 subjects (group A) with a uterine septumand no other attributable cause of infertility to 132 women(group B) with unexplained infertility. The pre-operativesize of the septum was not described in the study. Following

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FIGURE 3

Forest plot of studies of non-cavity-distorting intramural fibroids versus no fibroids in women undergoing IVF treatment for outcome of live birthrates.Penzias. Recurrent IVF failure. Fertil Steril 2012.

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resection, a post-operative hysteroscopy to confirm a normaluterine cavity and a 12-month follow-up period, the live birthrate was significantly higher in group A than in group B(34.1% and 18.9%, respectively; P< .05). The small studysize a) does not permit assessment of potential complicationsfrom surgery and b) limits one's ability to extrapolate to thegeneral population.

The question of whether a septum plays a causative role inrecurrent failure to become pregnant following ART is ad-dressed in the literature without a conclusive answer (18,19). The reader is left to use clinical judgment in individualpatients with recurrent IVF failure without apparentexplanation.

THYROID DYSFUNCTIONThe thyroid gland is most commonly associated with meta-bolic rate, but it's clear that thyroid hormone is necessaryfor the normal function of numerous other body organs andtissues. The definition of hypothyroidism remains controver-sial. At the present time, most laboratories report the normalreference range of thyroid stimulating hormone (TSH) level as0.4–4.5 mIU/L. The National Academy of Clinical Biochemis-try, part of the Academy of the American Association forClinical Chemistry (AACC) reported in 2002 that, ‘‘In the fu-ture, it is likely that the upper limit of the serum TSH euthy-roid reference range will be reduced to 2.5 mIU/L becausemore than 95% of rigorously screened normal euthyroid vol-unteers have serum TSH values between 0.4 and 2.5 mIU/L’’(20). Thus far, the American Academy of Clinical Endocrinol-ogists has not yet adopted this position due to insufficientdata of health improvement of cardiac, lipid and neuropsychi-atric function.

Baker et al. (21) evaluated the impact of TSH above or be-low 2.5 mIU/L on pregnancy outcome in IVF. They report thatin ‘‘women who become pregnant through IVF, gestationalage at delivery and birth weight were lower in cycles with

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a TSH >2.5 mIU/L compared with cycles with TSH <2.5mIU/L. TSH levels >2.5 mIU/L had a possible weak positiveassociation with spontaneous abortion rate that did not reachstatistical significance.’’

Reh et al. (22) found no difference in clinical pregnancy,delivery or miscarriage rates in 1055 women when those withTSH<2.5mIU/Lwere compared to those with TSH>2.5mIU/L.Toulis et al. (23) evaluated the association between risk forspontaneous miscarriage in subfertile, euthyroid women withthyroid autoimmunity (TAI) (defined as the presence ofautoantibodies against thyroid peroxidase (TPOab) and/or thy-roglobulin (TGab) ) undergoing IVF. They found that the risk ofmiscarriage was nearly double that of women without TAI (RR:1.99, 95% confidence interval: 1.42–2.79, P< .001). The mech-anism for this association is unclear. Revelli et al. (24) compared129 euthyroid anti-thyroid antibody-positive (ATAþ) womenundergoing IVF to 200 matched, ATA-negative controls. Dur-ing IVF cycle, 38 ATAþ patients did not take any adjuvanttreatment, 55 received levothyroxin (LT), and 38 received LTþacetylsalicylic acid (ASA)þ prednisolone (P). Patients receiv-ing LTþASAþP had significantly higher pregnancy and im-plantation rates than untreated ATAþ patients (PR/ET 25.6%and IR 17.7% vs. PR/ET 7.5% and IR 4.7%, respectively), andoverall IVF results comparable to patients without ATA (PR/ET 32.8% and IR 19%). The authors concluded that euthyroidATAþ patients undergoing IVF could have better outcome ifgiven LTþASAþP as adjuvant treatment. They cautioned,however, that this must be verified in further randomized, pro-spective studies.

EMBRYO TRANSFER TECHNIQUEThe Cochrane Database study of ultrasound vs. clinical touchfor catheter guidance during embryo transfer (25) (Fig. 4) cit-ing 17 studies that compared 3244 ultrasound guided transferswith 3171 clinical touch showed an odds ratio of 1.31 (95% CI1.18–1.46) in favor of ultrasound guidance. While this factor

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FIGURE 4

Forest plot of studies of clinical touch embyro transfer (CTET) versus ultrasound-guided embryo transfer (UGET) for outcome of clinical pregnancyrate.Penzias. Recurrent IVF failure. Fertil Steril 2012.

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isn't in and of itself an independent contributor to the problemof recurrent IVF failure, it is a factor that impacts outcomes,and as such should be considered at least when evaluatingthe patient who has not succeeded in multiple IVF cycles.

The techniques associated with ultrasound-guided em-bryo transfer vary from clinic to clinic. We have found it use-ful to advise patients to consume enough liquid prior to theprocedure to create an acoustic window directly above theuterus. Bladder filling is especially helpful in obese patientsin whom imaging can be a challenge. We favor placementof a trial catheter with an echogenic inner catheter tip to es-tablish continuity with the internal cervical os. We leave theouter sheath in place while the active transfer catheter isloaded. A second set of hands provided by an assistant inthe operating room is useful to help position the abdominalultrasound probe prior to catheter placement. The physicianperforming the transfer thereafter can make minor adjust-ments to the probe position.

When a difficult transfer is in progress, direct visualiza-tion is a significant aid. There are times when it's possibleto see a trial catheter stuck in a particular position and know-ing the direction and angle of the cervical canal is a plus. Fur-ther, watching a catheter go in with ease but double back onitself averts the problem of depositing precious embryos in thecervical canal rather than the endometrium.

A side benefit to the use of ultrasound-guided embryotransfer is patient comfort. Not so much due to an easier tech-nique, though this can be true, and certainly not due to the fullbladder, but rather the patient is able to visualize the processthus removing one of the moremysterious elements of the IVFexperience.

IMMUNE FACTORS AND THROMBOPHILIASFew topics in reproductive medicine elicit as many opinionsor as much controversy as the impact of immune factors

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and hereditary and acquired thrombophilias on IVF outcome.The known or purported causality of phospholipid antibodiesand coagulation factors on recurrent pregnancy loss long agospilled over into the arena of conception with IVF or moreprecisely, the lack of it. Some have argued that without im-plantation to signal the arrival of an embryo, it would be im-probable for serum or tissue-based response elements toprevent implantation. Others have argued that the effect isunrelated to the embryo, but rather the negative impact isat the level of the endometrium. The Practice Committee ofthe American Society for Reproductive Medicine releaseda Committee Opinion in 1999 which it reviewed again in2008, ‘‘Anti-phospholipid antibodies (APA) do not affectIVF success’’ (26). The review culled 16 peer reviewed papers,of which 7 included appropriate endpoints and controls. Therewas no statistically significant impact of the presence ofphospholipid antibodies on IVF outcomes when the studieswere examined individually nor when the data were aggre-gated in the 2,053 patients studied. The authors concludedthat ‘‘assessment of APA is not indicated among couples un-dergoing IVF. Therapy is not justified on the basis of existingdata.’’

A review was recently published on the topic of thrombo-philias and IVF outcome (27). The authors' initial searchyielded 694 studies. Case reports, editorials, reviews, meta-analyses, studies with inadequate outcomes, absence ofthrombophilia/anti-phospholipid antibodies, and more thanone of the above were excluded and 33 (6,092 patients) wereultimately analyzed. They report that twenty-nine studies(5,270 patients) assessed anti-phospholipid antibodies inwomen treated with ART. The prevalence of antibodies in in-fertile patients varied from 0%–45%. When examining case-control studies, the authors write ‘‘overall, the presence ofone or more anti-phospholipid antibodies was associatedwith a 3-fold higher risk of ART failure.’’ There was a signifi-cant degree of heterogeneity across these case-control studies

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with some using parous controls and others usingwomenwhohad achieved a live birth following ART. In addition to case-control studies, the authors also evaluated cohort studies. Incontrast to the findings of the case-control studies, analysisof cohort studies showed that anti-phospholipid antibodieswere not associated with a lower rate of viable pregnancy,live birth, or a higher incidence of negative pregnancy tests.

Ten of the studies in the review evaluated the relationshipbetween inherited thrombophilia and ART. Seven studieswere case-control, 2 were cohorts, and in 1 case-control studypatients undergoing IVF (cases) were followed to assess thepregnancy outcomes. Pooled data from patients in 8 case-control studies showed an overall 3-fold increased risk ofART failure in association with factor V Leiden. In the 3 co-hort studies, there was no difference in outcome betweenthose with and those without the factor V Leiden mutation.

True to form, the conflicting findings in the literature giveadvocates and detractors of a role for phospholipid antibodiesand thrombophilias ammunition to bolster their arguments.The advocates can cite the case-control studies, while the de-tractors can cite the cohort studies. From a methodologystandpoint, both study types are Level II-2 (28) with theirown particular strengths and limitations. Treatment trialssimilarly suffer from methodological flaws and a lack of con-clusive answers. Level I evidence is clearly needed.

CONCLUSIONSIt is clear that there are other factors beyond the egg, embryoand endometrium that contribute to the success or failure ofan IVF cycle. These factors, if present in serial IVF cycles,may serve to diminish the actual odds of conception belowthe population-based odds estimated by patient age and ovar-ian reserve testing alone. Our mission is twofold: 1) reduce thenegative impact of factors over which we have controlthrough treatment or behavior modification; and 2) continueour efforts to identify as yet unknown factors that prevent ourpatients from achieving a successful outcome.

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22. Reh A, Grifo J, Danoff A. What is a normal thyroid-stimulating hormone(TSH) level? Effects of stricter TSH thresholds on pregnancy outcomes afterin vitro fertilization. Fertil Steril 2010;94:2920–2.

23. Toulis KA, Goulis DG, Venetis CA, Kolibianakis EM, Negro R, Tarlatzis BC,Papadimas I. Risk of spontaneous miscarriage in euthyroid women with thy-roid autoimmunity undergoing IVF: a meta-analysis. Eur J Endocrinol 2010;162:643–52.

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26. Practice Committee of theASRM. Anti-phospholipid antibodies do not affectIVF success. Practice Committee of the ASRM. Fertil Steril 2008;90:S172–3.

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