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Recurrent IVF failure: other factorsAlan S. Penzias, M.D.Boston IVF, Beth Israel Deaconess Medical Center, Harvard Medical...
VIEWS AND REVIEWSimplantation rates in women with BMI >35. Ryley et al. (5)                                               ...
Fertility and Sterility®CIGARETTE SMOKE                                                  FIGURE 2The incidence of cigarett...
VIEWS AND REVIEWSFIGURE 3 Forest plot of studies of non-cavity-distorting intramural fibroids versus no fibroids in women un...
Fertility and Sterility®FIGURE 4 Forest plot of studies of clinical touch embyro transfer (CTET) versus ultrasound-guided ...
VIEWS AND REVIEWSwith some using parous controls and others using women who                              9.   Robert Koch-...
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Other factors IVF failure


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Other factors IVF failure

  1. 1. Recurrent IVF failure: other factorsAlan S. Penzias, M.D.Boston IVF, Beth Israel Deaconess Medical Center, Harvard Medical School, Waltham, MassachusettsIVF 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 but many which 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 SterilÒ 2012;97:1033–8. Ó2012 by American Society for Reproductive Medicine.)Key Words: Recurrent IVF failure, ART, obesity, fibroids, cigarette smokePROBABILITY, future. Often, they provide the public significantly to predictive models ofMETEOROLOGY, AND IVF with the odds of an event occurring, outcome. The list of other factors con- much like I do when meeting with a pa- tained herein is incomplete but grow-Whenever I quote statistics to an indi- tient at the time of embryo transfer. ing. When this elusive list is finallyvidual patient regarding her likelihood If the meteorologist tells me that complete, perhaps then we will be ableof having a baby, I have at my disposal there is a 65% chance of rain, I to forecast the outcome with 100%direct knowledge of her medical his- shouldnt be surprised when the clouds certainty.tory, past successes or failures and in- roll in and the raindrops fall. However, Iformation about other patients Ive know that I will be pleased if the 35%treated and their outcomes. I talk about chance of sunshine rules the day. Thats OBESITYher personal odds in the setting of a single day and just about everyone The World Health Organization (WHO)population statistics. There are many can accept whichever outcome occurs. defines overweight as a body mass in-quotes about statistics, what they hide If my weeklong holiday is punctuated dex (BMI) equal to or more than 25,and what they reveal, and many times by 7 consecutive days of rain despite and obesity as a BMI equal to or moregambling analogies are invoked as the 35% chance of sun forecast daily, than 30. According to the WHO, onea comparator. How many times a tossed I begin to doubt their forecasting abil- billion adults are overweight andcoin will land heads or tails; the odds of ity. The lack of sun in any of 7 days more than 300 million are obese. Oncered or black at the Roulette table, etc. seems improbable despite the forecast associated with high-income countries,None of these analogies seems to im- odds of only 1 chance in 3 each day. obesity is now also prevalent in low-press, amuse, or otherwise satisfy a pa- My ability to accept the weather and middle-income countries (1). Ap-tient looking to me for answers when outcome on a single day but my rejec- proximately one third of U.S. adultsshe has completed an IVF cycle that tion of a string of 7 such days is proba- are obese and in 2010, 12 states hadhas not resulted in a baby. bly attributable to human nature. Why an obesity prevalence of 30% or more Ive now turned to meteorology for was the weather forecaster unable to (2). The lay press has devoted many pa-some answers. Much like IVF where tell me that there would be 7 consecu- ges to the negative health conse-a positive or negative outcome has tive days of rain? Clearly, the model quences of obesity but with regard toa cause, so does the weather. Weather was lacking data on an important fac- fertility, most press coverage regardingis not random; there are forces, condi- tor or factors that shifted the true female obesity focuses on disorders oftions and factors that determine where odds beyond the 65:35 split churned ovulation and polycystic ovary syn-rain will fall and when, whether it will out by the existing formula. drome. One of the earliest studies onbe warm or cool, sunny or cloudy, When it comes to predicting IVF the subject of BMI and IVF outcomewindy or still. Meteorologists use so- outcomes, we know that oocyte found no difference when 76 patientsphisticated models of past history and biology, embryonic development and with a BMI >27.9 were compared tocurrent circumstances to predict the endometrial receptivity contribute 152 normal controls; or 35 under- weight patients (BMI <19) were com-Received January 16, 2012; revised and accepted March 14, 2012; published online March 28, 2012. pared to 70 normal controls (3). InA.S.P. has nothing to disclose. 2003 a study by Doody et al. (4), the in-Reprint requests: Alan S. Penzias, M.D., Boston IVF, Beth Israel Deaconess Medical Center, 130 Second Avenue, Waltham, MA 02451 (E-mail: vestigators stratified 822 women over four WHO BMI categories with meanFertility and Sterility® Vol. 97, No. 5, May 2012 0015-0282/$36.00Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. age range of 33.1 to 33.7 years anddoi:10.1016/j.fertnstert.2012.03.017 demonstrated lower pregnancy andVOL. 97 NO. 5 / MAY 2012 1033
  2. 2. VIEWS AND REVIEWSimplantation rates in women with BMI >35. Ryley et al. (5) FIGURE 1confirmed 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 calculation Implantation, pregnancy, and live birth rates in IVF-ICSI cycles according to the womens BMI. Each point represents percentagesof BMI. The 345 member clinics comprised more than 90% of and 95% CI.all centers performing ART in the U.S. The authors limited Penzias. Recurrent IVF failure. Fertil Steril 2012.analysis 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 pregnancy comes between groups when thawed cryopreserved embryosrates, especially in women under age 35 using their own oo- were transfered. The authors offer an explanation for the cu-cytes. The adverse effects of high BMI were mitigated by the rious success of obese men and normal weight females anduse of donor oocytes. cite a study by the Robert Koch Institute (9), which associates While all of the aforementioned studies focused exclu- the combination with couples of higher social status. The au-sively on female obesity, the largest study to date by Kupka thors postulate ‘‘the increased pregnancy rate in this groupet al. (8) included men. The investigators analyzed 12 years might as well be related to other lifestyle factors associatedof data (1997–2008) from the national German IVF Registry. with higher social status.’’A total of 706,360 cycles from as many as 120 centers were Overall, while some smaller studies have not found an as-included, from which 650,452 cycles where information con- sociation between elevated BMI and pregnancy outcome, thecerning weight was given were analyzed. Obesity, defined as preponderance of data including two national data setsBMI >30, was assigned to four groups: none, female, male or clearly demonstrates the negative impact of elevated BMIboth. Compared to non-obese couples (28.15%), the highest on achievement of pregnancy through ART. An important fi-clinical pregnancy rate in fresh IVF cycles was found in cou- nal distinction to be made about obesity is that while it isples with an obese male partner (30.38%, P¼ .0028). In the known to be associated with lower per cycle pregnancy andgroup of obese women, the pregnancy rate decreased to delivery rates, it is not, by itself, a cause of recurrent implan-27.2%. There was no statistically significant difference in out- tation failure. TABLE 1 IVF outcome stratified by BMI. Characteristic All cycles BMI <20 BMI 20–24.9 BMI 25–29.9 BMI 30–34.9 BMI >35 P value n (total) 6827 466 3605 1632 724 400 Age (y), mean 36.5 36.3 36.6 36.6 36.2 35.2 < .0001a BMI, mean 24.9 18.9 22.1 26.8 31.8 37.4 N/A Cycles/patient 2.7 2.6 2.6 2.7 2.7 2.6 .14 Peak estradiol 1290 1424 1333 1222 1233 1135 < .0001b No. of mature follicles 6.1 6.0 6.1 6.0 6.2 6.2 .34 No. of oocytes retrieved 9.4 9.5 9.4 9.4 9.4 8.7 .18 No. of mature oocytes 7.7 7.7 7.8 7.7 7.8 7.2 .35 No. of embryos transfered 2.6 2.5 2.6 2.6 2.6 2.5 .56 Implantation rate (%) 18 20 19 20 18 13 < .0001a Clinical pregnancy rate (%) 28.3 32.9 31.4 27.6 27.9 21.8 < .0001a a 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 2012.1034 VOL. 97 NO. 5 / MAY 2012
  3. 3. Fertility and Sterility®CIGARETTE SMOKE FIGURE 2The 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%. Pregnancy rate and implantation rate following IVF for controls The effects of cigarette smoking are felt not just by the without fibroids and subjects with fibroids stratified by their uterine position. SS ¼ subserosal; IM ¼ intramural; SM ¼ submucosal.smokers themselves, but to women trying to become pregnant *P<.05 for IM vs. controls or SS; **P<.005 for IM vs. controls.who suffer from secondhand tobacco smoke (STS) exposure. Penzias. Recurrent IVF failure. Fertil Steril 2012.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 to 2355 control cycles. The comparison showed a statisticallyexamine the relationship between secondhand tobacco smoke significant 21% relative reduction in live birth rate in womenexposure and implantation failure. They reported a 52% in- with non-cavity-distorting intramural fibroids comparedcrease in the risk of implantation failure among women ex- with women without fibroids (RR ¼ 0.79, 95% CI: 0.70–posed to STS compared with those unexposed. They also 0.88; P¼ .0001).found a 25% decrease in the odds for a live birth among Somigliana et al. (16) performed a prospective study ofSTS-exposed women. 119 cases of women with intramural (n ¼ 80) or subserosal fi- The summary point is that women trying to get pregnant broids (n ¼ 39) under 50 mm and 119 controls and found noshould stop smoking, but non-smoking women, too, should differences in embryo implantation or delivery. The smallremove themselves from chronic exposure to secondhand sample size and the two locations of fibroids under consider-smoke. ation may explain the variance from the findings of Sunkara et al. (15).UTERINE FIBROIDS What is most striking is the paucity of literature following surgery to demonstrate improved IVF outcomes followingLeiomyomata have long been a source of gynecological prob- myomectomy. The practitioner whose patient has uterine fi-lems for women. A number of studies have been performed broids that distort or enter the endometrial cavity may rea-looking at the impact of uterine fibroids on ART outcomes. sonably conclude that surgical restoration of the uterineFarhi et al. (13) studied 46 patients with uterine fibroids anatomy is rational given the data of negative outcomes.who underwent 172 IVF cycles (range 1–9 attempts) between The mixed data on intramural fibroids allow room for clinical1986 and 1992. The mean Æ SD age of the patients was 34.0 Æ judgment prior to a first attempt at IVF. In cases of recurrent4.5 years (range 23–40) with a mean duration of infertility of implantation failure with no other attributable factors, surgi-6.1 Æ 4.5 years (range 1–17). They concluded that fibroids im- cal removal becomes a very reasonable choice. The questionpaired implantation and successful pregnancy only when the that remains unresolved is how large an intramural fibroiduterine cavity was distorted. A subsequent study by Eldar- has to be in order to exert its negative influence.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 of UTERINE ANOMALIES88 patients undergoing 106 IVF cycles, they found that preg- The uterine septum has been implicated as a cause of recurrentnancy and implantation rates were significantly lower in the pregnancy loss and its resection touted to improve outcomes46 patients with intramural fibroids and no cavity distortion in those affected by them. Whether infertility is caused by theand the 9 patients with submucosal fibroids. presence of a uterine septum is the subject of much specula- In an effort to determine whether intramural fibroids are tion. Most published works on the topic are small, uncon-associated with lower pregnancy and live birth rates than is trolled trials; case studies of experiences. Mollo et al.observed in women without fibroids, Sunkara et al. (15) recently published a controlled trial on the subject (17). The(Fig. 3) performed a meta-analysis. The authors search authors compared 44 subjects (group A) with a uterine septumyielded 19 studies that met inclusion criteria, 11 of which and no other attributable cause of infertility to 132 womenused live birth as an endpoint. There were 1626 cycles with (group B) with unexplained infertility. The pre-operativenon-cavity distorting intramural fibroids compared with size of the septum was not described in the study. FollowingVOL. 97 NO. 5 / MAY 2012 1035
  4. 4. VIEWS AND REVIEWSFIGURE 3 Forest plot of studies of non-cavity-distorting intramural fibroids versus no fibroids in women undergoing IVF treatment for outcome of live birth rates. Penzias. Recurrent IVF failure. Fertil Steril 2012.resection, a post-operative hysteroscopy to confirm a normal a TSH >2.5 mIU/L compared with cycles with TSH <2.5uterine cavity and a 12-month follow-up period, the live birth mIU/L. TSH levels >2.5 mIU/L had a possible weak positiverate was significantly higher in group A than in group B association with spontaneous abortion rate that did not reach(34.1% and 18.9%, respectively; P< .05). The small study statistical significance.’’size a) does not permit assessment of potential complications Reh et al. (22) found no difference in clinical pregnancy,from surgery and b) limits ones ability to extrapolate to the delivery or miscarriage rates in 1055 women when those withgeneral population. TSH <2.5 mIU/L were compared to those with TSH >2.5 mIU/L. The question of whether a septum plays a causative role in Toulis et al. (23) evaluated the association between risk forrecurrent failure to become pregnant following ART is ad- spontaneous miscarriage in subfertile, euthyroid women withdressed in the literature without a conclusive answer (18, thyroid autoimmunity (TAI) (defined as the presence of19). The reader is left to use clinical judgment in individual autoantibodies against thyroid peroxidase (TPOab) and/or thy-patients with recurrent IVF failure without apparent roglobulin (TGab) ) undergoing IVF. They found that the risk ofexplanation. miscarriage 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) comparedTHYROID DYSFUNCTION 129 euthyroid anti-thyroid antibody-positive (ATAþ) womenThe thyroid gland is most commonly associated with meta- undergoing IVF to 200 matched, ATA-negative controls. Dur-bolic rate, but its clear that thyroid hormone is necessary ing IVF cycle, 38 ATAþ patients did not take any adjuvantfor the normal function of numerous other body organs and treatment, 55 received levothyroxin (LT), and 38 received LTtissues. The definition of hypothyroidism remains controver- þacetylsalicylic acid (ASA) þ prednisolone (P). Patients receiv-sial. At the present time, most laboratories report the normal ing LTþASAþP had significantly higher pregnancy and im-reference range of thyroid stimulating hormone (TSH) level as plantation rates than untreated ATAþ patients (PR/ET 25.6%0.4–4.5 mIU/L. The National Academy of Clinical Biochemis- and IR 17.7% vs. PR/ET 7.5% and IR 4.7%, respectively), andtry, part of the Academy of the American Association for overall IVF results comparable to patients without ATA (PR/Clinical Chemistry (AACC) reported in 2002 that, ‘‘In the fu- ET 32.8% and IR 19%). The authors concluded that euthyroidture, it is likely that the upper limit of the serum TSH euthy- ATAþ patients undergoing IVF could have better outcome ifroid reference range will be reduced to 2.5 mIU/L because given LTþASAþP as adjuvant treatment. They cautioned,more than 95% of rigorously screened normal euthyroid vol- however, that this must be verified in further randomized, pro-unteers have serum TSH values between 0.4 and 2.5 mIU/L’’ spective studies.(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- EMBRYO TRANSFER TECHNIQUEatric function. The Cochrane Database study of ultrasound vs. clinical touch Baker et al. (21) evaluated the impact of TSH above or be- for catheter guidance during embryo transfer (25) (Fig. 4) cit-low 2.5 mIU/L on pregnancy outcome in IVF. They report that ing 17 studies that compared 3244 ultrasound guided transfersin ‘‘women who become pregnant through IVF, gestational with 3171 clinical touch showed an odds ratio of 1.31 (95% CIage at delivery and birth weight were lower in cycles with 1.18–1.46) in favor of ultrasound guidance. While this factor1036 VOL. 97 NO. 5 / MAY 2012
  5. 5. Fertility and Sterility®FIGURE 4 Forest plot of studies of clinical touch embyro transfer (CTET) versus ultrasound-guided embryo transfer (UGET) for outcome of clinical pregnancy rate. Penzias. Recurrent IVF failure. Fertil Steril 2012.isnt in and of itself an independent contributor to the problem and hereditary and acquired thrombophilias on IVF outcome.of recurrent IVF failure, it is a factor that impacts outcomes, The known or purported causality of phospholipid antibodiesand as such should be considered at least when evaluating and coagulation factors on recurrent pregnancy loss long agothe patient who has not succeeded in multiple IVF cycles. spilled over into the arena of conception with IVF or more The techniques associated with ultrasound-guided em- precisely, the lack of it. Some have argued that without im-bryo transfer vary from clinic to clinic. We have found it use- plantation to signal the arrival of an embryo, it would be im-ful to advise patients to consume enough liquid prior to the probable for serum or tissue-based response elements toprocedure to create an acoustic window directly above the prevent implantation. Others have argued that the effect isuterus. Bladder filling is especially helpful in obese patients unrelated to the embryo, but rather the negative impact isin whom imaging can be a challenge. We favor placement at the level of the endometrium. The Practice Committee ofof a trial catheter with an echogenic inner catheter tip to es- the American Society for Reproductive Medicine releasedtablish continuity with the internal cervical os. We leave the a Committee Opinion in 1999 which it reviewed again inouter sheath in place while the active transfer catheter is 2008, ‘‘Anti-phospholipid antibodies (APA) do not affectloaded. A second set of hands provided by an assistant in IVF success’’ (26). The review culled 16 peer reviewed papers,the operating room is useful to help position the abdominal of which 7 included appropriate endpoints and controls. Thereultrasound probe prior to catheter placement. The physician was no statistically significant impact of the presence ofperforming the transfer thereafter can make minor adjust- phospholipid antibodies on IVF outcomes when the studiesments to the probe position. were examined individually nor when the data were aggre- When a difficult transfer is in progress, direct visualiza- gated in the 2,053 patients studied. The authors concludedtion is a significant aid. There are times when its possible that ‘‘assessment of APA is not indicated among couples un-to see a trial catheter stuck in a particular position and know- dergoing IVF. Therapy is not justified on the basis of existinging the direction and angle of the cervical canal is a plus. Fur- data.’’ther, watching a catheter go in with ease but double back on A review was recently published on the topic of thrombo-itself averts the problem of depositing precious embryos in the philias and IVF outcome (27). The authors initial searchcervical canal rather than the endometrium. yielded 694 studies. Case reports, editorials, reviews, meta- A side benefit to the use of ultrasound-guided embryo analyses, studies with inadequate outcomes, absence oftransfer is patient comfort. Not so much due to an easier tech- thrombophilia/anti-phospholipid antibodies, and more thannique, though this can be true, and certainly not due to the full one of the above were excluded and 33 (6,092 patients) werebladder, but rather the patient is able to visualize the process ultimately analyzed. They report that twenty-nine studiesthus removing one of the more mysterious elements of the IVF (5,270 patients) assessed anti-phospholipid antibodies inexperience. women 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 ofIMMUNE FACTORS AND THROMBOPHILIAS one or more anti-phospholipid antibodies was associatedFew topics in reproductive medicine elicit as many opinions with a 3-fold higher risk of ART failure.’’ There was a signifi-or as much controversy as the impact of immune factors cant degree of heterogeneity across these case-control studiesVOL. 97 NO. 5 / MAY 2012 1037
  6. 6. VIEWS AND REVIEWSwith some using parous controls and others using women who 9. Robert Koch-Institut. Gesundheitsberichterstattung des Bundes, Bundeshad achieved a live birth following ART. In addition to case- Gesundheitssurvey 1998. Available at: rechnung.prc_abr_test_logon?p_uid¼gastg&p_aid¼&p_knoten¼FID&p_control studies, the authors also evaluated cohort studies. In sprache¼D&p_suchstring¼8397::BMI. Accessed December 30, 2011.contrast to the findings of the case-control studies, analysis 10. Centers for Disease Control and Prevention. Cigarette smoking among adults—of cohort studies showed that anti-phospholipid antibodies United States, 2006. MMWR Morb Mortal Wkly Rep 2007;56(44):1157–61.were not associated with a lower rate of viable pregnancy, 11. Waylen AL, Metwally M, Jones GL, Wilkinson AJ, Ledger WL. Effects of cig-live birth, or a higher incidence of negative pregnancy tests. arette smoking upon clinical outcomes of assisted reproduction: a meta- Ten of the studies in the review evaluated the relationship analysis. Hum Reprod Update 2009;15:31–44.between inherited thrombophilia and ART. Seven studies 12. Benedict MD, Missmer SA, Vahratian A, Berry KF, Vitonis AF, Cramer DW, Meeker JD. Secondhand tobacco smoke exposure is associated with in-were case-control, 2 were cohorts, and in 1 case-control study creased risk of failed implantation and reduced IVF success. Hum Reprodpatients undergoing IVF (cases) were followed to assess the 2011;26:2525–31.pregnancy outcomes. Pooled data from patients in 8 case- 13. Farhi J, Ashkenazi J, Feldberg D, Dicker D, Orvieto R, Ben Rafael Z. Effect ofcontrol studies showed an overall 3-fold increased risk of uterine leiomyomata on the results of in-vitro fertilization treatment. HumART failure in association with factor V Leiden. In the 3 co- Reprod 1995;10:2576.hort studies, there was no difference in outcome between 14. Eldar-Geva T, Meagher S, Healy DL, MacLachlan V, Breheny S, Wood C. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcomethose with and those without the factor V Leiden mutation. of assisted reproductive technology treatment. Fertil Steril 1998;70:687–91. True to form, the conflicting findings in the literature give 15. Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The effect ofadvocates and detractors of a role for phospholipid antibodies intramural fibroids without uterine cavity involvement on the outcome of IVFand thrombophilias ammunition to bolster their arguments. treatment: a systematic review and metaanalysis. Hum Reprod 2010;25:The advocates can cite the case-control studies, while the de- 418–29.tractors can cite the cohort studies. From a methodology 16. Somigliana E, De Benedictis S, Vercellini P, Nicolosi AE, Benaglia L,standpoint, both study types are Level II-2 (28) with their Scarduelli C, et al. Fibroids not encroaching the endometrial cavity and IVF success rate: a prospective study. Hum Reprod 2011;26:834–9.own particular strengths and limitations. Treatment trials 17. Mollo A, De Franciscis P, Colacurci N, Cobellis L, Perino A, Venezia R, et al.similarly suffer from methodological flaws and a lack of con- Hysteroscopic resection of the septum improves the pregnancy rate ofclusive answers. Level I evidence is clearly needed. women with unexplained infertility: a prospective controlled trial. Fertil Steril 2009;91:2628–31.CONCLUSIONS 18. Marcus S, al-Shawaf T, Brinsden P. The obstetric outcome of in vitro fertiliza- tion and embryo transfer in women with congenital uterine malformation.It is clear that there are other factors beyond the egg, embryo Am J Obstet Gynecol 1996;175:85–9.and endometrium that contribute to the success or failure of 19. Lavergne N, Aristizabal J, Zarka V, Erny R, Hedon B. Uterine anomalies andan IVF cycle. These factors, if present in serial IVF cycles, in vitro fertilization: what are the results? Eur J Obstet Gynecol Reprod Biolmay serve to diminish the actual odds of conception below 1996;68:29–34. 20. The National Academy of Clinical Biochemistry. Laboratory medicine practicethe population-based odds estimated by patient age and ovar- guidelines. Laboratory support for the diagnosis of thyroid disease, Volumeian reserve testing alone. Our mission is twofold: 1) reduce the 13. Washington, D.C.: The National Academy of Clinical Biochemistry; 2002.negative impact of factors over which we have control 21. Baker VL, Rone HM, Pasta DJ, Nelson HP, Gvakharia M, Adamson GD. Cor-through treatment or behavior modification; and 2) continue relation of thyroid stimulating hormone (TSH) level with pregnancy outcomeour efforts to identify as yet unknown factors that prevent our in women undergoing in vitro fertilization. Am J Obstet Gynecol 2006;194:patients from achieving a successful outcome. 1668–74. 22. Reh A, Grifo J, Danoff A. What is a normal thyroid-stimulating hormone (TSH) level? Effects of stricter TSH thresholds on pregnancy outcomes afterREFERENCES in vitro fertilization. Fertil Steril 2010;94:2920–2. 1. World Health Organization. Facts on Obesity. Available at: 23. Toulis KA, Goulis DG, Venetis CA, Kolibianakis EM, Negro R, Tarlatzis BC, features/factfiles/obesity/facts/en/index1.html. Accessed December 30, 2011. Papadimas I. Risk of spontaneous miscarriage in euthyroid women with thy- 2. Centers for Disease Control and Prevention. Overweight and Obesity. 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The American College of Obstetricians and Gynecologists. Reading the 8. Kupka MS, Gnoth C, Buehler K, Dahncke W, Kruessel JS. Impact of female Medical Literature. Available at: and male obesity on IVF/ICSI: results of 700,000 ART cycles in Germany. Gy- Publications/Department_Publications/Reading_the_Medical_Literature. necol Endocrinol 2011;27:144–9. Accessed March 11, 2012.1038 VOL. 97 NO. 5 / MAY 2012