2. VIEWS AND REVIEWS
implantation rates in women with BMI >35. Ryley et al. (5)
FIGURE 1
confirmed these findings the following year in a study of
6,827 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, and
no 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 BMI
groups. However, the implantation rate, pregnancy rate and
live birth rate were clearly and adversely affected by elevated
BMI (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 added
to the Clinic Online Reporting System, permitting calculation Implantation, pregnancy, and live birth rates in IVF-ICSI cycles
according to the women's BMI. Each point represents percentages
of 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 of
45,163 cycles were analyzed. The investigators found that
higher BMI was associated with lower clinical pregnancy comes between groups when thawed cryopreserved embryos
rates, 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 and
use 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 group
et al. (8) included men. The investigators analyzed 12 years might as well be related to other lifestyle factors associated
of 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, the
cerning weight was given were analyzed. Obesity, defined as preponderance of data including two national data sets
BMI >30, was assigned to four groups: none, female, male or clearly demonstrates the negative impact of elevated BMI
both. 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 is
ples with an obese male partner (30.38%, P¼ .0028). In the known to be associated with lower per cycle pregnancy and
group 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. Fertility and Sterility®
CIGARETTE SMOKE FIGURE 2
The incidence of cigarette smoking in the U.S. population
dropped by half between 1965 and 2006; 42% to 20.8% of
adults (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 of
individuals, many of who are trying to become pregnant.
In their meta-analysis, Waylen et al. (11) evaluated 17
studies and showed in aggregate significantly lower odds of
live 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 IVF
failure. Women who smoke cigarettes should be strongly
counseled that smoking cuts their odds of live birth nearly
in 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 cycles
from 1909 non-smoking women between 1994 and 2003 to 2355 control cycles. The comparison showed a statistically
examine the relationship between secondhand tobacco smoke significant 21% relative reduction in live birth rate in women
exposure and implantation failure. They reported a 52% in- with non-cavity-distorting intramural fibroids compared
crease 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 of
STS-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 no
should stop smoking, but non-smoking women, too, should differences in embryo implantation or delivery. The small
remove 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 following
Leiomyomata 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 uterine
Farhi 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 clinical
1986 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 recurrent
4.5 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 question
paired implantation and successful pregnancy only when the
that remains unresolved is how large an intramural fibroid
uterine 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 control
patients without fibroids undergoing IVF. In their series of UTERINE ANOMALIES
88 patients undergoing 106 IVF cycles, they found that preg- The uterine septum has been implicated as a cause of recurrent
nancy and implantation rates were significantly lower in the pregnancy loss and its resection touted to improve outcomes
46 patients with intramural fibroids and no cavity distortion in those affected by them. Whether infertility is caused by the
and 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 septum
yielded 19 studies that met inclusion criteria, 11 of which and no other attributable cause of infertility to 132 women
used live birth as an endpoint. There were 1626 cycles with (group B) with unexplained infertility. The pre-operative
non-cavity distorting intramural fibroids compared with size of the septum was not described in the study. Following
VOL. 97 NO. 5 / MAY 2012 1035
4. VIEWS AND REVIEWS
FIGURE 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 <2.5
uterine cavity and a 12-month follow-up period, the live birth mIU/L. TSH levels >2.5 mIU/L had a possible weak positive
rate 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 one's ability to extrapolate to the delivery or miscarriage rates in 1055 women when those with
general 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 for
recurrent failure to become pregnant following ART is ad- spontaneous miscarriage in subfertile, euthyroid women with
dressed in the literature without a conclusive answer (18, thyroid autoimmunity (TAI) (defined as the presence of
19). 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 of
explanation. 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) compared
THYROID DYSFUNCTION 129 euthyroid anti-thyroid antibody-positive (ATAþ) women
The thyroid gland is most commonly associated with meta- undergoing IVF to 200 matched, ATA-negative controls. Dur-
bolic rate, but it's clear that thyroid hormone is necessary ing IVF cycle, 38 ATAþ patients did not take any adjuvant
for the normal function of numerous other body organs and treatment, 55 received levothyroxin (LT), and 38 received LT
tissues. 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), and
try, 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 euthyroid
ture, it is likely that the upper limit of the serum TSH euthy- ATAþ patients undergoing IVF could have better outcome if
roid 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 insufficient
data of health improvement of cardiac, lipid and neuropsychi- EMBRYO TRANSFER TECHNIQUE
atric 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 transfers
in ‘‘women who become pregnant through IVF, gestational with 3171 clinical touch showed an odds ratio of 1.31 (95% CI
age at delivery and birth weight were lower in cycles with 1.18–1.46) in favor of ultrasound guidance. While this factor
1036 VOL. 97 NO. 5 / MAY 2012
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.
isn't 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 antibodies
and as such should be considered at least when evaluating and coagulation factors on recurrent pregnancy loss long ago
the 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 to
procedure to create an acoustic window directly above the prevent implantation. Others have argued that the effect is
uterus. Bladder filling is especially helpful in obese patients unrelated to the embryo, but rather the negative impact is
in whom imaging can be a challenge. We favor placement at the level of the endometrium. The Practice Committee of
of a trial catheter with an echogenic inner catheter tip to es- the American Society for Reproductive Medicine released
tablish continuity with the internal cervical os. We leave the a Committee Opinion in 1999 which it reviewed again in
outer sheath in place while the active transfer catheter is 2008, ‘‘Anti-phospholipid antibodies (APA) do not affect
loaded. 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. There
ultrasound probe prior to catheter placement. The physician was no statistically significant impact of the presence of
performing the transfer thereafter can make minor adjust- phospholipid antibodies on IVF outcomes when the studies
ments 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 concluded
tion is a significant aid. There are times when it's 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 existing
ing 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 search
cervical 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 of
transfer is patient comfort. Not so much due to an easier tech- thrombophilia/anti-phospholipid antibodies, and more than
nique, though this can be true, and certainly not due to the full one of the above were excluded and 33 (6,092 patients) were
bladder, but rather the patient is able to visualize the process ultimately analyzed. They report that twenty-nine studies
thus removing one of the more mysterious elements of the IVF (5,270 patients) assessed anti-phospholipid antibodies in
experience. 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 of
IMMUNE FACTORS AND THROMBOPHILIAS one or more anti-phospholipid antibodies was associated
Few 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 studies
VOL. 97 NO. 5 / MAY 2012 1037
6. VIEWS AND REVIEWS
with some using parous controls and others using women who 9. Robert Koch-Institut. Gesundheitsberichterstattung des Bundes, Bundes
had achieved a live birth following ART. In addition to case- Gesundheitssurvey 1998. Available at: http://www.gbebund.de/gbe10/ab
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 Reprod
patients 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 of
control studies showed an overall 3-fold increased risk of uterine leiomyomata on the results of in-vitro fertilization treatment. Hum
ART 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 outcome
those 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 of
advocates and detractors of a role for phospholipid antibodies intramural fibroids without uterine cavity involvement on the outcome of IVF
and 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 of
clusive 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 and
an IVF cycle. These factors, if present in serial IVF cycles, in vitro fertilization: what are the results? Eur J Obstet Gynecol Reprod Biol
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20. The National Academy of Clinical Biochemistry. Laboratory medicine practice
the population-based odds estimated by patient age and ovar-
guidelines. Laboratory support for the diagnosis of thyroid disease, Volume
ian 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 outcome
our 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 after
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