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ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 3  |  Page : 104-109

Antral follicle count: Is the right ovary more predictive than the left for live birth?


1 Reproductive Medicine Associates of Connecticut, Norwalk, CT, Sher Fertility Institute, Purchase, NY, USA
2 Kaali Institute, IVF Center, Budapest, Hungary, Europe
3 Wright-Patterson USAF Medical Center, Dayton, NY, USA
4 Reproductive Medicine Associates of Connecticut, Norwalk, CT, Sher Fertility Institute, Purchase; Wright-Patterson USAF Medical Center, Dayton, NY, USA

Date of Web Publication21-Apr-2017

Correspondence Address:
Steven R Lindheim
128 Apple Street, Suite 3800 Weber CHE, Dayton, OH 45409
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-2907.204671

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  Abstract 

Objective: The objective of this study was to assess the impact of discordant ovarian antral follicle counts (AFCs) on cycle stimulation and live birth in autologous in vitro fertilization (IVF) cycles. Materials and Methods: This is a retrospective analysis of first-time cycles of 153 patients undergoing gonadotropin-releasing hormone-antagonist IVF. Results: While AFC significantly correlated with cycle stimulation characteristics, only the right ovarian AFC significantly correlated with live birth (r = 0.18, P< 0.02). Right ovarian AFC was significantly greater in live birth cycles (12.3 ± 7.8) compared to cycles without a live birth (9.6 ± 6.0, P< 0.02). Using ≤ 7 as a threshold of low unilateral AFC, concordant low AFC was present in 28% (Group 1: n = 43); discordant low left and normal right in 13% (Group 2: n = 19); discordant low right and normal left in 11% (Group 3: n = 17); and concordant normal in both ovaries in 48% (Group 4: n = 74) of patients. Live birth was similar in Group 2 (36.8%), Group 3 (35.3%), and Group 4 (37.8%), but significantly less in Group 1 (9.3%) (P < 0.05). Conclusion: Live birth was higher with greater right AFC. Using threshold AFC, adverse outcomes were only noted when both ovaries had low counts. Individual AFC may serve as a more specific indicator than total AFC as a marker of ovarian reserve.

Keywords: Antral follicle count, in vitro fertilization, live birth rates, ovarian reserve


How to cite this article:
Simpson S, Ressler IB, Kovacs P, Warwar R, O'Leary K, Maxwell RA, Lindheim SR. Antral follicle count: Is the right ovary more predictive than the left for live birth?. IVF Lite 2016;3:104-9

How to cite this URL:
Simpson S, Ressler IB, Kovacs P, Warwar R, O'Leary K, Maxwell RA, Lindheim SR. Antral follicle count: Is the right ovary more predictive than the left for live birth?. IVF Lite [serial online] 2016 [cited 2019 Sep 16];3:104-9. Available from: http://www.ivflite.org/text.asp?2016/3/3/104/204671


  Introduction Top


The success of in vitro fertilization and embryo transfer (IVF-ET) cycles is primarily dependent on the recruitment and development of multiple follicles to controlled ovarian hyperstimulation which lead to the development of multiple and high-quality embryos for the selection of ET.[1] Identification of patients at risk of poor ovarian response by the assessment of ovarian reserve before an IVF cycle can help tailor advice to individual couples about whether to proceed with a costly, demanding, and disappointing IVF treatment.[2],[3]

Historically, biochemical markers of ovarian reserve including early follicular-phase follicle-stimulating hormone (FSH), estradiol, inhibin B, and the clomiphene citrate challenge test have been used to assess ovarian capacity.[4] None of these are particularly reliable, and their accuracy of predicting pregnancy outcomes is at best limited.[5] Anti-Mullerian hormone (AMH), produced by granulosa cells of early follicles, has now become a promising screening test in the general IVF population and in women at a high risk for diminished ovarian reserve. Low AMH levels are fairly specific for poor ovarian response, with some reports also suggestive of suboptimal pregnancy outcomes.[6]

Antral follicle counts (AFCs), obtained by measuring follicles 2–10 mm, have emerged as a useful, simple, and noninvasive indicator of stimulation quality in IVF cycles.[7] An AFC of 3–6 is considered low and is highly specific for predicting poor ovarian response including cycle cancellation and ≤5 retrieved oocytes.[8] It is also recognized as a biomarker that is associated with live birth independent of age [9] but, similar to other markers, has not uniformly predicted pregnancy outcomes.[10]

Independent observations have been noted that discordant AFCs are seen but their significance is unclear. It has been recognized that while the right and left ovaries are embryologically and histologically similar, there are distinct anatomic differences.[11],[12] Differences in the cyclical physiological control of ovulation have been noted as ovulation takes place significantly more from the right than the left ovary.[13],[14] To our knowledge, the significance of discordant AFC between ovaries has not been addressed. This study was undertaken to assess the association and impact between total left and right ovarian AFC, cycle stimulation characteristics, and pregnancy outcomes.


  Materials and Methods Top


This retrospective study was reviewed and approved by our Institutional Review Board. Data on all eligible cycles from January 2012 to December 2014 were reviewed, and if eligible, total and individual left and right AFCs measuring 2–10 mm and early follicular phase FSH were documented. All patients were 38 years old or younger and were undergoing their first autologous IVF cycle using gonadotropin-releasing hormone-antagonist (GnRH-ant). Cycles with a single ovary, uterine myoma (s) >3 cm, severe male factors (<1 million/cc or testis sperm extraction), those with clinical evidence of polycystic ovarian syndrome (PCOS),[15] and an ovarian cyst measuring >20 mm were excluded from the analysis.

A transvaginal ultrasound (TVS) using a GE 3600-7 MHz vaginal transducer was performed on cycle days 2 or 3 of a withdrawal bleed following 1–2 months of oral contraceptive use (Mircette ® , Duramed Pharmaceuticals, Inc., Pomona, NY, USA) for cycle synchronization before starting the treatment. Follicles were measured in the sagittal and transverse planes, and the mean of the two measurements was used. Follicles measuring 2–10 mm were counted in both ovaries for the individual AFC and their sum for total AFC. Ultrasounds were performed by a single physician (SL) to reduce observer bias.

Ovarian stimulation using daily injections of 150–300 IU of recombinant and urinary follicle-stimulating hormone (Follistim TM; Organon Inc., West Orange, NJ, USA, and Ferring Pharmaceuticals) was started on cycle day 3 following an oral contraceptive pill withdrawal bleed. Ovarian stimulation protocols were chosen by the treating physician based on ovarian reserve markers. All cycles were monitored by serum estradiol levels and TVS, and the dose was adjusted according to response. GnRH-ant (Ganirelix) 0.25 mg, subcutaneously daily (Merck Inc., West Orange, NJ, USA), was initiated when lead follicles were 12–13 mm. When ≥3 follicles reached 18–20 mm, urinary human chorionic gonadotropin (hCG) 10,000 IU was given and followed by transvaginal oocyte aspiration 35 h later. Cycles were canceled for poor response, defined as ≤4 dominant follicles on the day of hCG or hyper-response with serum estradiol >6500 pg/mL.

All oocytes were fertilized by standard insemination or intracytoplasmic sperm injection for male factor. Embryos were transferred transcervically 5 days postretrieval under ultrasound guidance. Pregnancy was confirmed by serum β-hCG 2 weeks following oocyte aspiration. Clinical pregnancy was defined as an intrauterine gestational sac 3–4 weeks after ET, and live birth was defined as delivery of a fetus >24 weeks of gestation.

Outcomes measured were live birth rates of normal and abnormal, total and individual AFCs, and correlated to ovarian reserve markers (total AFC, individual right and left AFC, basal FSH, and estradiol levels) and cycle stimulation characteristics. In addition, we identified an optimal threshold for classifying total and individual AFCs related to live birth rates.

Serum samples were assayed for FSH (DPC, Los Angeles, CA, USA) on cycle day 3 and estradiol (DPC, Los Angeles, CA, USA) using CIA Immulite kits. Intra- and inter-assay CV for FSH were 5.4% and 8.1% and 6.3% and 6.4% for estradiol, respectively.

Statistical analysis was performed using the SPSS statistical package version 18.0 (SPSS Inc., Chicago, IL, USA). Student's t-test and Chi-square test were computed for clinical and cycle stimulation characteristics for cycles with and without live birth. Logistic regression was used to identify significant predictors of live birth. Receiver operator curve was used to determine the optimal threshold for total, right ovary, and left ovary AFC and to determine the predictive accuracy of the cutoff point identified, yielding values from 0.5 (no predictive power) to 1.0 (perfect prediction). Significance was defined as P< 0.05.


  Results Top


One hundred and fifty-three initiated autologous cycles resulted in 143 retrievals (93%; 10 cancelled for poor response) and 138 ETs (90%; [no sperm (n = 1), concurrent illness (n = 1), and embryos failed to survive (n = 3)]). No cycles were canceled for hyperstimulation. The mean age of participants was 32.8 ± 4.3 years; day 3 serum FSH was 6.3 ± 2.1 mIU/ml; and body mass index (BMI) was 29.1 kg/m 2 ± 7.2. Sixty-five cycles resulted in a pregnancy (42% per initiated cycle and 47% per ET); 52 in clinical pregnancies (34% per initiated cycle and 38% per ET); and 45 in a live birth (29% per initiated cycle and 33% per ET).

With respect to those with and without a live birth, significant differences included right ovarian AFC (12.3 ± 7.8 vs. 9.6 ± 6.0, P< 0.02), number of follicles >16 mm (8.9 ± 4.0 vs. 7.4 ± 4.0, P< 0.04), and those with embryo cryopreservation (51% vs. 38%, P= 0.01). Total AFC (23.1 ± 13.3 vs. 19.2 ± 11.3) and left ovarian AFC (10.7 ± 6.3 vs. 9.5 ± 6.0) were higher in those with a live birth but failed to achieve statistical difference [Table 1].
Table 1: Clinical and cycle characteristics in those with and without live births

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There were significant correlations for age, basal FSH, estradiol, total and individual ovarian AFCs, and cycle stimulation characteristics. Specifically, there were negative correlations between age and total (r = − 0.49, P< 0.001) and individual ovarian AFC (right [r = − 0.48, P< 0.001] and left [r = − 0.42, P< 0.001]). Only right ovarian AFC had a significant correlation with live birth (r = 0.18, P< 0.02) in contrast to total AFC (r = 0.15, P= 0.07) and left ovarian AFC (r = 0.09, P< 0.27). Logistic regression was used to determine the effects of total and individual ovarian follicle counts on live birth. Age, basal FSH, estradiol, and BMI were added to the model to account for possible covariance effects. While total, right, and left ovarian AFCs were significant with respect to cycle stimulation characteristics, only right ovarian AFC remained significantly correlated with live birth (r = 0.29, P< 0.03) [Table 2].
Table 2: Logistic regression for total antral follicle count, right and left antral follicle count, stimulation characteristics, and clinical outcomes

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The diagnostic accuracy of total and individual right and left ovarian AFCs to discriminate cycles resulting in a live birth was ≥13, ≤7, and >7, respectively. The sensitivity and 1-specificity of total and individual right and left ovarian AFCs were 75% and 67%, 78% and 54%, and 76% and 53%, respectively. The predictive values are shown in [Table 3], and respective plots for right ovarian AFC are shown in [Figure 1]. Using >7 as the cutoff threshold for normal reserve for a single ovary, an AFC ≤7 in both ovaries was present in 28% (n = 43) of patients (concordant low, Group 1); ≤7 on the left and AFC >7 on the right in 13% (n = 19) of patients (discordant left, Group 2); an AFC ≤7 on the right and AFC >7 on the left in 11% (n = 17) of patients (discordant right, Group 3); and >7 AFC on both ovaries in 48% (n = 74) of patients (concordant normal, Group 4). No differences in cycle stimulation characteristics were noted in Groups 2 and 3 compared to Group 4 though each resulted in greater peak estradiol, total number of oocytes, #MII, and less cycle cancellation, and more cryopreserved cycles compared to and more cryopreserved cycles and required significantly less gonadotropins than Group 1 [Table 4]. Live birth outcomes were similar in Group 2 (36.8%), Group 3 (35.3%), and Group 4 (37.8%) but significantly less in Group 1 (9.3%) (P < 0.01) [Table 5].
Table 3: Results of receiver operator curve analysis for live birth depending on total and individual ovarian antral follicle count

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Figure 1: ROC curve of the right ovarian antral follicle count and predicting live birth

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Table 4: Baseline characteristics and cycle stimulation outcomes for individual ovarian antral follicle counts

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Table 5: Clinical pregnancy and live rates based bilateral low, unilateral low, and bilateral normal antral follicle counts

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  Discussion Top


Many studies have described AFC as a predictor for cycle stimulation characteristics and clinical and live birth outcomes. To our knowledge, this is the first report to describe discordance in ovarian AFC. Higher right ovarian AFC is associated with a greater likelihood of live birth compared to left ovarian AFC. However, using established thresholds, this same likelihood was not observed. Discordant AFC was seen in almost one-quarter of women undergoing IVF; however, discordant groups (irrespective of side) had ovarian responsiveness to gonadotropin similar to those with concordant normal AFC. The presence of one ovary with low AFC, <7, did not adversely impact live birth rates, in contrast to those with bilateral low AFC.

Ovarian response markers including FSH, AMH, and AFC have been employed to predict ovarian response to gonadotropin stimulation and pregnancy outcomes in both autologous and oocyte donation cycles.[16],[17] Reviews have shown that AFC and AMH have the best and comparable performance in predicting both poor and excessive ovarian response and are recognized as the biomarkers of choice for the prediction of ovarian response.[5],[18] However, both have not reliably predicted pregnancy outcome,[6],[10],[19] and currently there is insufficient evidence to use either of them as a test for inability to conceive. Each has also been applied to models in predicting IVF success and enables providers and patients to make informed decisions regarding treatment,[2],[3],[20] however either can underestimate or overestimate success rates.

It has been established that the number of 2–10 mm follicles counted by TVS in both ovaries in the early follicular phase correlates with the number of growing follicles in response to exogenous FSH in IVF cycles.[9] While discordant AFC is frequently seen, its significance is unclear. There are clear anatomic and physiologic differences between the two ovaries.[11],[12],[13],[14] Observations also suggest that ovulation takes place significantly more frequently from the right ovary (55%) compared to the left (45%),[13],[14] suggesting differences in intra-ovarian physiological control of folliculogenesis. It has also been shown that pregnancy is more likely to be achieved when ovulation occurs from the right ovary although the mechanism is poorly understood.[13] Attempts to discern differences in embryo quality and pregnancy outcomes specific to the right or left ovary have previously been reported in IVF patients with "healthy ovaries."[21] The authors reported no differences in ovarian response to gonadotropin stimulation, number of retrieved oocytes, fertilization rates, embryo quality, and pregnancy outcomes, suggesting that the regulatory mechanisms that control normal folliculogenesis are overridden by IVF treatment protocols.

Our results corroborate the extensive literature suggesting that total AFC correlates with response to ovulation induction in IVF cycles. However, absolute right ovarian AFC only appears to correlate with live birth in contrast to total and left ovarian AFCs. On the other hand, when using a discriminatory threshold of normal individual AFC >7, those with discordant ovarian AFC did not appear to adversely impact the chance of live birth similar to those with concordant normal AFC, but in contrast to those with concordant low AFC.

There are clear limitations to our results including the retrospective design and inclusion of only cycles undergoing GnRH-ant, limiting the generalizability to all IVF cycles. Our starting Gn dose for all cycles was not standardized and was significantly higher for both the discordant and low concordant groups which could have affected stimulation characteristics and clinical outcomes. Moreover, embryos from either ovary were not cultured individually to assess for specific differences in embryo quality and pregnancy outcomes unlike findings by Thomson et al. where oocytes from each ovary were handled separately and outcomes were recorded.[21] Finally, while statistical differences were found in several measured outcomes, the overall size of the study was small and therefore the numbers reported might not be considered clinically significant. However, our work demonstrates that there may be relevance in individual ovarian AFC and correlation to live birth rate that should be further studied with a larger study size and in a prospective manner.


  Conclusion Top


Our study shows that AFC (total and individual) correlates with stimulation outcome among women undergoing GnRH-ant IVF cycles. Right ovarian AFC correlated with live birth, and IVF outcome was poorest when AFC was low in both ovaries. Using threshold AFC, discordant ovarian AFC did not appear to adversely impact pregnancy outcomes. The finding of higher right AFC and its association with live birth needs to be further evaluated and it may serve as a more specific indicator than total AFC as a marker of ovarian reserve. There is a hypothesis that differences in individual ovarian count make anatomic and physiologic sense, and prospective studies are now ongoing to assess the impact of discordant AFC on embryo quality and pregnancy outcomes.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no confl icts of interest.

 
  References Top

1.
Vrontikis A, Chang PL, Kovacs P, Lindheim SR. Antral follice counts (AFC) predict ovarian response and pregnancy outcomes in oocyte donation cycles. J Assist Reprod Genet 2010;27:383-9.  Back to cited text no. 1
    
2.
Dhillon RK, McLernon DJ, Smith PP, Fishel S, Dowell K, Deeks JJ, et al. Predicting the chance of live birth for women undergoing IVF: A novel pretreatment counselling tool. Hum Reprod 2016;31:84-92.  Back to cited text no. 2
    
3.
Nelson SM, Fleming R, Gaudoin M, Choi B, Santo-Domingo K, Yao M. Antimüllerian hormone levels and antral follicle count as prognostic indicators in a personalized prediction model of live birth. Fertil Steril 2015;104:325-32.  Back to cited text no. 3
    
4.
te Velde ER, Pearson PL. The variability of female reproductive ageing. Hum Reprod Update 2002;8:141-54.  Back to cited text no. 4
    
5.
Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update 2006;12:685-718.  Back to cited text no. 5
    
6.
Muttukrishna S, McGarrigle H, Wakim R, Khadum I, Ranieri DM, Serhal P. Antral follicle count, anti-mullerian hormone and inhibin B: Predictors of ovarian response in assisted reproductive technology? BJOG 2005;112:1384-90.  Back to cited text no. 6
    
7.
Ebner T, Sommergruber M, Moser M, Shebl O, Schreier-Lechner E, Tews G. Basal level of anti-müllerian hormone is associated with oocyte quality in stimulated cycles. Hum Reprod 2006;21:2022-6.  Back to cited text no. 7
    
8.
McIlveen M, Skull JD, Ledger WL. Evaluation of the utility of multiple endocrine and ultrasound measures of ovarian reserve in the prediction of cycle cancellation in a high-risk IVF population. Hum Reprod 2007;22:778-85.  Back to cited text no. 8
    
9.
Frattarelli JL, Levi AJ, Miller BT, Segars JH. A prospective assessment of the predictive value of basal antral follicles in in vitro fertilization cycles. Fertil Steril 2003;80:350-5.  Back to cited text no. 9
    
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Iliodromiti S, Kelsey TW, Wu O, Anderson RA, Nelson SM. The predictive accuracy of anti-müllerian hormone for live birth after assisted conception: A systematic review and meta-analysis of the literature. Hum Reprod Update 2014;20:560-70.  Back to cited text no. 10
    
11.
La Marca A, Nelson SM, Sighinolfi G, Manno M, Baraldi E, Roli L, et al. Anti-müllerian hormone-based prediction model for a live birth in assisted reproduction. Reprod Biomed Online 2011;22:341-9.  Back to cited text no. 11
    
12.
Khader A, Lloyd SM, McConnachie A, Fleming R, Grisendi V, La Marca A, et al. External validation of anti-müllerian hormone based prediction of live birth in assisted conception. J Ovarian Res 2013;6:3.  Back to cited text no. 12
    
13.
Nelson SM, Klein BM, Arce JC. Comparison of antimüllerian hormone levels and antral follicle count as predictor of ovarian response to controlled ovarian stimulation in good-prognosis patients at individual fertility clinics in two multicenter trials. Fertil Steril 2015;103:923-30.e1.  Back to cited text no. 13
    
14.
Hendriks DJ, Mol BW, Bancsi LF, Te Velde ER, Broekmans FJ. Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: A meta-analysis and comparison with basal follicle-stimulating hormone level. Fertil Steril 2005;83:291-301.  Back to cited text no. 14
    
15.
Gray H. Gray's Anatomy: Descriptive and Applied. 35th ed. United Kingdom: Longman; 1973.  Back to cited text no. 15
    
16.
Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: International consensus definitions. Hum Reprod Update 2003;9:505-14.  Back to cited text no. 16
    
17.
Nelson SM, Yates RW, Fleming R. Serum anti-müllerian hormone and FSH: Prediction of live birth and extremes of response in stimulated cycles – Implications for individualization of therapy. Hum Reprod 2007;22:2414-21.  Back to cited text no. 17
    
18.
Nelson SM, Anderson RA, Broekmans FJ, Raine-Fenning N, Fleming R, La Marca A. Anti-müllerian hormone: Clairvoyance or crystal clear? Hum Reprod 2012;27:631-6.  Back to cited text no. 18
    
19.
Broer SL, Dólleman M, Opmeer BC, Fauser BC, Mol BW, Broekmans FJ. AMH and AFC as predictors of excessive response in controlled ovarian hyperstimulation: A meta-analysis. Hum Reprod Update 2011;17:46-54.  Back to cited text no. 19
    
20.
Broer SL, Mol BW, Hendriks D, Broekmans FJ. The role of antimullerian hormone in prediction of outcome after IVF: Comparison with the antral follicle count. Fertil Steril 2009;91:705-14.  Back to cited text no. 20
    
21.
Thomson AJ, Gazvani MR, Wood SJ, Meacock SC, Lewis-Jones DI, Kingsland CR. Comparison of ovarian response in right and left ovaries in IVF patients. Hum Reprod 2001;16:1694-7.  Back to cited text no. 21
    

 
  Authors Top


Steven R. Lindheim, MD, MMM joined the Wright State Physician in 2014. He is board certifi ed in Obstetrics and Gynecology and in Reproductive Endocrinology and Infertility. Dr. Lindheim is Professor at Wright University, Boonshoft School of Medicine, an active member of the American Congress of Obstetricians and Gynecologists and of the American Society for Reproductive Medicine and serves on the Board of Director for the Society of Reproductive Surgeons. Dr. Lindheim is editor for peer reviewed journals in the area experienced in all areas of infertility and gynecologic surgery, and his clinical and research interests focus on polycystic ovarian syndrome, endometriosis, and third party reproduction


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