Bisphenol A and implantation failure in women sample as compared with two urine samples during their treatment cycle (data not shown). For the 20% of cycles with one urine sample, the BPA concentration for that single urine sample was used as the cycle­specific urinary BPA concentration. Detectable concentrations of BPA were measured in 88% (287/325) of samples (Table 3). In unadjusted logistic regression models, women ≥ 37 years of age had more than twice the odds of implantation failure as compared with women < 37 years of age, and women on a flare or antagonist protocol had a more than three times the odds of implantation failure as compared with women on the luteal phase protocol (Table 4). In IVF cycles in which the embryo transfer occurred on day 5, there was a 50% decreased odds of implanta­ tion failure compared with a day­ 3 embryo transfer. Day­ 3 FSH (international units per liter) was marginally associated with increased odds of implantation failure, but showed no association after adjustment for other covari­ ates (age, day of embryo transfer, and IVF protocol type) in the multivariate model. The remaining covariates were not significantly associated with implantation on univariate analyses (p < 0.2) and therefore did not qual­ ify for inclusion in our multivariate model. Urinary BPA concentrations were significantly higher in women who underwent a low responder treatment protocol as compared with the regular luteal phase protocol (4.08 vs. 2.61 µg/L, p < 0.001). BPA concentrations did not vary significantly by levels of other covariates of interest that were considered for inclusion in the multivariable model. In the unadjusted model, the odds of implantation failure increased linearly with increasing quartiles of urinary BPA con­ centrations: odds ratios (OR) [95% confi­ dence interval (CI)] were 1.01 (0.38, 2.66), 1.57 (0.70, 3.52), and 2.38 (0.97, 5.83) for quartiles 2, 3, and 4, respectively, compared with the lowest quartile (p­ trend = 0.03) (Table 4 and Figure 1). Results were simi­ lar after adjusting for older age (> 37 years) and day of embryo transfer (day 5 vs. day 3), although slightly attenuated for the fourth ver­ sus first quartile of exposure (pt­rend = 0.06). Finally, after adjustment for IVF protocol, the associations were further attenuated but remained consistent with a positive linear dose–response relationship. In models stratified by IVF protocol, there was a stronger association of urinary BPA con­ centration with implantation failure among women undergoing flare/antagonist protocols (n = 51 women, 71 cycles) compared with women undergoing the luteal protocol (n = 95 Table 3. Distribution of cycle-specific urinary BPA concentrations (µg/L) among 137 women undergoing 180 IVF cycles (325 urine samples). BPA SG-adj BPA Detection rate 88% GM (SD) 1.53 (2.22) 2.56 (1.87) Min < LOD < LOD 10th 0.60 1.27 25th 0.89 1.69 Abbreviations: < LOD, below limit of detection (0.4 µg/L); Max, maximum; Min, minimum; SG-adj BPA, specific-gravity– – adjusted BPA concentrations. All values below LOD were assigned a value equal to the LOD divided by √2. Nine (5%) cycle-specific BPA concentrations were < LOD and are included in the percentiles. Thirty-eight (12%) individual urine samples had BPA concentrations < LOD. There was an 88% detection rate for all individual urine samples [SG range (1.001–1.035)]. Table 4. Crude and adjusted ORs (95% CIs) for associations of quartiles of urinary BPA concentrations with implantation failure among 137 women undergoing 180 IVF cycles. Percentile 50th 75th 1.50 2.33 2.40 3.79 90th 3.76 5.91 95th 6.04 7.82 Max 22.07 26.48 Characteristic SG-adjusted BPA quartiles (range µg/L) 1 (≤ 1.69) 2 (1.70–2.33) 3 (2.34–3.79) 4 (3.80–26.48) p-Trend Age (≥ 37 vs. < 37 years) Embryo transfer day (day 5 vs. day 3) IVF protocol (flare/antagonist vs. luteal) No. embryos transferred (1, ≥ 2) Day-3 FSH (IU/L) Peak E2 (pg/mL) Endometrial thickness (≤ 8 mm vs. > 8 mm) Ever smoker vs. never smoker BMI (≥ 25 kg/m2 vs. < 25 kg/m2)c Urine collection year (continuous) n 45 45 46 44 Unadjusted p-Value Adjusteda Reference 1.01 (0.38, 2.66) 1.57 (0.70, 3.52) 2.38 (0.97, 5.83) 0.03 2.22 (1.15, 4.28) 0.48 (0.24, 0.95) 3.16 (1.70, 5.87) 0.67 (0.29, 1.54) 1.87 (0.95, 1.28) 1.00 (0.99, 1.00) 1.50 (0.69, 3.24) 1.09 (0.55, 2.16) 1.35 (0.69, 2.64) 0.84 (0.56, 1.27) 0.02 0.03 < 0.001 0.35 0.19 0.68 0.30 0.80 0.38 0.42 Reference 1.02 (0.35, 2.95) 1.60 (0.70, 3.78) 2.11 (0.84, 5.31) 0.06 1.89 (0.97, 3.65) 0.53 (0.26, 1.08) IVF-protocol adjustedb 1.05 (0.36, 3.03) 1.52 (0.65, 3.55) 1.90 (0.73, 4.96) 0.12 1.50 (0.76, 2.95) 0.68 (0.32, 1.45) 2.09 (1.03, 4.24) aAdjusted for age [≥ 37 years vs. < 37 years (referent group)] and day of embryo transfer [day 5 vs. day 3 (referent group)]. bAdjusted for age (≥ 37 years vs. < 37 years), day of embryo transfer (day 5 vs. day 3), and IVF protocol [flare/ antagonist vs. luteal (referent group)]. cOne missing value. Environmental Health Perspectives • volume 120 | number 7 | July 2012 women, 109 cycles). Nine women were in the luteal protocol group for one cycle and the flare/antagonist group for a subsequent cycle. Among women in the flare/antagonist proto­ col, the ORs (95% CI) for implantation failure by quartile of urinary BPA concentration, after adjustment for age (years) and day of embryo transfer (day 5 vs. day 3), were 1.50 (0.26, 8.58), 2.12 (0.47, 9.62), and 3.59 (0.74, 17.43) for quartiles 2, 3, and 4, respectively, compared with the lowest quartile (p­trend = 0.07). In contrast, corresponding estimates for women in the luteal protocol group were 0.68 (0.13, 3.55), 1.02 (0.35, 2.95), and 1.04 (0.36, 3.04) for quartiles 2, 3, and 4, respectively, com­ pared with the lowest quartile (pt­rend = 0.83). Women treated with the alternative flare or antagonist protocols were more likely than women treated with the luteal protocol to have had past IVF treatment cycle failures (73% vs. 34%), diminished ovarian reserve (mean day3­ FSH 8.8 IU/L vs. 6.6 IU/L), and dimin­ ished ovarian response to controlled ovarian FSH hyperstimulation (mean peak serum E2 1,735 pg/mL vs. 2,258 pg/mL, mean number of eggs retrieved 7.6 vs. 12.7). Finally, women on the alternative protocol were almost 4 years older than women on the luteal phase protocol (mean age 38.1 years vs. 34.3 years). Discussion In the present study, the association between urinary BPA concentrations and implanta­ tion failure increased with increasing urinary BPA quartiles after adjusting for age and day of embryo transfer. Women in the fourth quartile of exposure (SGa­djusted urinary BPA, 3.80–26.48 µg/L) had almost twice the odds of implantation failure as women in the first quartile of exposure (≤ 1.69 µg/L). This trend remained after adjusting for IVF protocol. Crude Adjusteda IVF Protocol adjustedb 10.0 e r u l i a f ion 3.0 tta 2.0 n a lp 1.0 m i r f)o 0.5 I C % 5 9 ( R O 0.1 Q1 ≤ 1.69 Q2 1.70–2.33 Q3 2.34–3.79 Q4 ≥ 3.80 Quartiles of SG-adjusted urinary BPA concentration (μg/L) Figure 1. Crude and adjusted OR (95% CI) for the associations of quartiles (Q) of urinary BPA concen- trations in relation to implantation failure among 137 women undergoing 180 IVF cycles. aAdjusted for age (≥ 37 years vs. < 37 years) and day of embryo transfer (day 5 vs. day 3). bAdjusted for age (≥ 37 years vs. < 37 years), day of embryo transfer (day 5 vs. day 3), and IVF protocol (flare/antagonist vs. luteal). 981