Materials and Methods
The Partners Healthcare Institutional Review Board at the Massachusetts General Hospital reviewed and approved this study. IUI cycles at our institution from late December 2003 through early January 2012 that met the following criteria were eligible for inclusion: patients who underwent the IUI cycles underwent their first cycle within the study’s time frame at our institution, cycles were either natural or superovulation cycles using either clomiphene citrate or gonadotropins, total motile sperm count >1 million after washing at pretreatment evaluation, and known type of provider performing the procedure. For each woman, we included all IUI cycles that met the above criteria, up to cycle 6 or until a live birth was achieved. After a live birth was achieved, all future cycles for that woman were excluded.
Patients who underwent natural cycles did not receive clomiphene citrate or gonadotropins. Typically, patients undergoing superovulation received clomiphene citrate 50-100 mg orally on cycle days 3-7 or 5-9 or recombinant gonadotropin beginning on cycle day 3, followed by ovulation induction with 250 μg of recombinant human chorionic gonadotropin (hCG) (Ovidrel; Serono Laboratories, Norwell, MA) subcutaneously when the lead follicle reached at least 16 mm in diameter. Washed sperm meeting the above specifications was inseminated 35-36 hours after hCG injection. All patients were monitored with either ultrasound or both serum estradiol and ultrasound.
Cycles were stratified into 3 groups according to the type of provider who performed the procedure: attending physician, fellow physician (fellow) or RN. Regardless of the type of provider ultimately performing the procedure, the attending physician on call reviewed ultrasound findings and estradiol levels and made all medical decisions relating to the cycle, including dose of medication prescribed, time to follow-up, and when the procedure was to occur. Clinical decisions were made by physicians without knowledge of the type of provider who would ultimately perform the insemination, as patient appointments were made independently of these decisions. A patient was scheduled for her procedure as indicated by her cycle, and the provider was dictated by a predetermined schedule based on availability. Schedules were created 6 months in advance and distributed equally among providers of the same type. The schedules included coverage schemes for vacations as well as weekend coverage, and were created prior to any patients being booked for visits. On any given day, 1 provider (an RN, fellow physician, or attending physician) was scheduled to perform the inseminations. Rarely, changes in the daily schedules for IUI coverage occurred based on the volume of patients for that particular day and availability of staff. Infertility diagnosis was designated using Society for Assisted Reproductive Technologies categories. Note that at our institution, we define diminished ovarian reserve as serum follicle-stimulating hormone >10 (IU/L).
The primary outcome of interest was live birth; secondary outcomes included positive pregnancy test, defined as a positive serum beta-hCG and clinical pregnancy, defined as a normal intrauterine gestational sac seen on ultrasound at 6 weeks’ gestation. Descriptive data are reported as mean (±SD), median (interquartile range), or proportion, depending on data type and distribution. We used generalized estimating equations to perform repeated measures log binomial regression to account for the lack of independence among cycles from the same women while estimating the risk ratio (RR) and 95% confidence intervals (CIs) for the outcomes of interest. We did not identify any potential confounders that we believed would influence both the provider type and the primary outcome. However, we included in the model several variables thought to potentially influence IUI outcomes, such as the woman’s age, partner’s age, and cycle type, to account for possible differences among groups. A sensitivity analysis was performed to account for missing outcome data, and post hoc power and sample size calculations were done. All statistical analyses were performed using software (SAS 9.3; SAS Institute Inc, Cary, NC). All tests were 2-sided, and P values < .05 were considered statistically significant.
Results
A total of 1575 women had a first IUI cycle that met eligibility criteria initiated at Massachusetts General Hospital during the study period. These women underwent 3475 IUI cycles before achieving a live birth, discontinuing care, or completing 6 cycles. The median number of cycles per woman was 2.0 (interquartile range, 1.0–3.0). During the 8 years that cycles were evaluated in this study, 8 fellows and 14 RNs have been trained. In addition, 8 attending physicians are on staff.
Of the 3475 cycles, 395 (11.4%) were performed by an attending physician, 734 (21.1%) were performed by a fellow, and 2346 (67.5%) were performed by an RN. During the study period, the proportion of cycles performed by fellows increased from 14.4% at the start of the fellowship in 2005 to approximately 25% in later years as the fellowship expanded and the volume of IUI procedures increased. A similar pattern was observed for cycles performed by RNs, which increased from approximately 50-70% over the study period. Table 1 shows baseline characteristics for first cycles performed by RNs and fellows compared with attending physicians. The average age of women undergoing IUI was significantly higher among first cycles performed by a fellow compared with those performed by an attending ( P = .007). There were no significant differences in partner age, body mass index (kg/m 2 ), infertility diagnosis, cycle day 3 follicle-stimulating hormone (IU/L), number of follicles >12 mm, or total motile sperm count among the groups. An idiopathic diagnosis was the cause of infertility for one third of the cohort. Male factor infertility, diminished ovarian reserve, and combined factors were the next most frequent diagnoses.
| Characteristic | Full cohort, n = 1575 | Attending physician, n = 184 | Registered nurse, n = 1100 | P value a | Fellow physician, n = 291 | P value a |
|---|---|---|---|---|---|---|
| Woman’s age, y | 35.2 ± 4.4 | 34.8 ± 4.3 | 35.1 ± 4.5 | .42 | 35.9 ± 4.1 | .007 |
| <35 y | 700 (44.4) | 86 (46.7) | 510 (46.4) | .24 | 104 (35.7) | .05 |
| 35 to <38 y | 370 (23.5) | 50 (27.2) | 241 (21.9) | 79 (27.2) | ||
| 38 to <40 y | 217 (13.8) | 23 (12.5) | 145 (13.2) | 49 (16.8) | ||
| ≥40 y | 288 (18.3) | 25 (13.6) | 204 (18.5) | 59 (20.3) | ||
| Partner’s age, y | 36.9 ± 5.8 | 36.8 ± 5.5 | 36.7 ± 5.8 | .83 | 37.9 ± 6.1 | .06 |
| Body mass index, kg/m 2 | 23.0 (21.0–26.2) | 23.0 (21.0–26.0) | 23.1 (21.2–26.4) | .21 | 23.1 (21.1–26.1) | .36 |
| Cycle day 3 FSH, IU/L | 7.2 (5.9–8.9) | 7.6 (6.0–9.3) | 7.1 (5.9–8.8) | .15 | 7.1 (5.8–8.9) | .14 |
| No. of follicles >12 mm | 2.0 (1.0–2.0) | 2.0 (1.0–3.0) | 2.0 (1.0–2.0) | .24 | 2.0 (1.0–2.0) | .18 |
| Total motile sperm count, million | 27.5 (11.0–56.2) | 25.7 (11.7–61.0) | 27.7 (10.9–55.6) | .75 | 26.0 (10.9–57.6) | .93 |
| Diagnosis | .73 | .75 | ||||
| Idiopathic | 520 (33.0) | 55 (29.9) | 370 (33.6) | 95 (32.7) | ||
| Anovulatory/PCOS | 204 (13.0) | 25 (13.6) | 141 (12.8) | 38 (13.1) | ||
| Male factor | 221 (14.0) | 30 (16.3) | 145 (13.2) | 46 (15.8) | ||
| Diminished ovarian reserve | 205 (13.0) | 24 (13.0) | 138 (12.5) | 43 (14.8) | ||
| Tubal factor | 50 (3.2) | 9 (4.9) | 35 (3.2) | 6 (2.1) | ||
| Combined factors | 233 (14.8) | 26 (14.1) | 168 (15.3) | 39 (13.4) | ||
| Other b | 142 (9.0) | 15 (8.2) | 103 (9.4) | 24 (8.2) |
a Compares registered nurse to attending physician or fellow physician to attending physician
b Includes endometriosis, uterine factor, diethylstilbestrol exposure, single mother, same-sex relationship, other, and missing.
There were opposing trends in the proportion of clomiphene citrate and natural IUI cycles as cycle number increased ( Table 2 ). The use of clomiphene citrate decreased with increasing cycle number through cycle 4, at which point use plateaued. The proportion of natural IUI cycles steadily increased, from 12.1% in the first cycle to 30.7% in the sixth cycle. The median number of follicles >12 mm for the first 4 cycles was 2, and for cycles 4 and 5 was 1. Other parameters, including median number of follicles >12 mm, IUI preparation/sperm (millions), total gonadotropin dose, and peak estradiol remained relatively stable across cycles.
| Characteristic | Cycle 1, n = 1575 | Cycle 2, n = 918 | Cycle 3, n = 535 | Cycle 4, n = 239 | Cycle 5, n = 133 | Cycle 6, n = 75 |
|---|---|---|---|---|---|---|
| Cycle type | ||||||
| Gonadotropin | 924 (58.7) | 527 (57.4) | 307 (57.4) | 155 (64.9) | 78 (58.7) | 39 (52.0) |
| Clomiphene citrate | 462 (29.3) | 259 (28.2) | 136 (25.4) | 37 (15.5) | 22 (16.5) | 13 (17.3) |
| Natural | 189 (12.0) | 132 (14.4) | 92 (17.2) | 47 (19.7) | 33 (24.8) | 23 (30.7) |
| Cycle day 3 FSH, IU/L | 7.2 (5.9–8.9) | 7.2 (6.0–8.8) | 7.2 (6.0–8.8) | 7.3 (6.0–9.0) | 7.4 (6.1–8.9) | 7.5 (6.2–8.8) |
| Peak estradiol, pg/mL a | ||||||
| Day before hCG | 309.5 (207.0–471.0), n = 450 | 317.0 (214.0–476.0), n = 254 | 306.5 (228.0–498.0), n = 152 | 299.5 (190.5–440.0), n = 68 | 254.5 (190.0–380.0), n = 30 | 311.0 (270.0–465.0), n = 18 |
| Day of hCG | 478.0 (309.0–676.0), n = 415 | 464.0 (298.0–642.0), n = 209 | 437.0 (306.0–618.0), n = 126 | 466.0 (308.0–734.0), n = 58 | 395.0 (294.0–658.0), n = 33 | 414.0 (256.0–683.0), n = 15 |
| Total gonadotropins, IU a | 600.0 (450.0–875.0) | 675.0 (450.0–950.0) | 675.0 (475.0–1125.0) | 600.0 (450.0–1200.0) | 600.0 (400.0–1125.0) | 675.0 (450.0–1050.0) |
| No. of follicles >12 mm | 2.0 (1.0–2.0) | 2.0 (1.0–2.0) | 2.0 (1.0–2.0) | 2.0 (1.0–2.0) | 1.0 (1.0–2.0) | 1.0 (1.0–2.0) |
| IUI prep/sperm parameters, million | 27.5 (11.0–56.2) | 25.0 (10.2–52.1) | 24.5 (10.8–48.5) | 19.6 (9.2–47.0) | 17.5 (9.8–43.2) | 23.5 (12.0–45.4) |
Among all cycles, 14.0% resulted in a positive pregnancy test, 11.8% resulted in a clinical pregnancy, and 8.8% resulted in a live birth. The success of the IUI cycle did not differ based on the type of provider performing the procedure. After adjusting for the woman’s age, partner’s age, and cycle type, there was no difference in the probability of live birth for procedures performed by an RN compared with an attending physician (RR, 0.80; 95% CI, 0.58–1.1) or for those performed by a fellow compared with an attending physician (RR, 0.84; 95% CI, 0.58–1.2). Similar results were observed for positive pregnancy test and clinical pregnancy ( Table 3 ).
| Outcome | Incidence, n (%) | Crude RR (95% CI) | Adjusted RR a (95% CI) |
|---|---|---|---|
| Positive pregnancy test | |||
| Registered nurse | 330 (14.1) | 1.0 (0.77–1.3) | 1.0 (0.76–1.3) |
| Fellow physician | 101 (13.8) | 0.98 (0.71–1.3) | 1.0 (0.75–1.4) |
| Attending physician | 55 (13.9) | Reference | Reference |
| Clinical pregnancy b | |||
| Registered nurse | 281 (12.0) | 0.95 (0.71–1.3) | 0.95 (0.71–1.3) |
| Fellow physician | 78 (10.6) | 0.83 (0.60–1.2) | 0.90 (0.64–1.3) |
| Attending physician | 50 (12.7) | Reference | Reference |
| Live birth c | |||
| Registered nurse | 200 (8.5) | 0.77 (0.56–1.0) | 0.80 (0.58–1.1) |
| Fellow physician | 62 (8.4) | 0.76 (0.52–1.1) | 0.84 (0.58–1.2) |
| Attending physician | 44 (11.1) | Reference | Reference |
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