Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: Results of 4,062 intrauterine insemination cycles

Risk factors for high-order multiple pregnancy and multiple birth after controlled ovarian hyperstimulation: results of 4,062 intrauterine insemination cycles Richard P. Dickey, M.D., Ph.D.,a,b Steven N. Taylor, M.D.,a Peter Y. Lu, M.D.,a,b Belinda M. Sartor, M.D.,a,b Phillip H. Rye, M.D.,a and Roman Pyrzak, Ph.D.a a

The Fertility Institute of New Orleans and the b Section of Reproductive Endocrinology, Department of Obstetrics and Gynecology, Louisiana State University School of Medicine, New Orleans, Louisiana

Objective: To determine factors responsible for high-order multiple pregnancy (HOMP) and high-order multiple births when multiple cycles of controlled ovarian hyperstimulation–IUI (COH-IUI) are performed. Design: Retrospective analysis. Setting: Private infertility clinic. Patient(s): Women (n ⫽ 2,272) who underwent 4,067 consecutive COH-IUI cycles. Intervention(s): None. Main Outcome Measure(s): High-order multiple pregnancy rate, pregnancy rate (PR), and birth rate (PR) per cycle. Result(s): High-order multiple pregnancy was related to number of follicles of diameter ⱖ10 mm, age, and treatment cycle. For age ⬍32 years, HOMP was 6% for three to six follicles and 20% for seven or more follicles. For ages 32 to 37 years, HOMP was 5% for three to six follicles and 12% for seven or more follicles. In the first COH-IUI cycle, HOMP was 8% for three to six follicles and 15% for seven or more follicles. In the second cycle, HOMP did not occur unless there were more than six follicles. No HOMP occurred after the second cycle. Pregnancy rate did not increase significantly when there were more than four follicles. Continuing COH-IUI past the third cycle resulted in additional pregnancies in patients with one to eight follicles. Conclusion(s): High-order multiple pregnancy can be predicted by age and number of follicles of diameter ⱖ10 mm. Controlled ovarian hyperstimulation is not necessary to achieve satisfactory overall pregnancy rates if ovulation induction is continued past the third cycle in low responders. (Fertil Steril威 2005;83:671– 83. ©2005 by American Society for Reproductive Medicine.) Key Words: Controlled ovarian hyperstimulation, high-order multiple pregnancy, intrauterine insemination, multiple births

Infertility treatment has been estimated to be responsible for 224,000 excess multiple births in the United States between 1980 and 1997 (1). In 2000, 118,997 babies were born as twins, and 7,328 were born as triplets, quadruplets, and higher orders (2). Ovulation induction (OI) outside of assisted reproductive technologies (ART), IVF, and related procedures was estimated to be responsible for 20% of twin births and for 38% of triplet and higher order multiple births (HOMB), whereas ART procedures were responsible for 11% of twin births and 45% of HOMB in 2000 (3). Between 1998 and 2000, the percentage of HOMB caused by ART decreased from 48.6% to 42.5% (3). The decrease in ART-related HOMB coincided with a decrease in the average number of embryos transferred to women aged ⬍35 years, from 3.2 in 1998 to 2.9 in 2000 (4, 5). During the same Received March 1, 2004; revised and accepted October 28, 2004. Reprint requests: Richard P. Dickey, M.D., Ph.D., The Fertility Institute of New Orleans, 6020 Bullard Avenue, New Orleans, Louisiana 70128 (FAX: 504-246-9778; E-mail: [email protected]).

0015-0282/05/$30.00 doi:10.1016/j.fertnstert.2004.10.030

time period, HOMB caused by OI outside of ART was estimated to have increased by 246 births in real numbers and proportionally from 34.9% to 39.7% (3). At the present time, the proportional and real contribution of IVF to triplet and higher order multiple pregnancies (HOMPs) is diminishing and has the possibility of being eliminated entirely, whereas the contribution due to OI outside IVF is rising. Older recommendations to prevent HOMP and HOMB caused by OI and controlled ovarian hyperstimulation (COH) have included withholding human chorionic gonadotropin (hCG) administration when more than six follicles are ⱖ12 mm in diameter (6); when more than three follicles are ⱖ14 mm (7, 8) or ⱖ16 mm in diameter (9); when more than two (10) or three (11, 12) follicles are ⱖ18 mm in diameter; and when E2 concentration exceeds 400 pg/mL (13), 600 pg/mL (14), 1,000 pg/mL (6, 12), or 2,000 pg/mL (15, 16). Recent studies have suggested variously that HOMP could be reduced or prevented entirely by withholding hCG for patients aged ⱕ32 years, when four or more follicles are ⱖ10 mm in diameter and E2 is ⱖ862 pg/mL

Fertility and Sterility姞 Vol. 83, No. 3, March 2005 Copyright ©2005 American Society for Reproductive Medicine, Published by Elsevier Inc.

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(17), or when six or more follicles are ⱖ12 mm in diameter for patients aged ⬍35 years (18). The effectiveness of withholding hCG to prevent HOMP has been contested by a 2000 study that reported that withholding hCG when three or more follicles were ⱖ16 mm in diameter did not prevent HOMP in COH-IUI cycles (19). However, in the same study, no HOMP occurred when there were fewer than 10 total follicles on the day of hCG administration, and the incidence of HOMP was significantly increased when there were 7 or more total follicles or when E2 concentration was ⱖ1,385 pg/mL. The objective of the present study was to determine the factors associated with HOMP and HOMB in COH-IUI cycles by analyzing patient and stimulation cycle characteristics that had been prospectively entered into a computer database at the time the procedures were performed, at the time of the first postconception ultrasound (US), and after birth. We also wanted to determine how pregnancy rates and HOMP rates were affected when multiple cycles of COHIUI were performed. MATERIALS AND METHODS Patients The 2,272 patients and 4,067 cycles analyzed in the present report include all IUI cycles performed in a private infertility clinic between July 1987 and August 2002 in which hMG, urinary FSH, or recombinant FSH were administered. Patient characteristics, the type and dose of OI drug, sperm quality before and after processing, follicle size and number, and E2 concentrations on the day of hCG administration were entered into a computer database on the day that IUI was performed. Patients and their male partners signed informed consents for partner or donor insemination. Institutional review board approval was not considered necessary by that body because patients were treated according to usual and customary clinical practice. Patient Evaluation The majority of patients had been evaluated by hysterosalpingogram or laparoscopy; semen analysis; basal temperature or endometrial biopsy; and FSH, LH, PRL, DHEAS, and TSH concentrations before referral to our clinic. After arrival in our clinic, a postcoital test, pelvic US, midluteal phase serum P, and additional endocrine tests were performed as needed. If not performed previously, laparoscopy was performed before initiating IUI when there was a history of pelvic inflammatory disease, previous pelvic surgery, symptoms of dyspareunia or severe dysmenorrhea, or physical findings of endometriosis; otherwise, a hysterosalpingogram was performed if not performed previously, and diagnostic laparoscopy was performed after three cycles of COH-IUI if pregnancy had not occurred. Patients were classified as follows: as ovulatory dysfunction if they were anovulatory, had polycystic ovaries, or had 672

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luteal insufficiency (defined as midluteal P concentrations of ⬍1,600 ng/dL), and they did not have endometriosis or tubal factor; as endometriosis, with and without tubal involvement; as tubal factor if they had unilateral tubal obstruction or tubal adhesions without endometriosis; and as other if they had male factor, cervical factor, or unexplained infertility after laparoscopy and had regular cycles without luteal insufficiency or polycystic ovaries. Evaluation of Male Partner Intrauterine insemination with husband’s sperm was performed if sperm quality was below World Health Organization criteria for normal sperm (20) or if there were fewer than five progressively motile sperm on repeated overnight postcoital tests (21). Husband sperm was classified as follows: as WHO quality if there were ⱖ20 million count per mL, ⱖ40 million total count, progressive motility was ⱖ50%, and normal forms were ⱖ30% before processing; as IUI threshold quality if sperm did not meet WHO criteria but progressive motility was ⱖ30% and there were ⱖ5 million motile sperm before processing, with criteria previously determined as necessary to achieve a pregnancy rate of ⱖ8% when used for IUI (22); or as sub-IUI–threshold quality if sperm did not meet those criteria. Cryopreserved donor sperm with ⱖ30 million motile sperm was used if there was severe oligospermia or azoospermia. During the period of study, 51% of pregnancies resulting from hMG or FSH, exclusive of ART, were the result of IUI, and 49% were the result of hCG-timed intercourse. Treatment Protocol Patients received one of the following: hMG (Perganol [Serono Laboratories Inc., Norwell, MA], Humegon [Organon Inc., West Orange NJ], Repronex [Ferring Pharmaceuticals Inc., Tarrytown, NY]), purified follicle-stimulating hormone (urofollitropin [urinary FSH]), Metrodin [Serono]), or recombinant follicular stimulating hormone (Follistim [Organon] or Gonal F [Serono]). During their first cycle, patients received continuous hMG-FSH regimens: hMG or FSH (75 to 150 IU; hMG-FSH) starting on cycle day 3 (1,459 cycles), or hMG or FSH (75 to 150 IU) plus clomiphene citrate (CC; 50 to 100 mg; hMG-FSH & CC) starting on cycle day 3 (976 cycles), or a sequential CC– hMG-FSH regimen, consisting of CC (50 to 100 mg) for 5 days, followed by hMG-FSH (75 to 150 IU) for ⱖ3 days (CC ⫹ hMG-FSH; 1,618 cycles). In second and latter cycles, the dose of hMG-FSH was increased or the regimen was changed from sequential to continuous in patients who developed single follicles during the initial cycle. The dose of hMG-FSH was decreased or patients were changed from continuous to sequential regimen in cases in which patients developed excessive numbers of follicles or experienced hyperstimulation. Although there were differences between regimens in preovulatory E2 concentrations and number of follicles ⱖ10 mm, ⱖ12 mm, and Vol. 83, No. 3, March 2005

ⱖ14 mm in diameter, there were no statistical differences in number of follicles of diameter ⱖ16 mm, clinical pregnancy rate, numbers of gestational sacs on initial US, or pregnancies with three or more gestational sacs. Cycles were numbered consecutively from the first COH-IUI cycle performed in our clinic, with cycle numbering restarted after a clinical pregnancy, hysterosalpingogram, or laparoscopy.

cian, or to a maternal-fetal medicine specialist in cases of HOMP, for the remainder of prenatal care and delivery. Pregnancy outcome, length of gestation, and birth weight were determined from information provided by patients or their physicians in 95% of singleton pregnancies and in 100% of multiple gestations.

Human chorionic gonadotropin (10,000 IU) was administered when one or two follicles had diameter of ⱖ16 mm or when E2 concentration was ⱖ2,000 pg/mL and at least two follicles were ⱖ14 mm in diameter. Monitoring with pelvic US and serum E2 and LH was started after 7 days of stimulation for continuous regimens, or after the 3rd day of hMG-FSH for the sequential regimen, and was repeated every 1 to 2 days until criteria for hCG administration were met. A single IUI with fresh sperm, processed by wash or swim-down as described elsewhere (22), was performed 24 to 36 hours after hCG administration. Cryopreserved sperm was processed by wash, and IUI was performed 36 hours after hCG administration. In hMG-FSH cycles that did not include CC, patients received oral micronized P (200 mg; three or four times daily), beginning 36 hours after IUI.

Statistical Analysis Stepwise multiple logistic regression tests were performed for binomial outcomes (pregnant versus not pregnant, low order [one or two gestational sacs] pregnancy versus HOMP) by an SPSS/PC⫹ statistical program (SPSS Inc., Chicago, IL). Variables tested included E2 concentration; the number of follicles of diameter ⱖ10, 12, 14, 16, and 18 mm on the day of hCG administration; age; diagnosis; sperm quality; and cycle of COH-IUI. Two-tailed Fisher’s exact test was used to compare clinical pregnancy rates per cycle and incidence of twin and triplet or higher order implantations and births. Pregnancy and multiple pregnancy rates for the first three treatment cycles, stratified by patient and ovarian response variables, were analyzed by Mantel-Haenszel odds ratio, with confounding factors excluded. Cumulative pregnancy rates were plotted for diagnosis, age, sperm quality, and number of follicles. Results were considered significant when P was ⬍.05.

Follicle and E2 Measurement Vaginal US was performed with an ATL Ultramark 4 with a 5.0-MHz transducer (Advanced Technology Laboratories, Inc., Bothell, WA) from 1987 to 1993 and was performed with an ATL Ultramark 9 with a 5.0-MHz transducer after 1993. Follicle sizes are reported as the average of two dimensions, measured from the outer wall of one side to the inner wall of the other, in the most rounded configuration. Serum E2 was measured by coated tube RIA (DPC Coat-ACount; Diagnostic Products, Los Angeles, CA) until 1995, by monoclonal antibody (Tosoh; San Francisco, CA) during 1995 and 1996, and by chemiluminescence (ASC; Chiron/ Bayer, Norwood, MA) after 1996. Duplicate E2 assays were performed during periods of change from one analytical method to another. Compared with chemiluminescence, RIA results averaged 18% lower, and monoclonal antibody results averaged 22% higher. Results of monoclonal antibody assays and RIA assays were adjusted to chemiluminescence values during the present analysis. An E2 of 1,000 pg/mL by chemiluminescence is equivalent to 820 pg/mL by RIA and to 1,224 pg/mL by monoclonal antibody. Outcome Evaluation Patients were instructed to perform a urine pregnancy test if menses had not occurred 14 days after IUI. Positive urine pregnancy test results were confirmed by serum beta-hCG of ⱖ25 mIU. Clinical pregnancies were confirmed, and the number of gestational sacs (GS) was determined, by vaginal US that was performed 21 ⫾ 2 days after IUI. Tubal pregnancies were counted as clinical pregnancies with a single GS. After confirmation of a fetal heart rate, patients with continuing pregnancies were referred to their own obstetriFertility and Sterility姞

RESULTS Pregnancy Rates and Multiple Pregnancy Rates Clinical pregnancies occurred in 587 (14.4%) of 4,067 cycles. Multiple gestations occurred in 146 (24.9%) of 587 pregnancies: twins, 108 (18.4%); triplets, 26 (4.4%); quadruplets, 10 (1.7%); quintuplets, 1 (0.017%); and sextuplets, 1 (0.017%). Of the 26 pregnancies with three gestational sacs, 1 spontaneously aborted all sacs, 15 (58%) underwent spontaneous reduction that resulted in twin or singleton births, and 38% resulted in triplet births. Of 10 pregnancies with four sacs, 1 spontaneously aborted in the second trimester, 4 underwent spontaneous reduction that result in triplet births, and 5 elected to undergo selective reduction to twins. Of 2 pregnancies with more than four sacs, 1 quintuplet pregnancy delivered successively at 31 weeks of gestation, and 1 sextuplet pregnancy was selectively reduced to twins. There were 461 births, of which 99 (21.5%) were multiple: twins, 78 (16.9%) and triplets and higher order births, 21 (4.5%), with selectively reduced multiple pregnancies counted as if they had not been reduced. Relationship of Pregnancy and HOMP to Treatment Cycle and Preovulation Follicle Number Pregnancy rates and HOMP rates were inversely related to the treatment cycle number (P⬍.001; Table 1). Pregnancy rates per cycle decreased after the initial cycles, from 16.4% in cycle one to 15.1% in cycle two, to 10.9% in cycle three, to 5.4% in cycles four and five, and to 2.4% in cycle six, with no pregnancies in 41 attempts after cycle six. The decrease in 673

674 Dickey et al. Risk factors for HOMP

TABLE 1 Pregnancy and multiple pregnancy rates per cycle: all patients. ≥Quadruplets

No.

% Preg.

No.

% Preg.

No.

% Cycle

No.

% Births

No.

% Births

No.

% Births

1 2 3 4 5 6 7 Total

27 6 0 0 0 0 0 26

5.4 3.9 0.0 0.0 0.0 0.0 0.0 4.4

7 5 0 0 0 0 0 12

1.9 3.3 0.0 0.0 0.0 0.0 0.0 2.0

289 124 36 8 3 1 0 461

12.7 12.1 8.4 4.3 4.0 2.3 0.0 11.3

56 11 7 0 0 0 0 78

19.4 8.9 14.9 0.0 0.0 0.0 0.0 16.9

9 5 0 0 0 0 0 14

3.1 4.0 0.0 0.0 0.0 0.0 0.0 3.0

4 3 0 0 0 0 0 7

1.4 2.4 0.0 0.0 0.0 0.0 0.0 1.5

2279 1015 431 185 74 42 41 4067

373 153 47 10 3 1 0 587

16.4 15.1 10.9 5.4 5.4 2.4 0.0 14.4

70 25 13 0 0 0 0 108

18.8 16.3 27.6 0.0 0.0 0.0 0.0 18.4

3 Sacsc

≥4 Sacsc

Pregnanciesa 2 Sacsb Patients Cycle starting % % no. cycle No. Cycle No. Preg.

Births

Twins

Triplets

Note: % Cycle ⫽ percentage of cycles in which pregnancy or birth, respectively, occurred; % Preg ⫽ percentage of pregnancies in which 2, 3, or 4 sacs were present, respectively; % Births ⫽ percentage of births in which twins, triplets, or quadruplets or more occurres, respectively. a Relation of pregnancy rate to cycle number: ␹2 with 6 degrees of freedom, P⬍.0001. b Incidence of two sacs: cycles 1–3 vs. ⱖ4 cycles: Fisher’s two-tailed exact test, P⫽.0001. c Incidence of three or more sacs: cycles 1–2 vs. ⱖ3 cycles; Fisher’s two-tailed exact test, P⫽.0006. Dickey. Risk factors for HOMP. Fertil Steril 2005.

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pregnancy rate after the first cycle occurred despite use of higher doses of gonadotropins in the second and latter cycles. The total dose of gonadotropin and number of follicles of diameter ⱖ10 mm increased from 875 IU and 4.8, respectively, in the first cycle, to 942 IU and 5.1 in the second cycle and averaged 980 IU and 5.1 in the third through sixth cycles. After each cycle, approximately 50% of patients who failed to become pregnant did not attempt further COH-IUI cycles. The principal reasons patients gave for discontinuing COH-IUI were expense and the desire to switch to IVF. Three or more follicles of diameter ⱖ10 mm were present on the day of hCG administration in all pregnancies with at least three gestational sacs. The number of follicles of diameter ⱖ16 mm and ⱖ18 mm were particularly unsatisfactory for predicting HOMP. There were fewer than three follicles sized ⱖ12 mm in 15%, sized ⱖ14 mm in 45%, sized ⱖ16 mm in 72%, and sized ⱖ18 mm in 92% of pregnancies with at least three gestational sacs. In the first cycle, HOMP occurred in 7.9% of pregnancies when there were three to six follicles of diameter ⱖ10 mm and in 16.0% of pregnancies when there were seven or more follicles of diameter ⱖ10 mm. In the second cycle, HOMP did not occur when there were three to six follicles (P⫽.036), and it occurred in 24.4% of pregnancies when there were seven or more follicles. No HOMP occurred after the second cycle (P⫽.0006). Relationship of Pregnancy and HOMP to Patient Characteristics and Ovarian Response Variables significantly associated with pregnancy by stepwise logistic regression analyses were, in order of significance, treatment cycle (r ⫽ ⫺.108), number of follicles ⱖ12 mm in diameter (r ⫽ .084), sperm quality (r ⫽ .079), age (r ⫽ ⫺.059), diagnosis (r ⫽ ⫺.058), and E2 concentration (r ⫽ .038). Variables significantly associated with HOMP were, in order of significance, number of follicles of diameter ⱖ10 mm (r ⫽ .290), sperm quality (r ⫽ .144), age (r ⫽ ⫺.108), and treatment cycle number (r ⫽ ⫺.108). Variables not significantly associated with either HOMP or pregnancy per cycle were treatment regimen and number of follicles of diameter ⱖ14 mm, ⱖ16 mm, or ⱖ18 mm. Clinical pregnancy rates per cycle, and HOMP rates for the first three treatment cycles, arranged by patient characteristics and ovarian response to treatment, are presented in Table 2. Pregnancy rates were significantly decreased for tubal factor alone (P⫽.006) and for endometriosis with tubal involvement (P⫽.002; Table 2), for ages ⱖ38 years (P⬍.008; Table 2), and for sperm quality below IUI threshold values (P⬍.001; Table 2), Pregnancy rates were significantly increased when there were four follicles of diameter ⱖ10 mm, compared with one to three follicles (P⫽.027; Table 2). Pregnancy rates were not significantly increased, compared with four follicles, when there were five to six follicles (P⫽.275), seven to eight follicles (P⫽.535), or nine or more follicles (P⫽.066; Table 2). Pregnancy rates were Fertility and Sterility姞

significantly increased when E2 concentration was ⱖ1,000 pg/mL (Table 2). Triplet and higher order pregnancies were significantly increased for ages ⬍32 years compared with ages ⱖ32 years (P⫽.025; Table 2), for donor sperm compared with WHO quality sperm (P⫽.041; Table 2), for seven or more follicles of diameter ⱖ10 mm (17.0%) compared with three to six follicles of such diameter (5.6%; P⬍.001; Table 2), and for E2 of ⱖ1,000 pg/mL (13.6%) compared with E2 of ⬍1,000 pg/mL (5.1%; P⫽.003; Table 2). The lowest E2 concentration on the day of hCG administration, in a cycle that resulted in a triplet pregnancy was 397 pg/mL. Very highorder pregnancies, with four or more GS, were significantly increased for E2 of ⱖ1,000 pg/mL (6.0%) compared with ⬍1,000 pg/mL (0.4%; P⬍.001), and for seven or more follicles (6.5%) compared with the case of four to six follicles (1.4%; P⫽.036; Table 2). Relationship of HOMP to Age, Preovulation Follicle Number, and E2 Concentration The collective effect of age, follicle number, and E2 concentration on the incidence of singleton, twin, and high-ordermultiple pregnancies and of singleton, twin, and high-ordermultiple births over the first three cycles of COH-IUI, in patients without tubal factor or poor sperm quality, stratified by age, E2 concentration, and follicle numbers at which significant differences were identified in Table 2, are summarized in Table 3. For age ⬍32 years, the incidences of HOMP and HOMB were 5.9% and 2.4%, respectively, for three to six follicles of diameter ⱖ10 mm, and were 20.5% and 15.7%, respectively, for seven or more follicles. For ages 32 to 37 years, the incidences of HOMP and HOMB were 5.2% and 2.7%, respectively, for three to six follicles and were 12.1% and 6.7%, respectively, for seven or more follicles. No HOMP occurred for age ⱖ38 years, irrespective of the number of follicles (P⫽.014). For ages 32 to 37 years, the incidence of HOMP was increased threefold when E2 was ⱖ1,000 pg/mL: from 3.1% to 9.7% for three to six follicles and from 3.8% to 16.7% for seven or more follicles (P⫽.022). Cumulative Pregnancy Rates in Extended Cycles of Treatment Cumulative pregnancy rates through five cycles, presented by diagnosis, age, sperm quality, and number of preovulatory follicles, are shown in Figure 1. For all diagnoses except tubal factor, cumulative pregnancy rates reached 60% by the fifth cycle when patients with poor sperm quality and age ⱖ38 years were excluded (Fig. 1A). No pregnancies occurred in patients with tubal factor or endometriosis involving fallopian tubes after the second cycle in 54 additional attempts (P⫽.002). For other diagnoses, pregnancies occurred at a decreased rate after the third cycle. For ages ⬍35 years, cumulative pregnancies reached 64% by the fifth cycle but increased by only 4% per cycle after the 675

TABLE 2 Relationship of patient characteristics and ovarian response to clinical pregnancy and multiple pregnancy rates—treatment cycles 1–3. Pregnancies Variable Diagnosisa Ovulatory dysfunction Cervical, male, unexplained endometriosis Without tubal invol. With tubal invol. Tubal factor without endometriosis Ageb (y) ⬍32 32–34 35–37 38–40 41–43 Spermc WHO IUI threshold Sub-IUI threshold Donor No. Follicles ⬎10 mmd 1 2 3 4 5–6 7–8 ⱖ9 Estradiold (pg/mL) ⬍500 500–999 1,000–1,499 1,500–1,999 ⱖ2,000

2 Sacs OR

95% CI

P

n

%

≥3 Sacs n

Cycles (n)

n

%

1,068 553

208 106

19.5 19.2

— — 0.98 0.76–1.27

— NS

41 19.5 20 9.5 8 3.8 26 24.5 11 10.4 2 1.9

753 126 226

121 10 26

16.1 7.9 11.5

0.79 0.62–1.01 0.36 0.18–0.69 0.54 0.35–0.83

NS .002 .006

26 21.5 1 10.0 4 15.4

1,203 636 535 379 182

129 120 86 49 11

19.0 19.2 16.1 12.9 6.0

— 0.99 0.81 0.63 0.27

1,056 971 213 347

194 164 19 77

18.4 16.9 8.9 22.2

— — — 43 0.90 0.72–1.14 NS 37 0.41 0.25–0.68 ⬍.001 4 1.27 0.94–1.71 NS 13

22.2 14 7.2 22.6 11 6.7 21.0 0 0.0 16.9 12 15.6

5 3 0 4

2.6 1.8 0.0 5.2

204 303 334 304 377 264 366

23 40 56 60 82 58 95

11.3 13.2 16.8 19.7 21.8 22.0 26.0

— 1.19 1.58 1.94 2.18 2.22 2.76

— — 0.69–2.07 NS 0.94–2.67 NS 1.15–3.25 .016 1.33–3.60 .003 1.31–3.74 .004 1.67–4.52 ⬍.001

0 9 10 14 16 10 27

0.0 0 0.0 0 23.2 0 0.0 0 17.8 3 5.4 0 23.3 3 5.0 1 19.5 5 6.1 1 16.9 8 13.6 4 28.4 18 18.9 6

0.0 0.0 0.0 1.7 1.2 6.9 6.3

538 798 401 188 178

90 146 95 43 45

16.7 18.3 23.7 22.9 25.6

— 1.11 1.54 1.48 1.68

— 0.84–1.49 1.12–2.13 0.98–2.22 1.21–2.53

8 32 21 9 14

8.9 4 4.4 0 21.9 8 5.5 1 23.1 11 11.6 4 20.9 6 14.0 4 31.1 8 17.8 3

0.0 0.7 4.2 9.3 7.0

6 0 1

%

≥4 Sacs n %

5.0 2 1.6 0.0 0 0.0 3.8 0 0.0

— — 46 20.1 24 10.5 10 7.8 0.77–1.26 NS 28 23.3 7 5.8 1 0.8 0.62–1.07 NS 19 22.1 6 7.0 1 1.2 0.45–0.88 .008 5 10.2 0 0.0 0 0.0 0.15–0.51 ⬍.001 1 9.1 0 0.0 0 0.0

— NS .01 NS .016

Note: CI ⫽ confidence interval; WHO ⫽ initial sperm quality ⱖ World Health Organization criteria of 20 million concentration, 40 million total count, 50% progressive motility, 30% normal forms; IUI threshold ⫽ initial sperm quality less than WHO criteria but ⱖ5 million total motile sperm and ⱖ30% initial motility; Sub-IUI threshold ⫽ initial motile sperm count ⬍5 million or motility ⬍30%. a Patients age ⱖ 38 years and cycles with total initial motile sperm count ⬍ 5 million or motility ⬍ 30% were excluded. b Patients with endometriosis with tubal involvement, tubal factor, and cycles with total initial motile sperm count ⬍ 5 million or motility ⬍ 30% were excluded. c Patients aged ⱖ 38 years, with endometriosis with tubal involvement, and with tubal factor were excluded. d Patients aged ⱖ 38 years, with endometriosis with tubal involvement, with tubal factor, and with cycles with total initial motile sperm count ⬍ 5 million or motility ⬍ 30% were excluded. Dickey. Risk factors for HOMP. Fertil Steril 2005.

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Fertility and Sterility姞

TABLE 3 Pregnancy rates per cycle and multiple rates per pregnancy: relation to age, number of follicles ≥ 10 mm, and E2 (pg/mL), in gonadotropin IUI cycles. 1–2 Follicles ≥ 10 mm E2 (pg/mL) by age group ⱕ32 y E2 ⬍ 1,000 E2 ⱖ 1,000 32–37 y E2 ⬍ 1,000 E2 ⱖ 1,000 38–43 y E2 ⬍ 1,000 E2 ⱖ 1,000

2 2 Cycles Preg Sacs Births Twins Cycles Preg Sacs (n) (%) (%) (%) (%) (n) (%) (%) 223 86 37 248 204 44 171 156 15

14.3 14.5 13.5 11.7 10.8 15.9 6.4 5.7 13.3

6.2 3.7 20.0 24.1 22.7 28.6 9.1 11.1 0.0

12.1 12.4 8.1 9.7 8.8 13.6 4.1 3.2 13.3

≥ 7 Follicles > 10 mm

3–6 Follicles > 10 mm

7.4 4.3 33.3 16.7 11.1 33.3 14.3 20.0 0.0

450 298 152 508 352 156 245 184 61

22.7 22.1 23.7 18.9 18.5 19.9 13.9 12.5 18.5

17.6 19.7 13.9 20.8 23.1 16.1 14.7 17.4 9.1

≥3 Sacs (%) (≥4) 5.9 6.1 5.6 5.2 3.1 9.7 0.0 0.0 0.0

(2) (1) (1) (0) (0) (0) (0) (0) (0)

Births Twins (%) (%) 18.7 18.1 19.7 14.4 13.9 15.4 9.4 7.6 8.2

16.7 20.4 10.0 17.6 14.3 25.0 5.3 7.1 0.0

Triplets (%) (≥4) 2.4 1.8 3.3 2.7 2.0 4.2 0.0 0.0 0.0

(1) (0) (1) (0) (0) (0) (0) (0) (0)

2 Cycles Preg Sacs (n) (%) (%) 344 143 201 272 106 166 84 30 54

24.4 18.2 28.8 27.2 24.5 28.9 16.7 20.0 14.8

20.5 3.8 28.1 27.0 23.1 29.2 0.0 0.0 0.0

≥3 Sacs (%) (≥4) 20.5 23.1 19.3 12.1 3.8 16.7 0.0 0.0 0.0

(8) (0) (8) (2) (0) (2) (0) (0) (0)

Births Twins Triplets (%) (%) (%) (≥4) 20.3 13.4 25.4 22.0 21.7 22.3 10.7 10.0 11.1

15.7 10.5 17.6 26.7 17.4 32.4 0.0 0.0 0.0

18.8 15.8 19.6 6.7 0.0 10.8 0.0 0.0 0.0

(4) (0) (4) (2) (0) (2) (0) (0) (0)

Note: Estradiol measured by CHL. 1000 pg/mL by CHL ⫽ 820 pg/mL by RIA and 1224 pg/mL by monoclonal antibody. Cycles 1–3: Patients without tubal factor, endometriosis with tubal involvement, or poor sperm quality. Age ⬍ 32 y: ⱖ 7 follicles vs. 3 to 6 follicles; ⱖ 3 implantations per pregnancy, P⫽.004; triplet or higher order birth, P⫽.008. Age ⱖ 38 y: ⱖ 3 follicles vs. age ⬍38 years, ⱖ 3 follicles; ⱖ 3 implantations per pregnancy P⫽.014. For 3– 6 follicles no HOMP (ⱖ3 sacs and ⱖ4 sacs) occurred after the first cycle of FSH/hMG-IUI. For ⱖ7 follicles no HOMP (ⱖ3 sacs and ⱖ4 sacs) occurred after the second cycle of FSH/hMG-IUI. No HOMP occurred when three cycles of CC-IUI were performed before COH-IUI without pregnancy and no HSG or surgical procedures had been performed between CC-IUI and COH-IUI. Dickey. Risk factors for HOMP. Fertil Steril 2005.

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FIGURE 1 Cumulative pregnancy rate. (A) Diagnosis. Male, Cervical, and Unexplained ⫽ normal cycles without endometriosis or tubal factor. Ovulatory Dysfunction ⫽ anovulatory, polycystic ovaries, or luteal insufficiency. Endometriosis ⫽ without tubal involvement. Tubal Factor ⫽ endometriosis with tubal involvement and tubal adhesions or unilateral tubal obstruction. Patients aged ⱖ38 years and cycles with total initial motile sperm count of ⬍5 million or motility of ⬍30% were excluded. (B) Age. Patients with endometriosis, tubal factor, and cycles with total initial motile sperm count of ⬍5 million or motility of ⬍30% were excluded. (C) Sperm characteristics. Donor ⫽ cryopreserved sperm with ⱖ30 million motile count. WHO Standard ⫽ ⱖ40 million total count, ⱖ50% progressive motility, 30% normal forms. IUI Threshold ⫽ less than WHO Standard but ⱖ5 million total motile sperm and ⱖ30% initial motility. ⬍IUI Threshold ⫽ initial motile sperm count of ⬍5 million or motility ⬍30%. Patients aged ⱖ38 years and patients with tubal factor were excluded. (D) Follicle count. Patients aged ⱖ38 years, with tubal factor, and cycles with total initial motile sperm count of ⬍5 million or motility of ⬍30%, were excluded.

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FIGURE 1 Continued

Dickey. Risk factors for HOMP. Fertil Steril 2005.

third cycle (Fig. 1B). For ages 35 to 37 years, cumulative pregnancies also reached 64% by the fifth cycle and increased by 9% per cycle after the second cycle. For ages 38 to 40 years and 41 to 43 years, cumulative pregnancies reached 44% and 26%, respectively, in the fourth cycle, with no further pregnancies in 18 and 17 attempts, respectively. Cumulative pregnancy rates reached 72% for donor sperm, 52% for WHO-quality sperm, 50% for IUI thresholdFertility and Sterility姞

quality sperm, and 21% for sub-IUI threshold– quality sperm by the third cycle (Fig. 1C). For sub-IUI– quality sperm, no additional pregnancies occurred after the third cycle in 15 further attempts. Pregnancies occurred after the third cycle of COH-IUI in inverse relation to the number of preovulatory follicles (Fig. 1D). No clinical pregnancies occurred after the third cycle in patients who developed nine or more follicles. Patients who 679

developed fewer than nine follicles continued to become pregnant at a reduced rate per cycle after the third cycle. In patients aged ⬍38 years without tubal factor or poor sperm quality, cumulative pregnancies reached ⬎70% in three cycles when there were at least nine follicles, in four cycles when there were seven or eight follicles, and in five cycles when there were five or six follicles. After five cycles, cumulative pregnancies reached 64% when there were three or four follicles and reached 47% when there were one or two follicles. DISCUSSION The 2,272 patients and 4,062 cycles that are included in the present study have the effect of doubling the total number of patients and cycles for which pregnancy rates for COH-IUI have been reported for more than one cycle. This is the first large series in which birth outcome has also been reported. The present study confirms the findings of previous investigators (17, 23–26) that follicles of diameter ⱖ10 mm on the day of hCG administration need to be measured when attempting to determine the risk of HOMP occurring in COHIUI cycles. The finding that fewer than three follicles of diameter ⱖ16 mm were present on the day of hCG administration in 72% of HOMP may explain why a recent study (19) did not find a correlation between follicles of this size and HOMP but did find a relationship between the number of total follicles and HOMP. Factors significantly related to pregnancy and HOMP in addition to number of follicles of diameter ⱖ10 mm, were age, E2 concentration, and number of previous cycles of COH-IUI. Critical points at which significant increases in HOMP occurred were three to six follicles and seven or more follicles, age ⬍32 years and ⱖ38 years, and E2 concentration of ⱖ1,000 pg/mL. The average pregnancy rate in cycles one through three was not significantly increased when there were more than four follicles of diameter ⱖ10 mm. In marked contrast to the failure of pregnancy rates to increase when there were more than four follicles, the incidence of HOMP increased significantly when higher numbers of follicles were present the day of hCG administration. The incidence of HOMP was increased from 5% to 6% with four to six follicles present, to 14% with seven to eight follicles present, and to 19% with nine or more follicles present. We conclude from these results that use of COH-IUI to develop more than four preovulatory follicles did not increase the probability of pregnancy but significantly increased the possibility of HOMP if seven or more follicles developed. The finding that pregnancy rate per cycle decreased after the first cycle of COH-IUI was expected. Pregnancy rates decreased slightly after the first cycle and decreased markedly after the third cycle for most patients. The finding that the incidence of HOMP per pregnancy also decreased after the first cycles of COH-IUI was not anticipated and had not been reported previously. High-order multiple pregnancy did not occur after the first cycle unless there were more than 680

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seven follicles and did not occur after the second cycle regardless of the number of follicles. This may indicate that the dose of OI drugs can be safely increased after the first cycle; however, the seven-follicles-or-more delineator of increased risk of HOMP must still be respected. A summary table was prepared, by using the results of this study, to show the incidence of singleton, twin, and highorder-multiple pregnancies and of singleton, twin, and highorder-multiple births during the first three cycles of COHIUI, according to the follicle numbers, ages, and E2 concentration at which significant differences occurred in patients without tubal factor or poor sperm quality. For patients at highest risk for HOMP because of age ⬍32 years and seven or more follicles of diameter ⱖ10 mm, the incidence of HOMP was 20%. Also at high (10% to 17%) risk for HOMP were patients aged 32 to 37 years with E2 concentration of ⱖ1,000 pg/mL by chemiluminescence. At moderate (3% to 6%) risk for HOMP were patients aged ⬍38 years with three to six follicles and aged 32 to 37 years with seven or more follicles and E2 concentration of ⬍1,000 pg/mL. At lowest risk for HOMP were patients aged ⱖ38 years and patients with one or two follicles, none of whom experienced HOMP in the present study. The incidence of HOMB was half that of HOMP because, as reported elsewhere (27), 53% of patients with three GS on their initial US undergo spontaneous reduction to twins or singletons, and 65% of patients with four or more GS undergo spontaneous reduction to triplets, twins, or singletons before the end of the first trimester. The collective effect of follicle number, age, and E2 concentration on the incidence of HOMP in COH-IUI has previously been examined in three large retrospective studies (17–19). Gleicher et al. (19) observed a 19% HOMP rate in 3,347 COH-IUI cycles when there were ⱖ10 total follicles and E2 concentration was ⱖ935 pg/mL by chemiluminescence, but they did not stratify patients by age. Tur et al. (17) observed an 18% HOMP rate in 1,878 COH-IUI pregnancies when there were six or more follicles of diameter ⱖ10 mm, E2 concentration was ⬎862 pg/mL by RIA, and age was ⱕ32 years. Dickey et al. (18) observed a 14% HOMP rate in 1,397 COH-IUI cycles, when there were at least six follicles of diameter ⱖ12 mm and age was ⬍35 years, but they did not stratify patients by E2 concentration. Despite minor differences between these studies, when they are combined with the present study, they provide unequivocal evidence that the risk of HOMP is related to the number of preovulatory follicles and that patients at highest risk for HOMP can be identified before administering hCG. Whether HOMP can be significantly reduced by canceling cycles at high risk because of the number of preovulatory follicles, without unduly affecting overall pregnancy rates, has been a subject of controversy. Gleicher et al. (19) concluded that if cycles were canceled when there were at least seven total preovulatory follicles, HOMP would still occur in 2% to 4% of pregnancies, depending on E2 concentration, Vol. 83, No. 3, March 2005

and would result in an unacceptable decrease in the possibility of patients conceiving. On the basis of results of the present study, we estimate that if hCG had been withheld from patients aged ⬍38 years when seven or more preovulatory follicles of diameter ⱖ10 mm were present during the first two cycles, HOMP and HOMB would have been reduced by 70% and 80%, respectively. This would have required canceling 26% of cycles for ages ⬍38 years, and 15% of all cycles. The pregnancy rate in the remaining cycles for patients aged ⬍38 years would have averaged 17% per cycle, and the HOMP and HOMB rates would have been 4% and 2%, respectively. In addition, if hCG had been withheld when there were three to six follicles in the first cycle, no HOMP would have occurred, but we would have had to cancel 55% of cycles for patients aged ⬍38 years, and 39% of all cycles. Clearly, canceling cycles for three or more follicles is impractical as the only means of preventing HOMP. Nonetheless, the present study shows that HOMP and HOMB caused by COH-IUI can be significantly reduced while only moderately affecting overall pregnant rates by withholding hCG when seven or more preovulatory follicles of diameter ⱖ10 mm are present. Other methods to reduce the incidence of HOMP caused by OI include use of low doses of gonadotropins (28) or GnRH (29), continuation of the lowest dose of gonadotropin that results in ovulation for three cycles before increasing the dose (30), use of CC-IUI for three cycles before COH-IUI (31), and aspiration of more than three follicles before IUI (32). Each of these has been reported to result in HOMP rates of ⬍3% and in pregnancy rates of ⬎19% per cycle under ideal conditions. All of these methods lack corroboration by large randomized prospective studies. In agreement with the majority of previous studies (8, 33–38), COH-IUI continued to result in pregnancies after the third cycle in most patients. Other studies (39 – 43) have not found COH-IUI to be effective after the third cycle. The observation in the present study, that the occurrence of pregnancies after the third cycle of COH-IUI was dependent on the number of preovulatory follicles, has not been reported elsewhere and may explain inconsistent results of earlier studies. Patients who developed fewer than nine follicles continued to became pregnant after three cycles of COH-IUI in inverse proportion to the number of preovulatory follicles developed during COH. Patients who consistently developed nine or more follicles of diameter ⱖ10 mm reached cumulative pregnancy rates of 70% by the third cycle of COH-IUI, with no additional clinical pregnancies after the third cycle. Patients who consistently developed seven to eight follicles and five to six follicles also reached cumulative pregnancy rates of 70% but required four and five cycles, respectively, to do so, and pregnancy rates per cycle decreased after the third cycle. Patients who consistently developed three to four and one to two follicles Fertility and Sterility姞

reached cumulative pregnancy rates of 64% and 47%, respectively, by the fifth cycle. Cumulative pregnancy results are inherently unreliable unless all patients who do not become pregnant continue to be treated for the maximum number of cycles, because patients with a low possibility of pregnancy may discontinue treatment more often than those with a good prognosis. Cumulative pregnancy rates presented in the present study are shown for comparative purposes only and should not be understood to represent overall pregnancy rates that can be achieved by a particular patient or group of patients. Despite the problems associated with retrospective studies and cumulative pregnancy rates, this study has a number of strengths. One is that follicle data and other pertinent information were collected at the time that IUI was performed, with the intention of later analysis when a sufficient number of cases had been collected. Second, follow-up of patient outcome was 100% for the initial number of gestational sacs and for birth outcome in multiple pregnancies and was 95% for birth outcome of singleton pregnancies. The principal weakness of this study, in addition to its retrospective nature, is that the number of patients treated for more than three cycles was low. This is a problem in all clinical studies in which patients are primarily responsible for the cost of their treatment (44). The incidence of quadruplet and higher order births may have been overstated because some of the pregnancies with four or more gestational sacs that underwent selective reduction to twins might have aborted during the second trimester. In conclusion, our results, in concert with results of previous large retrospective studies, demonstrate that patients at high risk for HOMP can be identified by counting all follicles of diameter ⱖ10 mm. We propose that by withholding hCG when there are seven or more preovulatory follicles of diameter ⱖ10 mm, physicians can significantly reduce the incidence of HOMP resulting from COH-IUI. The results of this retrospective analysis suggest that if minimal stimulation is used for the first two cycles and treatment is continued for more than three cycles, HOMP may be significantly reduced without severely affecting overall pregnancy rates. Whether this will indeed reduce HOMP without affecting overall pregnancy rates, and whether higher doses of gonadotropin can be safely used after the second cycle and in patients aged ⱖ38 years without risking HOMP, as results of the present study suggest, will require multiclinic prospective studies. Whether IVF should replace OI with gonadotropins in all patients, as has been suggested by other investigators (19), will depend on individual circumstances and the availability of advanced reproductive technologies. Finally, we believe that there is now sufficient evidence to support a conclusion that use of COH, rather than minimal stimulation, to increase the probability of pregnancy is unnecessary and increases the incidence of HOMP without increasing patients’ overall possibility of becoming pregnant. 681

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