Relationship of follicle numbers and estradiol levels to multiple implantation in 3,608 intrauterine insemination cycles.

OBJECTIVE: To determine the relationship of follicle numbers and estradiol (E(2)) levels to multiple implantations in human menopausal gonadotropin (hMG) and clomiphene citrate (CC) cycles. DESIGN: Fifteen-year prospective study. SETTING: Private infertility clinic. PATIENT(S): Women who underwent 3608 cycles of husband or donor intrauterine insemination (IUI). INTERVENTION(S): Ovulation induction (OI) with CC, hMG, or CC+hMG. MAIN OUTCOME MEASURE(S): Pregnancy and multiple implantations. RESULT(S): Triplet and higher-order implantations-but not twin implantations-were related to age, E(2) levels, and number of follicles > or = 12 mm and > or = 15 mm, but not number of follicles > or = 18 mm, in hMG and CC+hMG cycles. For patients less than 35 years old, three or more implantations tripled when six or more follicles were > or = 12 mm, in CC, hMG, and CC+hMG cycles, and when E(2) was > or = 1000 pg mL in hMG and CC+hMG cycles. For patients 35 or older, pregnancy rates in hMG and CC+hMG cycles doubled when six or more follicles were > or = 12 mm, or E(2) levels were >1000 pg mL, whereas 3 or more implantations were not significantly increased. CONCLUSIONS: Withholding hCG or IUI in CC, hMG, and CC+hMG cycles when six or more follicles are > or = 12 mm may reduce triplet and higher-order implantations by 67% without significantly reducing pregnancy rates for patients under 35 years of age.

Comparison of the sperm quality necessary for successful intrauterine insemination with World Health Organization threshold values for normal sperm.

OBJECTIVE: To compare World Health Organization threshold values for normal sperm with the initial sperm quality necessary for successful IUI. DESIGN: Retrospective study. SETTING: Private fertility clinic. PATIENT(S): One thousand eight hundred forty-one couples undergoing 4,056 cycles of IUI. INTERVENTION(S): Intrauterine insemination. MAIN OUTCOME MEASURE(S): Relation of initial sperm quality to fecundity. RESULT(S): Progressive motility and total motile sperm count were the initial sperm characteristics most closely related to pregnancy on discriminant analysis. The per-cycle pregnancy rate averaged 11.1% during the first three IUI cycles. Pregnancy rates were > or = 8.2% per cycle when the initial sperm values were a concentration of > or = 5 X 10(6)/mL, a total count of > or = 10 X 10(6), progressive motility of > or = 30%, or a total motile sperm count of > or = 5 x 10(6). Minimal increases in fecundity occurred when initial values were greater than these threshold levels. The lowest initial values that resulted in pregnancy were a concentration of 2 x 10(6)/mL, a total count of 5 x 10(6). motility of 17%, and a total motile sperm count of 1.6 X 10(6). Pregnancy rates were <3.6% when initial values were between the threshold levels and the lowest levels. CONCLUSION(S): The sperm quality that is necessary for successful IUI is lower than World Health Organization threshold values for normal sperm. Intrauterine insemination is effective therapy for male factor infertility when initial sperm motility is > or = 30% and the total motile sperm count is > or = 5 X 10(6). When initial values are lower, IUI has little chance of success.

Relationship of clomiphene dose and patient weight to successful treatment.

Our objective was to examine the relationship between patient weight and the dose of clomiphene required for pregnancy so as to assess the validity of recommendations that the dose of clomiphene be limited to 100 mg. We retrospectively analysed the weight-dose relationship in 1681 clomiphene pregnancies and the relationship between dose and pregnancy, births, multiple births, number of pre-ovulatory follicles and endometrial thickness in 2841 cycles of clomiphene treatment, 25-250 mg, for 5 days before intrauterine insemination (IUI). Doses of clomiphene >100 mg/day were used before pregnancies in 27.4% of patients who weighed >90 kg and in 14.7% of all pregnancies. In IUI cycles, pregnancies and births, but not multiple births or abortions, were related to dose. An increase in dose from 25 to 100 mg resulted in higher pregnancy and birth rates, and in an increase in the average number of pre-ovulatory follicles > or =12 mm in diameter, from 2.0 to 2.8, with no additional increase at higher doses. Endometrial thickness and cycle day of insemination were not related to dose. We conclude that doses of clomiphene may safely be increased beyond 100 mg, and that doses > or =100 mg are required in significant numbers of patients.

Doppler ultrasound investigation of uterine and ovarian blood flow in infertility and early pregnancy.

This review describes the current use of Doppler ultrasound to examine blood flow in the uterus and ovaries in infertile patients and during early pregnancy. The basics of Doppler ultrasound and the different methods of measuring blood flow are discussed from the viewpoint of the clinician who may be unfamiliar with Doppler physics and terminology. Normal values in the menstrual cycle and the relationship of uterine and ovarian blood flow to infertility and to implantation following in-vitro fertilization are presented. Normal values for uterine blood flow in the first 16 weeks of pregnancy and the effect of sex steroids and ovulation induction on their values are described. The possible relationship of defective uterine blood flow to recurrent abortion is examined. New areas of investigation, such as the effect of standing on blood flow, and the effect of drugs are explored. The findings of this review indicate that Doppler blood flow studies may provide significant information about possible causes of some disorders of infertility and early pregnancy and methods of treatment for the same.

Incidence of spontaneous abortion in clomiphene pregnancies.

The purpose of this study was to determine whether the use of clomiphene results in a higher incidence of spontaneous abortion than occurs naturally in subfertile patients. Reproductive outcomes of 1744 clomiphene pregnancies were compared to outcomes of 3245 spontaneous pregnancies in a prospective study. Abortion was classified as clinical if a sac was seen on ultrasound or if it occurred after 6 gestational weeks, and as preclinical if a quantitative human chorionic gonadotrophin (HCG) was > or = 25 mIU and no sac was seen or abortion occurred earlier. The overall incidence of abortion was higher for clomiphene pregnancies (23.7%), compared with spontaneous pregnancies (20.4%) (P < 0.01). Preclinical abortions were increased by clomiphene for all ages (5.8 versus 3.9%, P < 0.01) and for age > or = 30 years (8.0 versus 4.9%, P < 0.001), but not for age < 30 years (3.7 versus 3.0%). Clinical abortions were increased by clomiphene for age < 30 years (15.9 versus 11.2%) (P < 0.01), but not for age > or = 30 years (20.1 versus 22.3%) or all ages (18.0 versus 16.4%). Clinical abortions occurred 22% less often following clomiphene compared with spontaneous pregnancies for patients with luteal insufficiency (18.3 versus 23.6%, P < 0.05). We conclude that the increase in abortion due to clomiphene is small and may be related to different causes for women aged < 30 and > or = 30 years, and also that clomiphene may decrease clinical abortions in patients with luteal insufficiency.

Development, pharmacology and clinical experience with clomiphene citrate.

This review describes the development and pharmacology of clomiphene and those specific characteristics of both drug and patients which determine its clinical efficacy. The studies reviewed describe clinical observation of patient characteristics (age, additional infertility diagnosis, semen quality), vaginal ultrasound observations of ovaries (number and size of pre-ovulatory follicles) and endometrial lining (thickness, pattern) in 2841 clomiphene cycles in patients who required intrauterine insemination (IUI) because of poor sperm quality or an unsatisfactory postcoital test. They show that (i) conception in clomiphene cycles is related to the number and size of pre-ovulatory follicles, endometrial thickness, patient age, pelvic adhesions, type of anovulatory disorder and semen quality; (ii) pregnancy rates per clomiphene-IUI cycle are constant through at least six cycles; (iii) multiple births cannot be prevented by withholding human chorionic gonadotrophin or advising against coitus when multiple pre-ovulation follicles are present unless all follicles down to 10-12 mm diameter are counted. We also reviewed pregnancy outcome (number of gestational sacs, babies, preclinical and clinical abortion, ectopic pregnancy and birth sex) in 1744 clomiphene pregnancies from our clinic. We found that (i) preclinical and clinical abortions are increased only slightly by clomiphene use, compared to spontaneous pregnancy; (ii) clinical abortions are decreased in patients with polycystic ovaries and luteal insufficiency who use clomiphene; (iii) conception and preclinical abortions are related to endometrial thickness prior to ovulation; (iv) ectopic pregnancies are not increased by clomiphene and (v) the ratio of male births is not altered by clomiphene, except possibly in timed insemination cycles. These studies repudiate many misconceptions regarding clomiphene. They also show that clinical outcome may be improved by pre-ovulation ultrasound monitoring of ovarian and endometrial response.

Relationship of estradiol and progesterone levels to uterine blood flow during early pregnancy.

The purpose of this study was to examine the relationship of uterine blood flow to serum estradiol and progesterone during early pregnancy. Recumbent uterine artery average velocity, diameter, blood flow volume and uterine and spiral artery resistance were measured using vaginal Doppler ultrasound 118 times in 43 patients during gestational (postmenstrual) weeks 5 to 16. Relationships to serum progesterone and estrogen were analyzed before and after week 10, when intervillous circulation begins, by multiple linear regression analysis and analysis of covariance (ANCOVA) to correct for the effect of gestational age. After correction for gestational age, estradiol was negatively related to uterine artery flow volume (p < 0.05), diameter (p < 0.05), pulsatility index (p < 0.05) and resistance index (p < 0.01) for weeks 5-16 and to diameter (p < 0.05) after week 9. Progesterone was positively related to volume (p < 0.05) and velocity (p < 0.01) for weeks 5-16 and to volume (p < 0.05) for weeks 5 to 9. Spiral artery indices of resistance were unrelated to hormone levels. These results indicate that before the 10th gestational week, uterine blood flow volume is related to progesterone, but not estradiol levels, and suggest that high estradiol levels during and after the 10th week may be associated with decreased uterine blood flow volume.

Effect of ovulation induction on uterine blood flow and oestradiol and progesterone concentrations in early pregnancy.

To determine if oestradiol and progesterone concentrations are related to uterine blood flow in early pregnancy, we measured these hormones at the time of vaginal Doppler ultrasound before and after the beginning of intervillous circulation in spontaneous pregnancy (group I), after clomiphene citrate administration (group II), and after clomiphene citrate plus human menopausal gonadotrophin (HMG) administration (group III). Despite large increases of oestradiol concentration in group II (60%) and III (300%) and of progesterone in groups II (100%) and III (300%), compared with group I, increases in blood flow were modest during the first 9 weeks of gestation. Uterine artery flow volume increased by 20% in group II and 33% in group III (P < or = 0.02); average velocity increased by 37% in group III (P < or = 0.003) compared with groups I and II; vessel diameter increased by 15% in groups II (P < 0.025) and III (P < 0.001) compared with group I; and the uterine artery resistance index decreased by 3 to 5% in group III (P = 0.004) compared with groups I and II. Serum oestradiol and progesterone concentrations were unrelated to the uterine artery resistance index or volume by an analysis of covariance. We conclude that uterine artery blood flow is significantly increased during early pregnancy following HMG administration, and that the increase is unrelated to increases in oestradiol and progesterone concentrations.

Relationship of uterine blood flow to chorionic sac and embryo growth rates.

The embryonic period of development is characterized by marked variability in the rate of embryonic growth and development. Differences in uterine blood flow may explain this variability. We investigated the relationship between uterine artery blood flow volume (VOL), uterine artery pulsatility index (UA-PI), uterine artery resistance index (UA-RI), spiral artery pulsatility index (SA-PI), spiral artery resistance index (SA-RI), chorionic sac diameter (CSD), and crown-rump length (CRL) during 321 first trimester vaginal colour Doppler ultrasound examinations of 94 delivered or continuing pregnancies. After correcting for the confounding effect of gestational age, subject, and serum hormone levels by Analysis of Covariance, CRL was related to UA-PI (P = 0.025) and UA-RI (P < 0.001), but not to VOL, SA-PI, or SA-RI. No relationship was found between CSD and any uterine blood flow variables. Serum oestradiol levels were related to CSD and CRL (P < 0.001). No relationship was found to progesterone, maternal age, parity, or previous abortion. We conclude that differences in uterine blood flow and serum oestradiol explain some of the variability in the rate of embryo growth during the first 12 gestational weeks.

Ultrasonographic features of uterine blood flow during the first 16 weeks of pregnancy.

Uterine blood flow volume has been thought to increase in a linear fashion throughout pregnancy, but previous studies in early pregnancy may have not been performed often enough or in sufficient numbers of patients. We measured uterine artery blood flow volume, average velocity, vessel cross-sectional area, resistance index, and spiral artery resistance index with Doppler ultrasound at 1-3 week intervals from gestational (post-menstrual) weeks 5-6 to week 16 in 44 normal, spontaneous, single pregnancies. Uterine artery blood flow volume and velocity increased gradually until the end of week 9, and then rapidly from weeks 10-16. Uterine artery vessel size increased linearly. The uterine artery resistance index was the inverse of volume and velocity, in contrast to the spiral artery resistance index, which decreased linearly. These findings indicate that early pregnancy changes in uterine and spiral artery blood flow occur by different mechanisms, and that when investigating uterine blood flow in early pregnancy, studies need to begin by week 6 and need to be performed at least biweekly.