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.

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.

Relationship of initial chorionic sac diameter to abortion and abortus karyotype based on new growth curves for the 16th to 49th post-ovulation day.

In order to determine whether initial chorionic sac diameter is related to subsequent abortion, abortus karyotype, or birth weight and length, chorionic sac diameter was prospectively measured by transvaginal ultrasound in 700 singleton pregnancies before post-ovulation day 31, the latest day cardiac activity becomes detectable in normal pregnancy. Results were compared to values for the 10th to the 90th centiles, determined from 227 measurements of in-vitro fertilization and gamete intra-Fallopian transfer pregnancies. The abortion rate was 23.9% [95% confidence interval (CI) 19.2%, 28.6%] when initial chorionic sac diameter was below the 50th centile, compared to 6.9% (95% CI 4.9%, 9.4%) when equal to or above the 50th centile. Chorionic sac diameter was below the 50th centile in all anembryonic abortions and in 62% of embryonic abortions. Triploidy, trisomy 47 + 16, or trisomy 16 and the presence of satellite bodies on chromosome 22 were the only abortus karyotypes significantly associated with small chorionic sac diameter. Initial chorionic sac diameter was not associated with birth weight or length. We conclude that chorionic sac diameter is decreased in anembryonic and embryonic abortion and that normal pregnancy outcome may be expected in 90-95% of pregnancies in which initial chorionic sac diameter is equal to or above average.

The relationship of initial embryo crown--rump length to pregnancy outcome and abortus karyotype based on new growth curves for the 2-31 mm embryo.

The objective of this study was to determine if measurement of initial crown--rump length (CRL) is helpful in predicting low birth weight, newborn length, spontaneous abortions, or abortus karyotype. We measured CRL prospectively in 837 consecutive singleton pregnancies at the time a heart rate was first detectable with transvaginal ultrasonography and compared these measurements to normal values for the 10th through 90th centiles determined from 227 transvaginal ultrasound measurements in in-vitro fertilization and gamete intra-Fallopian transfer pregnancies with known ovulation dates. The relationship of initial CRL to birth weight and length and to abortion and abortus karyotype was analysed after all pregnancies had delivered. Initial CRL measured after the 28th post-ovulation day was predictive of subsequent abortion, but not of low birth weight or length. The abortion rate was 3.3% [95% confidence interval (CI) 1.5%, 5.1%] when initial CRL > or = 50th centile, compared to 19.4% (95% CI 15.4%, 23.4%) when < 50th centile. Initial CRL was < 50th centile in 13 out of 14 trisomic and in eight out of 10 other karyotypically abnormal aborti. These results indicate that initial CRL measured after the 28th post-ovulation day may help to identify pregnancies at increased risk of abortion due to abnormal karyotypes.

Relationship of endometrial thickness and pattern to fecundity in ovulation induction cycles: effect of clomiphene citrate alone and with human menopausal gonadotropin.

OBJECTIVE: To determine if preovulation endometrial thickness or pattern are related to fecundity and to use of clomiphene citrate (CC) or hMG in IUI. DESIGN: Prospective ultrasound evaluation the day of hCG after CC alone (n = 197), hMG alone (n = 49), concurrent hMG or sequential CC and hMG (n = 205), and no medications (n = 23). SETTING: Private fertility clinic. PATIENTS: Two hundred seventy-one patients undergoing 474 cycles of IUI. MAIN OUTCOME MEASURES: Endometrial thickness, pattern, per cycle fecundity, and continuing pregnancy. RESULTS: Endometrial thickness was related to fecundity and continuing pregnancy. No pregnancies occurred when thickness was < 6 mm. The continuing pregnancy rate was 12.6% when thickness was > or = 9 mm, compared with 6.9% when thickness was 6 mm to 8 mm. Endometrial pattern was unrelated to pregnancy. Average endometrial thickness was decreased when hMG and CC were used in combination (7.9 mm) compared with hMG alone (9.4 mm). Endometrial thickness was negatively related to CC dose and positively related to the day of hCG administration by ANOVA. CONCLUSIONS: Endometrial thickness the day of hCG administration is prognostic of fecundity and continuing pregnancy in cycles of ovulation induction.

Relationship of biochemical pregnancy to pre-ovulatory endometrial thickness and pattern in patients undergoing ovulation induction.

In order to assess the relationship between pre-ovulatory endometrial thickness and pattern and biochemical pregnancy, the pregnancy outcome was retrospectively analysed in 81 patients undergoing ovulation induction evaluated by vaginal ultrasound on the day of human chorionic gonadotrophin (HCG) administration or luteinizing hormone (LH) surge. Biochemical pregnancies occurred in 7/32 (21.9%) pregnancies when endometrial thickness was < 9 mm, compared to 0/49 when endometrial thickness was > or = 9 mm on the day of HCG administration or LH surge (P < 0.0025). Clinical abortions occurred in 5/32 (15.6%) pregnancies when endometrial thickness was 6-8 mm, compared to 6/49 (12.2%) when endometrial thickness was 6-8 mm (NS). Endometrial thickness was related to the cycle day of HCG or LH surge (r = 0.37, P < 0.001) but was unrelated to oestradiol level on the day of HCG administration or LH surge (r = 0.12). Biochemical pregnancies were related to endometrial pattern (r = -0.22, P = 0.02) but were unrelated to maternal age or previous abortions. Clinical abortions were related to age (r = 0.26, P = 0.01) and to previous abortion (r = 0.25, P = 0.013) but were unrelated to endometrial pattern. Neither biochemical pregnancy nor clinical abortion was related to oestradiol or LH levels on the day of HCG administration or LH surge. These findings suggest that the majority of biochemical pregnancies do not result from karyotypically abnormal embryos, as do clinical abortions.

Sequential clomiphene citrate and human menopausal gonadotrophin for ovulation induction: comparison to clomiphene citrate alone and human menopausal gonadotrophin alone.

The need for frequent injections and monitoring, the possibility of multiple gestations, and the higher cost compared to clomiphene citrate, prevents many clinicians from using human menopausal gonadotrophin (HMG) for ovulation induction. A sequential medication regimen, in which HMG is taken after clomiphene, overcomes these problems. We retrospectively compared per cycle fecundity and birth rates in 119 cycles of clomiphene-HMG, 524 cycles of clomiphene alone, 57 cycles of HMG alone, and 79 cycles of concurrent HMG and clomiphene in patients receiving intra-uterine insemination (IUI), who were free of endometriosis or tubal disease. Per cycle fecundity for clomiphene-HMG was 22% [95% confidence interval (CI) 12-34%], double that of clomiphene alone (11%) (95% CI 8-14%) (P < 0.01), and equal to HMG alone (18%) (95% CI 7-29%) or HMG and clomiphene together (19%) (95% CI 10-28%). The multiple birth rate for clomiphene-HMG (7/21) equalled that for HMG alone (3/12) and HMG and clomiphene together (3/8). The average number of ampoules of HMG required [follicle stimulating hormone (FSH) 75 mIU, luteinizing hormone (LH) 75 mIU] was decreased by 65% from 24.5 +/- 1.0 for HMG or HMG and clomiphene together to 8.6 +/- 0.3 for clomiphene-HMG (P < 0.001). Per cycle fecundity was identical when one, two or three ampoules of HMG per day were administered after clomiphene. We conclude that ovulation induction with sequential clomiphene-HMG results in fecundity double that of clomiphene alone and equal to HMG alone or concurrent with clomiphene, thereby reducing the requirement for HMG.

Incidence and significance of unequal gestational sac diameter or embryo crown-rump length in twin pregnancy.

The incidence of differences in gestational sac diameter and crown-rump length, measured at the time of the first ultrasound, in which at least one gestational sac or crown-rump length could be visualized, were analysed retrospectively in 260 twin pregnancies in which one or both fetuses were delivered at term. The difference in gestational sac diameter averaged 1.2 +/- 0.1 mm for pregnancies which ended in twin births, compared to 2.0 +/- 0.3 mm when pregnancy ended in single births (P less than 0.02). The difference in crown-rump length averaged 2.4 +/- 0.6 mm for pregnancies which ended in a single birth, compared to 0.9 +/- 0.1 mm for twin births (P = 0.02). Disparities of greater than or equal to 3 mm in gestational sac diameter (P less than 0.05) or crown-rump length (P less than 0.001) were associated with an embryo loss rate greater than or equal to 50%. The disparity in gestational sac diameter (P less than 0.04) and crown-rump length (P less than 0.01) was smaller in pregnancies resulting from assisted reproductive technologies, compared with pregnancies resulting from coitus or insemination. Differences in gestational sac diameter and crown-rump length in early pregnancy were unrelated to differences in birth weight, length or sex.

Relationship of first-trimester subchorionic bleeding detected by color Doppler ultrasound to subchorionic fluid, clinical bleeding, and pregnancy outcome.

We analyzed retrospectively the incidence of subchorionic fluid and embryonic death in 2116 consecutive patients evaluated with abdominal ultrasound and 783 patients evaluated with vaginal ultrasound. These women were examined during the first 12 postmenstrual weeks and had conceived as a result of infertility treatment. In addition, we analyzed the relationship of subchorionic bleeding to subchorionic fluid in 230 patients evaluated with color Doppler ultrasound and the relationship of subchorionic bleeding to clinical bleeding, precipitating factors, pregnancy outcome, and the karyotypes of abortuses. In single gestational sac pregnancies, subchorionic fluid was found equally often in women scanned with vaginal or color Doppler ultrasound, and less often with abdominal ultrasound (P less than .0001). Embryonic death was increased only in patients with large amounts of subchorionic fluid observed on abdominal ultrasound. Color Doppler ultrasound revealed subchorionic bleeding in 87 of 235 ultrasound scans (37%) and in 48 of 102 patients (47%) when subchorionic fluid was present. Subchorionic bleeding was associated with moderate or large amounts of subchorionic fluid (P = .041), with precipitating events (P less than .0001), and with clinical bleeding (P = .001). It was occult in ten of 48 patients (21%). Embryonic death occurred equally often in women with no fluid and in those with subchorionic fluid, with and without subchorionic bleeding. Abortuses were karyotypically abnormal in an equal proportion of cases with subchorionic bleeding, subchorionic fluid, and no fluid. These findings indicate that subchorionic fluid and subchorionic bleeding are common findings in early pregnancy and are not associated with embryonic death unless they are accompanied by clinical bleeding.

Relationship of small gestational sac-crown-rump length differences to abortion and abortus karyotypes.

We retrospectively reviewed ultrasound findings in 539 infertility patients to evaluate the incidence of small gestational sac syndrome and its association with abortion, karyotype of the abortus, and known abortion factors. Small gestational sac syndrome (gestational sac diameter minus crown-rump length less than 5 mm) occurred in 1.9% of pregnancies scanned with vaginal ultrasound 37-65 days after the first day of the last menstrual period. The rate of fetal death was 80.0% when the gestational sac diameter-crown-rump length difference was less than 5 mm, 26.5% when the difference was 5-7.9 mm (P less than .002 compared with less than 5 mm), and 10.6% when the difference was 8 mm or more (P less than .0001 compared with less than 5 mm). Karyotypes were normal in all eight fetuses when the gestational sac diameter-crown-rump length difference was less than 5 mm (P less than .03). Small gestational sac syndrome was present before fetal death in 10.7% of all cases, and in 24% in which the karyotype was normal. Of the factors analyzed--maternal age, previous abortions, low hCG or progesterone levels, and use of ovulation induction medications--only maternal age was significantly different (P = .011) in patients with small sac syndrome. We conclude that small gestational sac syndrome is an infrequent but important complication of early pregnancy, which occurs more often in karyotypically normal than in abnormal fetuses.