Nationwide Survey on the Usage of Ovulation-Induction Agents Among Obstetricians and Gynecologists in China
Ovulation induction is a critical aspect of infertility treatment, particularly for women with ovulatory disorders. The procedure aims to restore normal fertility by generating regular ovulatory cycles and inducing the selection of a single dominant follicle for ovulation. In China, a significant number of women with ovulatory disorders are treated by obstetricians and gynecologists (ob-gyns) who may not specialize in infertility. This study sought to investigate the self-reported proficiency of ob-gyns in ovulation induction and the most commonly used drugs for this procedure.
The study was conducted as a cross-sectional survey, with questionnaires distributed to 4,006 physicians attending workshops organized by the Gynecological Endocrinology Committee of the Chinese Maternal and Child Health Association. These workshops were held in 20 provinces across China from December 2017 to February 2018. Physicians were invited to complete the questionnaires voluntarily before the workshops began. The questionnaire took approximately three minutes to complete and did not collect any private details. The study received approval from the Ethics Committee of Peking Union Medical College Hospital.
The questionnaire covered several areas, including demographic information, self-evaluation of proficiency in ovulation induction, the first choice of ovulation drugs, preferred drug concentration and duration for clomiphene citrate treatment, and knowledge of the side effects of clomiphene citrate. Statistical analyses were performed using SPSS Statistics version 19.0, with a Chi-square test used to compare categorical data. Binary logistic regression analysis was employed to examine the influence of factors such as hospital type, education, title, specialty, and relevant training on the first choice of ovulation drugs, correct use of clomiphene citrate, and knowledge of its side effects. A p-value of less than 0.05 was considered statistically significant.
Out of the 4,006 questionnaires distributed, 3,401 were returned. After applying inclusion and exclusion criteria, 1,077 questionnaires (26.9%) were included in the final analysis. The demographic characteristics of the respondents revealed that 24.1% were ob-gyns specialized in infertility, while 75.9% were not specialized in infertility but were required to provide care for infertile couples. Notably, 76.7% of the respondents did not have any relevant training experience in infertility.
The study found that more than half of the respondents reported limited (20.5%) or no experience (34.9%) with ovulation induction. Only 10.1% of respondents considered themselves proficient, while 34.4% reported average proficiency. A significantly higher proportion of ob-gyns specialized in infertility or with relevant training experience considered themselves proficient or average in ovulation induction compared to those without these attributes (24.6% vs. 5.5%, p < 0.010; 24.3% vs. 5.8%, p < 0.010, respectively).
Clomiphene citrate was the first choice of ovulation drug for most ob-gyns, with 67.0% selecting it and 16.6% choosing letrozole. Additionally, 9.8% of respondents chose both drugs as their first choice. A significantly higher proportion of ob-gyns specialized in infertility or with relevant training experience chose letrozole compared to those without these attributes (41.5% vs. 21.7%, p < 0.010; 37.8% vs. 25.0%, p < 0.010, respectively).
Regarding the use of clomiphene citrate, less than half (43.0%) of the respondents believed it should not be used for more than six cycles, while a higher proportion (51.1%) thought it should be used for three cycles. A higher proportion of respondents specialized in infertility or with relevant training experience chose six cycles as the preferred duration (53.1% vs. 39.8%, p < 0.010; 53.0% vs. 40.0%, p < 0.010, respectively). Most respondents (85.1%) correctly identified five days as the duration of treatment for clomiphene citrate, and 70.8% reported 50 mg as the initial dose. However, a lower proportion of ob-gyns with relevant training experience chose five days as the usual treatment course or 50 mg as the initial dose (80.1% vs. 86.7%, p = 0.010; 60.6% vs. 74.0%, p < 0.010, respectively).
The study also highlighted insufficient awareness of the side effects of clomiphene citrate. Only 50.9% of respondents knew about its anti-estrogenic effects, and 51.1% were aware that it can thin the endometrium. Additionally, only 37.0% of respondents recognized that clomiphene citrate could increase the risk of luteinized unruptured follicle syndrome (LUFS). Ob-gyns specialized in infertility or with relevant training experience had better knowledge of the endometrium-thinning side effect but were less aware of the increased risk of LUFS.
Binary logistic regression analysis revealed that ob-gyns specialized in infertility or with relevant training experience were less likely to choose clomiphene citrate as the first-line ovulation-induction drug (odds ratio [OR]: 0.7; 95% confidence interval [CI]: 0.5–1.0; p = 0.032; OR: 0.5; 95% CI: 0.4–0.7; p < 0.010, respectively). Instead, they were more likely to choose letrozole (OR: 2.2; 95% CI: 1.6–3.0; p < 0.010; OR: 1.5; 95% CI: 1.1–2.0; p = 0.024, respectively) and were more likely to report the correct number of cycles for clomiphene citrate (OR: 1.5; 95% CI: 1.1–2.0; p = 0.009; OR: 1.4; 95% CI: 1.1–2.0; p = 0.020, respectively). Relevant training experience was negatively correlated with the correct rate of the usual course and initial dose of clomiphene citrate (OR: 0.6; 95% CI: 0.4–0.9; p = 0.012; OR: 0.5; 95% CI: 0.4–0.7; p < 0.010, respectively). In contrast, position titles had a positive correlation with these parameters. Associate chief physicians were over four times more likely to report the correct duration of treatment and initial dose of clomiphene citrate compared to residents.
Ob-gyns specialized in infertility were more likely to be aware of the side effects of a thinned endometrium induced by clomiphene citrate (OR: 1.6; 95% CI: 1.2–2.1; p = 0.003), while associate chief physicians or chief physicians were 1.7 to 2.5 times more likely to be aware of the anti-estrogenic and endometrium-thinning side effects compared to residents. Relevant training experience was negatively correlated with knowing the risk of LUFS during clomiphene citrate treatment (OR: 0.6; 95% CI: 0.5–0.9; p = 0.007). Hospital type had no correlation with any of the results, and educational background only slightly affected the correct response rate of the treatment duration and initial dose of clomiphene citrate.
Anovulatory subfertility is a heterogeneous condition with various underlying causes, including hypogonadism, normogonadotropic ovarian dysfunction, and hypergonadotropic hypogonadism. Other endocrinopathies, such as hyperprolactinemia, thyroid dysfunction, congenital adrenal hyperplasia, and androgen-secreting adrenal and ovarian tumors, can also lead to ovulation disorders. The most common type is normogonadotropic ovulation, with polycystic ovary syndrome (PCOS) being the predominant cause. Clomiphene citrate, a selective estrogen-receptor modulator, has been the most widely used ovulation drug for normogonadotropic anovulation since its introduction in 1960. Letrozole, an aromatase inhibitor, has shown higher ovulation and live-birth rates compared to clomiphene citrate in patients with PCOS and is recommended as the first-line ovulation drug by guidelines. Despite this, clomiphene citrate remains the most commonly used drug in China, similar to findings in the United States.
The study underscores the need for improved medical care for infertile women requiring ovulation induction. More than half of the ob-gyns involved in infertility care considered themselves limited or devoid of competency in performing ovulation induction. While clomiphene citrate remains the first choice for most ob-gyns, the standardized usage and knowledge of its side effects were poor overall. Physicians specialized in infertility performed better in these areas, but their proportion was low. These findings highlight the urgent need for pragmatic basic education programs for ob-gyns involved in infertility care to enhance their proficiency and knowledge in ovulation induction.
doi.org/10.1097/CM9.0000000000000450
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