Clomiphene citrate usage pattern in India: A knowledge, attitude, and practice survey among gynecologists

INTRODUCTION

Ovulatory dysfunction is an important and common cause of failure of reproduction in cases of female infertility,^[1] and it is mainly caused by hypothalamic-pituitary failure/dysfunction and ovarian failure.^[2] Anovulatory infertility is responsible for approximately 40% of cases of female infertility.^[3] Polycystic ovary syndrome (PCOS) is a leading cause and some other causes may be obesity, extreme weight loss, exercise or other stress, hyperprolactinemia, pituitary tumors, or thyroid disease. Anovulatory infertility may require evaluation to detect underlying systemic disease, followed by specific treatment.^[4]

Treatment for ovulatory dysfunction is induction of ovulation, and clomiphene citrate (CC) is considered as the drug of choice for the same. CC is a competitive estrogen antagonist used for the induction of ovulation. It binds to the estrogen receptor (ER) and depletes its concentrations by interfering with its replenishment. Decreased estrogen, by feedback mechanism, will trigger pulsatile secretion of hypothalamic gonadotropin-releasing hormone (GnRH) to increase the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which will, in turn, stimulate ovarian follicular activity. In successful cycles, one or more ovarian follicles will mature. CC is given orally, has few side effects, and is easily available and inexpensive, as a result of which this drug is widely prescribed.^[3,4]

A knowledge, attitude, and practice (KAP) survey measures, through a structured, standardized questionnaire, changes in the knowledge, attitude, and practice of a person in response to a specific intervention. A KAP survey is a representative survey conducted on a particular population on a specific topic. These surveys are popular and widely used because they utilize fewer resources and tend to be more cost-effective than other social research methods.^[5]

There are limited data about the knowledge, perception, and routine clinical usage pattern of CC among medical practitioners in India. The present survey was undertaken to explore Indian medical practitioners' knowledge, perception, and usage of CC in the real-life setting.

MATERIALS AND METHODS

RESULTS

In total, 771 gynecologists participated in this survey across India. The final data from 771 participants' responses were evaluated and analyzed as follows.

Efficacy assessment of CC

The majority of participants (89.47%) preferred CC for PCOS. Secondary amenorrhea, psychogenic amenorrhea, amenorrhea-galactorrhea syndrome were other conditions in which CC was preferred [Table 1].

Table 1 Preferred patient profile of ovulatory dysfunction for CC

Approximately 77% of the participants reported ovulation rates (percentage of patients ovulating with each cycle of CC 50 mg) varying in the range 21-60% [Figure 1].

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Figure 1

Ovulation rate with CC

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Almost 90% of participants reported the thickness of endometrium as being 7-10 mm with CC [Table 2].

Table 2 Thickness of endometrium with CC

A total of 45.3% participants noticed a pregnancy rate [gestational sac on ultrasonography (USG)] of 11-20%, while 34% participants noticed a pregnancy rate of 21-30% with each CC cycle [Figure 2].

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Figure 2

Pregnancy rate with CC

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According to a majority of participants (62.76%), 3-4 cycles of CC were required for conception, while 30% of participants observed that almost 5-6 cycles were required for conception [Table 3].

Table 3 No. of cycles of CC therapy required for conception

As per the global assessment of efficacy, approximately 65% of participants rated the efficacy of CC as very good to excellent, and 35% rated it as average [Figure 3].

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Figure 3

Global assessment of efficacy of CC

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According to 82% of participants, less than half the patients required additional drug(s) for induction of ovulation [Table 4].

Table 4 Percentage of patients requiring additional drug(s) for induction of ovulation

A majority of participants (65.13%) considered CC resistance when patients failed to ovulate with the maximum dose of 150 mg of CC in 3 cycles [Table 5].

Table 5 Practical criteria for CC resistance

Approximately 79% and 18% of participants reported that resistance to CC was encountered "sometimes" and "frequently," respectively [Figure 4].

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Figure 4

Occurrence of CC resistance

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Safety assessment of CC

Almost 45% of participants reported abdominal/pelvic discomfort or pain as a commonly encountered adverse effect, followed by 33% of participants reporting ovarian enlargement. Nausea and vomiting was reported by 29% of participants [Table 6].

Table 6 Common adverse effects with CC

Approximately 54%, 33%, and 16% of participants encountered multiple gestation, OHSS, and spontaneous abortion, respectively, as a frequent complication with CC [Table 7].

Table 7 Frequent complication of CC

However, according to the vast majority of participants (91.28%), only less than 5% of patients developed OHSS with CC [Figure 5].

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Figure 5

Percentage of participants reporting development of OHSS with CC

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As per the global assessment of tolerability, approximately 83% of participants felt that CC has very good to excellent tolerability [Figure 6].

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Figure 6

Global assessment of tolerability of CC

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Interestingly, as many as 6.45% of participants reported that they had noticed congenital malformations in a child born after CC treatment [Figure 7].

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Figure 7

Participants reporting congenital malformations with CC

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Perception about CC

Many participants (62.48%) preferred a dose of 50 mg/day of CC for 5 days, whereas 42.48% of the participants preferred a dose of 100 mg/day for 5 days [Table 8].

Table 8 Preferred dose of CC

According to almost 80% of participants, the preferred maximum duration of CC per cycle was 5 days [Figure 8].

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Figure 8

Preferred duration for CC

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Around 53% of participants preferred day 2, whereas 42% preferred day 3 of the cycle to start CC therapy in patients with ovulatory dysfunction [Table 9].

Table 9 Preferred day to start CC

Almost 38%, 24%, 23%, and 15% of participants considered a Graafian follicle size of 18 mm, 12 mm, 14 mm, and 16 mm respectively to anticipate ovulation/give an ovulatory trigger [Table 10].

Table 10 Preferred size of Graafian follicle to anticipate ovulation or give trigger

The majority of participants (76.9%) usually prescribed additional drug(s) to improve endometrium, whereas the remaining 23.1% of participants did not prescribe any additional drug to improve endometrium [Figure 9].

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Figure 9

Participants prescribing additional drug(s) to improve endometrium

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Almost 36% of participants preferred the sixth day and 30% of participants preferred the seventh day of the cycle to start estrogen in patients on CC therapy [Table 11].

Table 11 Preferred day to start estrogen in patients receiving CC

In total, 85% of the participants advised natural conception as the most preferred method of conception to patients on CC [Figure 10].

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Figure 10

Preferred method of conception with CC

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Almost 63% and 53% of participants preferred gonadotropins and metformin respectively as additional drug(s) for patients not responding to CC alone [Table 12].

Table 12 Preferred additional drug(s) in patients not responding to CC alone

DISCUSSION

CC is approved for induction of ovulation in patients with persistent ovulatory dysfunction.^[3] This drug has been available in India since 1974.^[6] This drug has a unique place in therapy and is used and misused very frequently in routine clinical practice. There are limited clinical data on CC in the real-life setting in India. Therefore, the present survey was taken to understand the current knowledge, attitude, and practice of Indian gynecologists related to CC. A KAP survey can be used to analyze the prescribing behavior of doctors.^[7] For the purposes of this survey, "knowledge" means knowing about CC, "attitude" refers to the way gynecologists think or feel about CC, and "practice" means the usage pattern of CC in routine clinical practice. To the best of our knowledge, this was the only KAP survey made with the participation of Indian gynecologists.

The most preferred patient profile for CC was PCOS with ovulatory dysfunction, which is as per the reported literature.^[1,3,4] Ovulation rate, i.e., the percentage of patients ovulating with each cycle of 50 mg CC was 21-60%, according to most participants. Endometrial thickness with CC was 7-10 mm, as observed by the majority of the participants. The pregnancy rate reported with each CC cycle was 11-30%.

The majority of participating doctors highlighted that anywhere between 3 and 6 cycles of CC were required for conception. According to most participants, CC alone is sufficient for the induction of ovulation in more than 50% of patients. CC resistance, which according to most participants was the failure to ovulate with a 150 mg dose for 3 cycles, was sometimes encountered. The overall global efficacy of CC was rated as very good to excellent.

Commonly observed adverse effects with CC were not serious and included abdominal/pelvic discomfort or pain, nausea, vomiting, hot flushes, and ovarian enlargement. According to most participants, multiple pregnancy and OHSS were frequently encountered complications with CC. Additionally, OHSS was reported in less than 5% of patients.

Overall, the global tolerability of CC was rated as very good to excellent. However, congenital malformations were reported in children born after CC therapy by quite a few participants.

Most of the participants usually preferred standard doses of CC, i.e., 50 mg/day or 100 mg/day prescribed for a maximum of 5 days per cycle starting usually on day 2 or day 3 of the cycle. Different participant doctors preferred different sizes of Graafian follicles, varying from 12 mm to 18 mm, for giving a trigger.

Additional drug(s) were needed to be prescribed to improve the endometrium, of which estrogen was usually started on day 6 or day 7 of the cycle. Metformin and gonadotropins were the most preferred drugs in patients not responding to CC. Most participants advised conception by natural methods and not by assisted reproductive techniques, in patients on CC therapy.

The present KAP survey was conducted across India and included a large number of experienced gynecologists responding to the questionnaire. A KAP survey, however, may have some obvious limitations: The multiple-choice format of the present survey questionnaire makes this survey closed-ended, thereby directing the participants to choose desirable answers. In spite of all these limitations, the present survey was an attempt to understand current knowledge, attitude, and practice among Indian gynecologists. This survey highlighted some interesting facts mentioned above in addition to known information. However, a systematic clinical trial may be further required to confirm these facts.

CONCLUSION

The present KAP survey highlighted that CC is a commonly used agent for ovulatory dysfunction, with or without other agents. On usage of CC, good ovulation and pregnancy rates were reported, with very good to excellent efficacy and tolerability. Resistance to CC was also reported in routine clinical practice.