IVF-M HP Warnings

1) IVF-M HP treatment should be precluded in which a satisfactory outcome cannot be expected, for example, ovarian dysgenesis, absent uterus, premature menopause or tubal occlusion.
2) Before starting treatment, patient should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia, or pituitary tumour, and appropriate specific treatment given first.
3) Evaluation of the partner's semen analysis should be available before IVF-M HP treatment.
4) In patients with amenorrhea and anovulation, adherence to recommended dosage, regimen of administration and careful monitoring of therapy will minimize the incidence of ovarian hyperstimulation. Excessive estrogenic responses to IVF-M HP seldom give rise to significant side effects unless hCG is administered to trigger ovulation. In case of high estrogen level and excessive follicular development, withheld administration of IVF-M HP and hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days.
5) In patients with amenorrhea and anovulation, the incidence of multiple births following IVF-M HP and hCG treatment has been reported to be 10~40%, the majority of them being twins. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient.
Some patients undergoing assisted reproductive technology with a history of tubal disease are at risk of ectopic pregnancy. The relationship between IVF-M HP treatment and ectopic pregnancy has not been established.
The incidence of pregnancy wastage by miscarriage or abortion is higher than in the normal population but comparable in women with other fertility problems. The prevalence of congenital abnormalities is not increased by IVF-M HP.
6) IVF-M HP should only be used by physicians who are thoroughly familiar with infertility problems and their management. Since the product is capable of causing mild to moderate adverse reaction, patients should be appropriately monitored.
Adherence to recommended dosage and careful monitoring of therapy will minimize the incidence of ovarian hyperstimulation and multiple pregnancy.
I. Ovarian Hyperstimulation may occur: Ovarian Enlargement: Mild to moderate ovarian enlargement which may be accompanied by abdominal distension and abdominal pain occurs in approximately 20% of women treated with IVF-M HP and hCG, and generally regresses naturally within two or three weeks. The lowest effective dose in relation to the treatment objective should be used and careful monitoring of the ovarian response is required to avoid such events. If abnormal ovarian enlargement occurs on the last day of IVF-M HP treatment, hCG should not be administered in order to minimize the risk of developing Ovarian Hyperstimulation Syndrome (OHSS).
Ovarian Hyperstimulation Syndrome (OHSS): OHSS may progress rapidly to become a serious medical event. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and rarely, in the pericardial cavities. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain.
The following symptoms may be observed: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhea, hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events.
When treated with this product, severe OHSS occurs in approximately 6% of anovulatory patients and 0.25% of patients undergoing in vitro fertilization.
As OHSS may progress rapidly, patients should be followed for at least two weeks after the hCG administration. Most often, OHSS occurs after the treatment has been discontinued and reaches its maximum severity at about 7~10 days following treatment. Usually OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration, the hCG administration should be withheld. If severe OHSS occurs, gonadotrophin treatment should be stopped and the patient hospitalised and specific therapy for OHSS such as rest, fluid and electrolyte management, and analgesics started.
In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. OHSS may be more severe and more protracted if pregnancy occurs. This syndrome occurs with higher incidence in patients with polycystic ovary syndrome (PCOS).
If the phenomenon of hemoconcentration associated with fluid loss occurs, intake and output of body fluid, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, and abdominal girth should be assessed daily or often.
A risk of injury to the ovary increases with OHSS. Pelvic examination should be avoided as it can cause rupture of the ovarian cyst, resulting in a hemoperitoneum. If bleeding occurs, the surgical intervention should be considered to retain ovarian tissue. In case of significant ovarian enlargement after ovulation, intercourse is prohibited because of the risk of hemoperitoneum caused by rupture of an ovarian cyst.
The management of OHSS is divided into three phases. Because the use of diuretics can accelerate the hypovolemia, it should be avoided except in the late phase of convalescence.
1. Acute phase: Prevent hemoconcentration, thromboembolic phenomena, and kidney damage. Control reduced blood volume and normalizes electrolytes. Watch out for the development of hyperkalemia.
2. Chronic phase: After the acute phase is successfully managed as previously mentioned, excessive fluid accumulation in abdominal cavity, thoracic cavity, and pericardium should be limited by instituting high potassium, high sodium, and fluid restriction.
3. Resolution phase: As body fluid returns from abdominal cavity, thoracic cavity, and pericardium to intravenous compartment, a fall in hematocrit and increasing urinary output may be observed. Because peripheral pulmonary edema may result in case the kidneys are unable to excrete the fluid rapidly, if necessary, diuretics can be used.
II. Pulmonary and vascular complications may occur (atelectasis, acute respiratory distress syndrome, thromboembolic events both in association with and without OHSS): This can lead to venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), arterial occlusion and loss of limb. Very rarely can lead to death.
III. Multiple birth related with this drug has been reported: In the clinical trial, single birth occurred in 79.2% and multiple birth (mainly twins) occurred in 20.8% of total pregnancies. The patient should be advised of the potential risk of multiple births before starting treatment.
IV. Hypersensitive/Anaphylaxis reaction has been reported regarding this drug: These reactions typically included urticaria, facial edema, angioneurotic edema, and dyspnea from laryngeal edema. The relationship between these symptoms and proteinuria has not been established.