What is ovarian hyperstimulation syndrome (OHSS)?

Ovarian hyperstimulation syndrome (OHSS) is a complication that can occur with assisted reproductive treatments. It is characterised by an abnormally high ovarian response to drugs given to stimulate the ovaries, especially in in vitro fertilisation (IVF).

Identifying the risks that favour the occurrence of this syndrome will allow the doctor to prevent and/or manage this alteration. If the patient manages to become pregnant during treatment, OHSS can become severe and have serious consequences.

What is OHSS and when does it happen?

Ovarian hyperstimulation syndrome is a complication that can occur with assisted reproductive treatments. The syndrome occurs more frequently in in vitro fertilisation (IVF) treatments, compared to insemination (IUI). This is because the doses of hormone administered in IVF are higher than in IUI. During IVF, the patient is given hormonal medication. The purpose is to increase the number of follicles that will reach maturity. In this way, more than one egg matures, which happens every month in a woman’s natural cycle. During fertility treatments, chorionic gonadotropin (hCG) will be administered about 36 hours before the follicles are punctured (ovulation). It is known that hCG is the source of OHSS in case we have a patient with a large number of follicles (>17). The most important consequence of OHS is the release of fluid into the abdominal and pulmonary cavity and lead to complications. OHSS is a syndrome that disappears with menstruation, when the hormone levels of the woman’s cycle are restored. At present, severe cases of OHSS are rare, as the types of ovarian stimulation protocols used in IVF and monitoring during follicular development make it possible to avoid OHSS.

Causes of the syndrome

The causes of this reaction to hormone stimulation are not fully understood. However, it is known that OHSS occurs after the administration of hCG. Only in the presence of this hormone does the excessive ovarian response that causes this syndrome occur. The administration of hCG is the last step in ovarian stimulation and is performed approximately 36 hours before ovulation. The purpose of this hormone is to help mature the eggs before ovulation. However, in patients at risk for OHSS, hCG will also be a concomitant cause of this syndrome. OHSS also promotes the release of certain substances that increase the permeability of blood vessels. This causes excessive release of fluids from the bloodstream. In this way, the functioning of the liver, haematological, renal and respiratory systems of the body can be compromised. The syndrome will not occur immediately after the administration of hCG, but the patient will begin to notice the first symptoms days or weeks after the administration of hCG.

Classification of ovarian hyperstimulation syndrome

The original OHSS classification has undergone several changes and modifications, but we can now talk about 3 types depending on the level of severity:

• Mild: characterised by increased levels of oestradiol and progesterone and slightly enlarged ovaries.
• Moderate: in addition to hormonal changes and an increase in the size of the ovaries, the patient experiences discomfort and an increase in the volume of the abdomen.
• Severe: characterized by an excessively large diameter of the ovaries and completely altered hormone levels. In addition, the patient’s daily weight gain is noticeable due to excess fluid in the abdominal and thoracic cavity. All this can cause a woman kidney and liver problems and a risk of thrombosis.

We can also classify OHSS according to the time it takes for the syndrome to manifest. Depending on how long it takes for the syndrome to debut, we will be able to distinguish between:

• Early OHSS: occurs 3-7 days after hCG administration, after ovarian puncture.
• Late OHSS: occurs 12-17 days after injection with hCG. This type of OHSS usually occurs when there is a pregnancy because the fetal sac produces hCG.

Symptoms of OHSS

OHSS occurs in 0.6-10% of women undergoing ovarian stimulation cycles. Below, we will look at the symptoms associated with this syndrome according to the severity of the syndrome. Most women who have mild or moderate OHSS experience symptoms such as:

• Swelling and mild pain in the abdomen
• Weight increase
• Nausea or vomiting
• Diarrhoea
• Mild to moderate abdominal pain

Although rare, severe cases only have an incidence of 0.5-2% and are accompanied by symptoms such as:

• Rapid weight gain: over 4.5 kg in 3-5 days
• Ascites – fluid accumulation in the abdomen
• Hypotension and tachycardia – increased heart rate
• Difficulty breathing

Early diagnosis of OHSS is very important to avoid possible complications that may arise, as they could endanger the patient’s life. Therefore, it is very important to monitor the woman’s symptoms closely.

Complications of the syndrome

The most important consequence of OHSS is the release of an abnormal volume of fluid into the abdominal and pulmonary cavity. The most common complications are:

• Fluid build-up around the lungs – which can lead to breathing problems
• Twisting of the ovaries
• Electrolyte imbalance: due to the large amount of fluid leaving the bloodstream can alter sodium/potassium levels
• Decreased urinary frequency and volume: the more fluid released into the abdominal cavity, the more a decrease in urine volume and urinary frequency can occur, leading to kidney failure

In addition, it should be noted that if a woman becomes pregnant, miscarriage may occur due to complications from OHSS.

Risk factors for OHSS

The risk factors that predispose to the onset of OHSS are:

• Age: the ovaries of young women (under 30) have a higher number of gonadotropin receptors or a higher number of follicles, making them more susceptible to this syndrome.
• Low muscle mass index (BMI): this syndrome has been described in a higher proportion of thin women.
• Polycystic ovary syndrome (PCOS): there is a clear association between PCOS and OHSS. Women with PCOS are more likely to develop OHSS during IVF.
• Multiple pregnancy: hCG, the hormone that promotes the development of OHSS, will double if the patient becomes pregnant with twins, worsening the progression of the syndrome.

What are the signs of a possible OHSS?

OHSS is not easy to predict during ovarian stimulation. However, there are some signs that may indicate to the doctor that the patient may be at risk for OHSS, such as:

• Increased serum estradiol: during ovarian stimulation, the woman should come in every 2 days or so for an ultrasound scan to check the development of her follicles. During these checks, the concentration of estradiol in the blood is also measured. This hormone is secreted by the follicles. Levels greater than 25000 pg/ml or rapid increases in a short period of time can put the doctor on alert for the possible onset of OHSS
• The gynaecological ultrasound image: women at risk for OHSS have a very distinctive ultrasound image, as the follicles are distributed around the ovary in a way that resembles the beads of a necklace.
• Possible previous episodes of OHSS: A previous OHSS can alert the doctor that this patient is sensitive to hormones for fertility treatment. He/she should therefore change the hormone dose to avoid a new OHSS.

In case of pregnancy, hCG levels will increase. Therefore, OHSS will worsen and may endanger both the progression of the pregnancy and the life of the pregnant woman. Therefore, if it is suspected that the syndrome may develop, implantation in the same cycle as ovarian stimulation should be avoided.

How can OHSS be prevented?

There are many protocols that can prevent the patient from having OHSS or make it worse, and the doctor can choose different solutions. The choice of procedure to prevent or reduce the symptoms of OHSS will be evaluated by the physician. Below we will explain in more detail some of the most commonly used strategies to avoid OHSS.

Lower doses of gonadotropins

Patients given high doses of gonadotropins are more likely to develop OHSS because there is a greater ovarian response. Therefore, those women who are at high risk of developing OHSS (such as young women, those who have PCOS or very low body mass index), it would be appropriate to start ovarian stimulation with low doses of gonadotropins and then assess how they respond.

Ovulation induction with GnRH agonists

One of the most effective ways to prevent the occurrence of OHSS is to replace hCG with another drug such as GnRH agonists. The main advantage that this type of drug offers is that it prevents the syndrome while causing ovulation. Most studies have shown that this drug reduces the risk of OHSS, but it also reduces the chance of implantation and pregnancy because it causes luteal phase deficiency.

Cycle cancellation

Suspension of hCG injection and cancellation of the cycle is one of the strategies that prevents the occurrence of OHSS. However very rarely is this necessary.

Embryo cryopreservation

In cases where it is suspected that OHSS may develop, one of the options to avoid worsening the situation is to cryopreserve (freeze) all embryos through vitrification, for transfer to a subsequent cycle. In this way, OHSS will not be prevented, but at least the deterioration resulting from a possible pregnancy is prevented (as no endogenous hCG will be produced). In conclusion, the most effective strategy is to induce ovulation with a GnRH agonist and freeze all embryos.

Reducing the dose of hCG

Since there is a direct relationship between hCG levels and the severity of the syndrome, another approach to avoid the development of OHSS is to reduce the dose given to induce ovulation. However, this measure does not completely eliminate the possibility of OHSS.

Treatment of ovarian hyperstimulation syndrome

The treatment indicated for each patient depends on the severity of OHSS. In the mildest cases, hospitalisation will not be necessary. However, in cases where the patient’s integrity is at risk, the patient should be hospitalized:

• Treatment of mild and moderate OHSS
• Treatment in severe OHSS

Treatment of mild and moderate OHSS

To reduce the discomfort caused, it is recommended to:

• Taking plenty of fluids, especially fluids rich in electrolytes (minerals)
• Avoiding alcohol and caffeine
• Avoiding intense exercise to prevent ovarian torsion
• Avoiding sex
• Taking pain medications for pain relief

Treatment in severe OHSS

In severe cases of OHSS, hospitalization of the patient will be necessary in order to thoroughly monitor the progression of the disease. In addition, fluids will be administered intravenously. In more severe cases, a surgical puncture may be necessary to remove the accumulated fluid. In severe cases of OHSS, it is extremely important to monitor:

• the functions of the liver
• the anticoagulants
• the electrolytic balance
• the function of the kidneys
• complications of the lungs