Enlarged ovaries after stimulation. Ovarian hyperstimulation syndrome - a modern view of the problem

Looking through the monitoring of the press, I came across an article about ovarian hyperstimulation syndrome. The material is written, in my opinion, very well and just at the level at which this topic should be known to all patients who plan to resort to IVF. So I am pleased to offer it to your attention.

One of the most common complications during IVF is ovarian hyperstimulation syndrome (OHSS), a condition that can develop in response to the use of hormonal drugs.

What is ovarian hyperstimulation syndrome?

In a woman's natural menstrual cycle, one egg matures, rarely two. To get several eggs at once and thereby increase the chances of a successful pregnancy, the doctor individually prescribes hormonal drugs with a specific scheme for their use. Under the influence of these drugs, several eggs (sometimes 20 or more) mature in the ovaries of a woman at once.

Ovarian hyperstimulation syndrome is an iatrogenic condition that can occur in response to the use of these drugs. The ovaries of a woman increase, fluid begins to accumulate in the abdominal cavity; other symptoms depend on the severity of OHSS.

Is ovarian hyperstimulation syndrome dangerous?

There are several degrees of severity of ovarian hyperstimulation syndrome: mild, moderate and severe. Severe forms of hyperstimulation are dangerous to a woman's health and can threaten her life, but today they are very rare.

Mild forms of hyperstimulation are not dangerous: they do not require hospitalization, and often do not require medical treatment. If necessary, the patient can receive treatment at home, maintaining constant contact with her doctor. Treatment of moderate and severe hyperstimulation is organized in a hospital setting.

The development of hyperstimulation syndrome depends on the woman's body - the doctor can do nothing to completely prevent this. However, an experienced doctor, thanks to the correct selection of drugs and their dosages, can minimize the likelihood of developing this syndrome, and if it does begin to develop, competently remove the patient from this state.

How does ovarian hyperstimulation syndrome manifest itself?

With a mild degree of hyperstimulation, the patient will experience only a slight deterioration in well-being, discomfort in the abdomen and slight swelling, which will soon disappear.

With moderate ovarian hyperstimulation syndrome, as a rule, there is a deterioration in general well-being, abdominal pain, nausea, vomiting, diarrhea, and pronounced edema. Also, fluid begins to accumulate in the abdominal cavity, due to which the stomach can visually increase in size.

Severe ovarian hyperstimulation syndrome is characterized by a significant deterioration in the woman's condition, severe abdominal pain, an increase in the volume and tension of the abdomen due to the accumulation of a large amount of fluid in the abdominal cavity. She may have severe repeated vomiting, low blood pressure, shortness of breath due to the accumulation of fluid in the chest and abdominal cavity, as well as disturbances in the work of the heart as a result of the accumulation of fluid in the pericardial cavity.

Which women are more likely to experience this syndrome?

At risk of developing ovarian hyperstimulation syndrome, in the first place, women with polycystic ovary syndrome. If a woman has PCOS, she is more likely to develop OHSS as a result of stimulation. An experienced doctor should take this into account: thanks to his correct actions, the problem can be mitigated as much as possible so that the woman has only a slight or at least a moderate degree of hyperstimulation.

There are also several other risk factors that the doctor doing IVF must take into account.

Can embryos be transferred if a woman has developed OHSS?

If the patient has developed early hyperstimulation syndrome (this is when OHSS develops in the luteal phase of the menstrual cycle, which occurs immediately after ovulation - the release of the egg from the ovary), it is advisable not to transfer the embryos. If pregnancy does not occur after OHSS, with the advent of the next menstruation, all unpleasant symptoms, as a rule, disappear.

If pregnancy occurs after the embryo transfer, at 5-12 weeks of gestation, the patient may develop late hyperstimulation syndrome, which can be quite difficult.

Thus, if the patient has OHSS, it is recommended to cryopreserve the embryos, and in the next cycle, defrost them and transfer them to the uterus. True, in each individual case, an individual approach is required - in some cases, the doctor may decide to still transfer the embryos, despite OHSS.

Introduction

Ovarian hyperstimulation syndrome (OHSS) is the most severe complication resulting from excessive ovarian stimulation as part of ART protocols. In terms of incidence, OHSS is second only to multiple pregnancies. In terms of the threat to the life of the patient, severe OHSS competes, perhaps, only with ectopic pregnancy.

Classification

The ubiquitous frequency of occurrence and the great destructive potential of OHSS in different groups of patients undergoing ART treatment immediately determined nosology as one of the dominant diagnoses in the practice of a reproductive specialist. In turn, to understand the tactics and correct reproducibility of diagnostic and treatment actions that are optimal in terms of efficiency, safety and cost, a clear and convenient classification was required, the development of which, as time has shown, has become a difficult task. With the accumulation of a large amount of analytical information, it turned out that one of the main features of the syndrome is the instability of the symptom complex from patient to patient, as well as the insufficient predictive value of the risk of progression of each of the symptoms separately.
Actually, therefore, the assessment and classification view of OHSS has been revised several times over the past 40 years, in general, during the entire period of the existence of OHSS, as such, since the appearance of ovulation inducers and GnRH agonists in wide practice.

The highest need for effective and safe IVF, the great dynamism of the implementation and evolution of the treatment technology itself has predetermined this medical field as the most open to reasoning and innovation. This principle has not bypassed such a complication of IVF, which is the most difficult to understand and treat, such as OHSS. The views on which were tested and tested right there, in practice. Thus, the classification of nosology has changed, supplemented, complicated and simplified, according to clinical convenience, several times. As time has shown, the most practical classification of OHSS was proposed by Rabau E et al., later supplemented by other authors (Schenker JG et al.; Golan A, Ron-el R, Herman A et al.). The classification proposes to divide the syndrome into degrees of severity: mild, moderate (moderate) and severe. Later, Navot D et al. singled out a special degree of the syndrome - critical OHSS, which speaks for itself, as a condition that requires special attention.

The success of the classification lies in the fact that the gradation by degree is based on the main significant beacons of the syndrome (complaints, ovarian enlargement, ascites, oliguria, dyspeptic manifestations, clinical blood tests, hormonal profiles, etc.), the dynamics of which, on the one hand, allows objectively to predict the course of the disease in a patient whose symptomatic correction, on the other hand, allows stopping or at least compensating for the development of a life-threatening condition. Once again, agreeing that OHSS, as such, is a disease that practically does not allow for etiological treatment.

Etiology of OHSS

To date, the etiology of OHSS remains unclear in many ways. In addition to the fact that this is a completely iatrogenic condition that occurs only in women receiving direct or indirect ovulation inducers that are capable of producing a super-response of the growth of a large number of follicles, it is unequivocally clear that this is an hCG-induced condition that never develops when the introduction of an ovulation trigger is refused, so as a continuation of the activation of the ovaries by the hCG hormone in early pregnancy or after additional administration, it provides a prolongation of the pathological condition.

In conditions of a generally understandable cause of the trigger factor and a vivid clinical picture caused by pathological vascular permeability, the mediating mechanisms for the development and course of OHSS remain unknown to the end. So, almost all substances produced by the ovaries with one or another physiological vasoactivity and proangiogenicity were suspected of complicity, including prorenin, renin, prostaglandins, angiotensin II, vascular endothelial growth factor (VEGF), tumor necrosis factor α (TNF-α), insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), basic fibroblast growth factor (BFGF), platelet growth factor (PDGF), transforming growth factors
(TGF) α and β, and interleukins 1β, 2, 6. At the same time, researchers emphasize the vascular endothelial growth factor (VEGF) (Levin ER, Rosen GF, Cassidenti DL et al., 1998; Neulen J, Yan Z, Raczek S et al. 1995; Pellicer A, Albert C, Mercader A et al. 1999). VEGF levels have been shown to correlate with the severity of OHSS, and recombinant VEGF has been shown to be able to induce manifestations of OHSS in rabbits.

Pathogenesis of OHSS

Clinical manifestations of OHSS are caused by a cascade of pathological processes arising from an increase in overall vascular permeability, but primarily in the capillary vascular bed. As a result of this, the intravascular fluid is redistributed into the third space (abdominal, thoracic cavities, pericardial cavity) and the intercellular space.
As a result, ascites, pleural and pericardial effusion, and hemoconcentration develop.
As a result of hypovolemia and compression of the inferior vena cava by increasing (tense) ascites, venous return (blood flow to the heart) decreases, cardiac output decreases, which in turn leads to a decrease in hepatic blood flow and a decrease in proximal renal perfusion, which, together with hypovolemia, leads to oliguria, electrolyte disorders (hyponatremia, hyperkalemia, hypocalcemia, prerenal azotemia and acidosis), renal failure. Increasing hypovolemia is complicated by thrombotic disorders, which in themselves carry potential risks, which, together with a decrease in capillary blood flow due to redistribution of blood, are realized in local ischemic manifestations with a variety of consequences. The increase in pleural and pericardial effusion further aggravates the course of OHSS. As can be seen, the pathological circles are closed at the level of hemoconcentration, hypovolemia, accumulation of fluid in the third space and oliguria.

Risk factors and prevention of OHSS

OHSS is a special condition in that it has a strong connection not only with the nature of the treatment, but, importantly, to a greater extent with the data of a particular patient undergoing a stimulation protocol. From the very beginning, it became clear that OHSS is a contrast disease that, in principle, does not occur in one group of patients and is difficult to manage with a huge destructive potential in another. Understanding this, in an attempt to properly plan the treatment logic and obtain the follicular response required from the standpoint of the quantity and consequences, each reproductologist automatically scrolls the same cycle of questions and answers in his head, helping to navigate the availability and activity of the follicular reserve, obtaining a proper response to stimulation, but avoiding the development of OHSS.

So, a number of comparative studies on the risk assessment of OHSS when using urinary (human menopausal gonadotropin (HMG-HMG)) and recombinant gonadotropins (rFSH) showed divergent conclusions, either highlighting HMG as safer drugs from the position of the risk of OHSS, then smoothing out which ones or statistical differences (Out HJ, Mannaerts BM, Driessen SG, Bennink HJ, 1995). Despite this, the greater biological potential of rFSH is probably still associated with a greater risk of developing clinically significant OHSS, as it is associated with a large number of oocytes obtained.

However, the choice of gonadotropin for induction is actually less important than the choice of protocol and tactics of induction.
An important point of controlled stimulation is the choice of tactics of induction. It is known that there are two types of tactics:

• Up-scaling protocol with a low start, with the possibility of adjusting the dose upwards, if necessary, to save more follicles from atresia
• On the other hand, a downsizing protocol implies a high dose of the inducer at the start, with the possibility of reducing the dose of FSH administered up to complete failure (controlled skidding or coasting) with a coasting of 1-3 or more days before the trigger is introduced (Sher G et al., 1993 , 1995).

To date, it is well known that the start of the complex mechanism of ovarian hyperstimulation syndrome is triggered by exogenous hCG. Understanding this principle has led reproductologists everywhere to abandon the use of hCG as an element of post-transfer support in cases of potential or even theoretical risk of OHSS, replacing it with progesterone and, if necessary, estrogen supplements. As well as the search for attempts to exterminate OHSS, as a practical nosological unit, by avoiding hCG in general, including in the form of an ovulation trigger.

The discovery of the principle of triggering follicles, through the introduction of hCG, was a breakthrough in reproductive medicine, as it made it possible to standardize the quality of treatment. But it was from this therapeutic step that the history of OHSS began.
Understanding this alignment prompted researchers to look for an alternative to exogenous hCG. And it is logical to assume that it was proposed to use exogenous LH as endogenous LH.

The obvious disadvantages of LH replacement include the high cost of recombinant LH and its short half-life (about 20 minutes), which forces the use of high doses of the drug, with possible repeated injections, to ensure close to physiological hormonal status, on the other hand, long-term administration and high doses of LH may not significantly reduce the risk of OHSS.
Comparison of rLH and rhCG in IVF cycles showed a reduced risk of progression of OHSS to moderate and severe stages (European Recombinant LH study group, 2001) in patients receiving a single dose of rLH.
Loumaye E, Piazzi A, Engrand P., 1998 published a comparative study of various doses of LH (from 5000 IU to 30000 IU) with 5000 IU rhCG. The authors concluded that adequate final induction was achieved in all groups and similar numbers of mature oocytes were obtained. At the same time, the risk of developing OHSS apparently directly depended on the dose of the administered trigger. Thus, in the group up to 10000 IU rLH OHSS of moderate and severe degree was not recorded. 1 out of 26 women who received 30,000 IU rLH developed moderate OHSS. While in 14 out of 121 women in the hCG (5000 IU) group, treatment was complicated by the progression of OHSS, with one in a severe degree.

The second trigger-replacement approach involves induction of native LH by administering a GnRH agonist in treatment cycles where possible (obviously, GnRH agonite cannot be used as an ovulation trigger in cycles where it was used as a pituitary desensitisation supplement).
Despite the theoretical logic of the approach, the first experience of using such tactics was not comforting (Breckwoldt M, Czygan PJ, Lehmann F., 1974; Crosignani PG, Trojsi L, Attanasio A, Tonani E., 1975), which diverted the attention of researchers from the topic for many years. However, they later returned to this topic. Lanzone A, Fulghesu AM, Apa R, Caruso A., 1989; Imoedemhe D, Chan R, Sigue A, Pacpaco E., 1991 approached the issue more consistently, being the first to report the successful use of a GnRH agonist as an ovulation trigger. This gave rise to numerous studies to evaluate the use of a GnRH agonist as an ovulation trigger in IVF cycles (Gonen Y, Balakier H, Powell W., 1990; Itskovitz J, Boldes R, Levron J, Erlik Y, Kahana L. 1991; Kulikowski M , Wolczynski S, Kuczynski W, Grochowski D., 1995), as well as cycles of controlled ovulation induction outside of in vitro fertilization (Gerris J, De Vits A, Joostens M.; Kulikowski M et al., 1995).
Most investigators agreed that the practice of using a GnRH agonist is associated with a reduced risk of developing moderate to severe OHSS by providing an adequate number of good quality oocytes. More importantly, during the entire period of using the approach, no unmanaged critical OHSS was recorded at all.
However, in the process of widespread practice, the approach revealed one significant minus - a decrease in the frequency of pregnancy, due to the deepest deficiency of the luteal phase. In such circumstances, a proposal for a two-stage treatment of patients with a high risk of OHSS, involving the replacement of the ovulation trigger with a GnRH agonist, the receipt of oocytes, and the subsequent cryopreservation of high-quality developing embryos, has matured by itself. Using them in the Thawing cycles of the second stage. Griesinger G et al., 2007, showed the adequacy of this approach with a commensurate cumulative pregnancy rate, with a complete absence of moderate and severe degrees of OHSS.

Engmann L, DiLuigi A, Schmidt D et al., 2008 compared cycles with a GnRH antagonist threatening to develop OHSS. In the first group, for the purpose of preventing OHSS, the principle of a downward protocol was used, if necessary with a controlled drift (coasting), in the second group, a GnRH agonist was used as a trigger, and in the second group of patients, the authors used an estrogen lutein supplement, in addition to progesterone. The authors found no difference in pregnancy rates between the two, but 31% of all patients in the hCG trigger group required medical attention for clinically significant forms of OHSS, compared with no such problems in patients in the agonist-trigger group.

An interesting question is the choice of the type of protocol and the risk of developing moderate and severe OHSS.
The practicing reproductive specialist knows that for all its advantages, the long "C" protocol with a GnRH agonist offers a significantly lower ability to control a cohort of developing follicles, compared with a protocol when a GnRH antagonist is used to suppress the ovulatory LH peak. It is logical to conclude that there is a greater risk of OHSS in patients in the long protocol.
However, for objectivity, it should be noted that the conclusions of the researchers in this part of the issue differed.
So Griesinger G, Diedrich K, Tarlatzis BC, 2006, did not reveal a difference in the incidence of moderate and severe OHSS when comparing the long protocol and the protocol with ant-GnRH.
In contrast, later volumetric meta-analyses (Al-Inany H, Abou-Setta AM, Aboulghar MA., 2007; Ludwig M, Katalinic A, Diedrich K., 2001) and multicenter studies (Ragni G et al., 2005), who demonstrated a statistically significant reduction in the incidence of OHSS in GnRH antagonist protocols, with cetrorelix being more preferable than ganirelix.

There are studies in which the authors suggest increasing the dose of a GnRH antagonist to more reduce the risk of developing severe forms of OHSS (de Jong D et al., 1998), suggesting that deeper suppression of gonadotropin excretion, in the OHSS-threatened group, may be more effective with positions of the discussed risks.
There are also works suggesting to continue desensitization of the pituitary gland in long and short protocols with a GnRH agonist (Endo T, Honnma H, Hayashi T et al., 2002) or to block the gonadotropin-secretory activity of the pituitary gland with a GnRH antagonist for a long (up to 7 days) period after the introduction of an ovulation trigger in cycles followed by embryo conservation. However, this approach seems to be controversial from the point of view of the efficiency/cost balance, since the activity of the corpus luteum, and therefore the risk of developing early OHSS in patients in protocols with a GnRH agonist, is provided primarily by stimulation of exogenously administered hCG, and not endogenous LH. And the exclusion of the risk of progression of OHSS in patients in the ant-GnRH protocol is almost guaranteed to be ensured by replacing the trigger with a GnRH agonist, which in itself provides adequate prevention of the risk of moderate and severe OHSS.

Considering that OHSS is accompanied by a decrease in the volume of circulating blood due to the loss of the liquid part of the blood, the use of colloidal blood substitutes at the time of follicle puncture was proposed for prophylactic purposes (Shalev E et al., 1995; Isik AZ et al., 1996; Gokmen O and et al., 2001). Such a strategy seems even more logical if we remember that at the time of puncture, in addition to the liquid part of the blood plasma, there is also latent blood loss in the cavity of multiple follicular cysts, which, despite a relatively small volume, can still acquire clinical significance in conditions of already progressive OHSS. At the same time, the value of albumin is considered to be reliably proven, and the value of hydroxyethyl starch preparations for prophylactic purposes remains unclear.
However, an understandable limitation to the use of albumin is its inherent allergic reactions, risk of viral and prion diseases, and cost.

Metformin and second-generation biguanide, insulin synthesizers, have proven to be potentially useful in a group of patients at risk for OHSS (DeLeo D., 1999; Khattab S. et al., 2006).

Corticosteroid drugs (Rjosk HK, Abendstein BJ, Kreuzer E, Schwartzler P., 2001) can still be considered only an experimental treatment step, since other studies have not shown themselves to be really effective (Lainas T, Petsas G, Stavropoulou G and et al., 2002; Tan SL, Balen A, el Hussein E, 1992).

At various points, opinions were expressed about the effectiveness of certain drugs in preventing the progression of OHSS (indomethacin, angiotensin-converting enzyme (ACE) inhibitors, pentoxifylline). Unfortunately, most of them have proven to be relatively ineffective or have potential teratogenic properties and thus are contraindicated when used in IVF cycles.

Interesting in terms of perspectives in the prevention of OHSS are studies aimed at VEGF as a significant participant in the development of the syndrome. Thus, encouraging data have been obtained using a VEGF receptor antagonist in a rat model (Gomez R et al., 2002).

From this position, the effect of cabergoline (Dostinex), a dopamine receptor agonist that inactivates the VEGF receptor-2, is understandable. A prospective, randomized, double-blind, controlled trial conducted by Alvarez C et al in 2007 showed the efficacy of the drug at a dose of 0.5 mg per day from the day of hCG administration as an ovulation trigger in induced cycles with oocyte donation.

Embryo transfer tactics
Given the importance of the presence of hCG in the blood for the development and maintenance of pathological ovarian activity in the context of OHSS, it became logical to offer cryopreservation of all developing high-quality embryos. This approach guarantees a block in the development of late OHSS, which manifests itself in response to the chorionic activity of the implanted embryo (Garrisi G, Navot D., 1992).

Another important observational nuance is the dynamics of OHSS development. As is known, early OHSS induced by a trigger dose of hCG gains its peak severity by 3-5 days after follicle puncture. Further dynamics often has a negative vector, which is easily explained by the presence of hCG in the blood. It has been noted that the absence of complicated OHSS on the day of blastocyst transfer is characterized by a good prognosis of late OHSS. On the other hand, higher rates of pregnancy during blastocyst transfer allow achieving a higher pregnancy rate for transfer, which insists on the practice of selective transfer, at least in the group of patients threatened by OHSS (Kinget K. et al., 2002; Trout SW, Bohrer MK , Deifer DB, 2001).

A promising direction in reproductive medicine from the standpoint of preventing the risk of OHSS is to improve work with immature oocytes (Child TJ et al., 2002; Tan SL et al., 2002)

Treatment

The treatment of OHSS is empirical in nature, so it depends entirely on the individual clinical case.

Mild forms of OHSS do not require medical treatment, only increased fluid intake. Without embryo transfer or in the event of no pregnancy, the cure resolves on its own within a few days, almost immediately after the removal of hCG from the blood, usually 7-10 days after the introduction of an ovulation trigger. When pregnancy occurs, mild OHSS can progress, but most often no further than moderate severity, which does not require hospitalization in most cases. The practice of IVF in most treatment cycles is accompanied by the development of mild OHSS, which allows us to call this form of the disease not a complication, but an expected consequence. Avoiding aggravation of the condition may be considered a logical management of a patient who required ovulation induction as such.

Patients with moderate OHSS need a significant increase in fluid intake, a protein diet, with the use of special protein preparations, if necessary, replenishment of the circulating blood volume and anticoagulant therapy. The patient is instructed to control the amount of fluid drunk, excreted urine (as an indicator of oliguria), the dynamics of body weight and abdominal circumference (as markers of an increase in intra-abdominal fluid and edema)

Dynamics of hematocrit, with an increase of > 45%, or 30% of baseline, indicates the development of severe OHSS, while an increase in hematocrit by 1% indicates a loss of 2% of the liquid part of the blood plasma. This ratio is useful to remember when planning fluid therapy, in which both under- and over-replenishment can have a negative effect. The second laboratory signal of worsening OHSS can be an increasing leukocytosis above 20-25,000/mm3 due to hemoconcentration and general stress response. This picture cannot be compensated by oral fluid intake. And although crystalloids are not able to adequately replenish the deficiency of the liquid part of the blood plasma, due to high vascular permeability, the state of hyponatremia insists on the need to use drugs of this series, the most logical of which can be considered saline, with calcium supplements if necessary. The volume of crystalloid infusion can vary from 1.0 L to 3.0 L, rarely more. It is important to remember that in conditions of high vascular permeability, despite a rapid improvement in renal perfusion, crystalloids tend to exacerbate ascites and hydrothorax. In contrast, the restriction of fluid intake / infusion has a positive effect on ascites, but negatively on renal and hepatic perfusion, threatening the development of multiple organ failure, hemoconcentration, which is certainly unacceptable in the treatment recommendation, as it will lead to the development of a critical condition.

The patient's condition is monitored according to the diary, where Blood pressure, Pulse, Abdominal circumference, Body weight, Volume of drunk and excreted liquid are recorded. As well as laboratory data reflecting hemoconcentration, electrolyte balance, liver and kidney function, blood proteins, as well as indicators of the hemostasis system. If the correction of the state with crystalloids is inadequate, colloid infusions (hydroxyethyl starch preparations (HES), albumin) are connected to therapy. Albumin has the most adequate replacement properties, since it is the main protein lost from the bloodstream when OHSS worsens. Doses of administered HES and albumin, the frequency of administration can vary widely. The reference point for the adequacy of treatment is hematocrit and diuresis. Awareness of the adequacy of the replenishment of the liquid part of the blood plasma, in conditions of persistent oliguria, may be the reason for the episodic use of furosemide at the height of the infusion. It is important to remember that the use of furosemide in conditions of hypovolemia can provoke hypovolemic shock, therefore, it is categorically unacceptable.
The risk of developing thrombotic complications insists on the background use of anticoagulants, however, the dose of the latter can be increased if necessary, according to laboratory data.

Paracentesis, as a way to evacuate ascitic fluid that accumulates excessively in the abdominal cavity, almost immediately established itself as a necessary method of treating patients with severe and critical OHSS.
It is performed under aseptic conditions under ultrasound guidance. Indications for paracentesis are intense ascites, which exacerbates hemodynamic disturbances by compression of the inferior vena cava, kidney and liver function.
The technique allows evacuation of excess fluid through a puncture of the anterior abdominal wall, including with the installation of a permanent catheter or through the vagina. Various options for fluid removal are also allowed, involving spontaneous evacuation under the action of gravity and intra-abdominal pressure, or using a vacuum pump. During the manipulation it is not recommended to simultaneously remove large volumes of fluid, it is also not recommended to remove all fluid from the abdominal cavity, it must be remembered that with the removal of ascitic fluid from the patient's body, large volumes of protein are permanently removed.
As a possible option for replenishing protein loss, suggestions can be found in the press for the use of recirculation of ascitic fluid into the venous bed (Koike T et al., 2000), which reduces the need for exogenous albumin and the volume of infusion therapy.
Paracentesis is contraindicated in patients with suspected intra-abdominal bleeding.

In case of aggravation of the course of OHSS, decompensation of the condition with the development of multiple organ failure in conditions of critical OHSS, unfortunately, almost the only effective method of treatment remains termination of pregnancy for health reasons.

As a conclusion

Ovarian hyperstimulation syndrome is perhaps the most recognized diagnosis in the field of clinical human reproduction. Unfortunately, for many years this nosology has actually been an indispensable companion of in vitro fertilization, being recognized as an inevitable price for the opportunities offered by the IVF technology itself (Abramov Y, Elchalal U, Schenker JG, 1999).
Meanwhile, OHSS is a complex and voluminous disease from the standpoint of understanding pathological processes, constantly striving to aggravate each symptom individually and the general condition of the patient's body as a whole. Dynamics of development, not always sufficient prognostic value of the symptomatic and laboratory picture, large devastating consequences and sometimes ineffective symptomatic therapy that we have, force us to recognize OHSS as a serious opponent. And here the paraphrased aphorism of Baurzhan Toyshibekov is best suited: “The best war is the one that was avoided.” And, fortunately, the history of human reproduction is replete not only with the facts of ascertaining the consequences of ineffective treatment of OHSS, but also with reasonable and balanced suggestions on how to prevent (“avoid”) it. Today, it is enough for the treating doctor who plans the logic of the stimulation protocol to correctly answer only a few simple questions, and thereby significantly reduce the risk of severe forms of OHSS that cannot be properly corrected, leaving only a few percent of the risk behind the unpredictability of the syndrome itself. Continuing the theme of war aphorisms: “If you want peace, prepare for war” - Flavius ​​Renat Vegetius, a statement that fully reflects the essence of OHSS, approaches to its prevention and treatment.

Pregnancy is a difficult period for a woman's body. Even in healthy patients, there is a risk of developing unpleasant complications that threaten both her health and the condition of the baby. In the presence of a number of gynecological problems, it is not possible to conceive a child at all. In such cases, they resort to artificial stimulation of the ovaries by introducing appropriate drugs. This method is highly effective, but leads to the development of unpleasant consequences if a woman has chronic diseases. Ovarian hyperstimulation is a problem that occurs during the hormonal correction of the hormonal background in order to achieve active growth and maturation of the follicles. This method of treating infertility is being used more and more often, and therefore the breadth of the spread of the disease is increasing. This disease requires immediate treatment.

Ovarian hyperstimulation syndrome (OHSS) can develop not only in a patient who is undergoing an in vitro fertilization (IVF) procedure. The disorder is also diagnosed in spontaneous pregnancy, although in such cases the risk of its occurrence is less.

Causes of ovarian hyperstimulation

The exact pathogenesis of the formation of the syndrome is unclear. It is known that the sexual cycle of a woman has several phases. During each period, the production of appropriate hormones is carried out, which ensure the process of growth and development of the follicle. When the oocytes mature, they rupture, and an egg ready for fertilization comes out of them. The fluid in the bubble moves into the pelvic and abdominal cavity, while its amount is insignificant. The cascade of reactions is regulated by substances such as estradiol, progesterone, histamine, and others. These compounds control not only gonadal function but also vascular permeability. It is the increase in the porosity of the veins and arteries that leads to the sweating of fluid outside the bloodstream.

With artificial stimulation of the maturation of the germ cell, a significant violation of physiological processes occurs. To increase a woman's chances of getting pregnant, doctors provoke the maturation of a large number of follicles at the same time. When performing a puncture to stimulate ovulation, a significant increase in vascular permeability and the release of the liquid part of the blood beyond their limits are recorded. A mature oocyte also contains a large number of immune cells that aggravate the course of the disease. There is the development of ascites or dropsy, as well as significant irritation of the peritoneum, which is accompanied by pain. OHSS after puncture develops quite often, but has a different intensity of clinical manifestations.

There are several factors that predispose to the development of ovarian hyperstimulation syndrome:

1. The woman's age is less than 35 years. In this case, most often the pathology is diagnosed in fair-haired women.
2. The low body weight of the patient is also associated with a higher risk of developing the problem.
3. A woman has a history of polycystic ovary syndrome. The diagnosis of this pathology is associated with existing malfunctions in the hormonal system of the body, therefore, artificial stimulation of ovulation is accompanied by even greater disturbances and the development of dangerous consequences.
4. Patients with high levels of estradiol are also more likely to suffer from pregnancy complications and in vitro fertilization.
5. Women who are prone to allergies are more prone to this problem. This is due to the supposed active involvement of immune factors such as cytokines, macrophages, and histamine in the pathology.

Classification and main symptoms

It is customary to distinguish between two forms of the disease:

1. Early ovarian hyperstimulation syndrome is recorded within a few days after ovulation. If the embryo does not implant into the endometrium, that is, it does not fix in the uterus and further develop, then OHSS ends on its own when menstrual bleeding forms. In cases where, after the maturation of the germ cell, it is possible to achieve pregnancy, unpleasant symptoms can disturb the woman for a long time, so they require treatment.
2. The late form of ovarian hyperstimulation syndrome arises from the early form with successful conception. As a rule, it is registered from the 5-week period and can appear up to 4 months of gestation. The problem must be treated, as it can cause serious harm to both the health of the mother and the condition of the child.

The symptoms of ovarian hyperstimulation vary in intensity depending on many factors. The main clinical signs of the disease include:

1. Heaviness, discomfort or even soreness in the lower abdomen. It is explained by irritation of the peritoneum as a result of an increase in the volume of the ovaries, and is also provoked by the accumulation of fluid in the cavity with an increase in vascular permeability.
2. Dyspeptic disorders are a common manifestation of OHSS associated with the anatomical features of the location of the genital organs and intestines. With the activation of the immune system and the development of ascites, mechanical compression and irritation of the digestive tract occurs, which is accompanied by vomiting and diarrhea.
3. An increase in the volume of the abdomen is usually detected in severe cases of OHSS. This is due to the accumulation of effusion in the abdominal cavity.
4. The formation of ascites is complicated by the development of hemodynamic disorders. The release of the liquid part of the blood from the circulatory system leads to a drop in blood pressure, heart failure and other symptoms.

Dangerous consequences of OHSS

In addition to the discomfort that occurs during pregnancy as a result of hyperstimulation of the gonads, more severe complications are possible. Due to the active growth of follicles and the formation of cysts, the risk of rupture of these formations, the development of an ectopic pregnancy and torsion of the appendages of the gonads and the ovaries themselves increases. Since OHSS also has a systemic effect, the possible consequences also include the formation of renal failure, impaired liver function, and the occurrence of thromboembolism of large arteries.

Diagnostics

Confirmation of the development of hyperstimulation is made on the basis of characteristic clinical manifestations. Analyzes are carried out to assess the severity of hemodynamic disorders and to identify the level of concentration of sex hormones. Ultrasound allows you to measure the ovaries and evaluate their structure by creating special photos of the pelvic organs. Gonads in the study of ultrasound have a characteristic appearance. Free fluid in the abdominal cavity is also determined, the amount of which depends on the severity of the disease.

Therapeutic measures

In order to prevent the dangerous consequences of the hyperstimulation syndrome, timely correction of the patient's condition is required. With mild OHSS, restriction of physical activity and sexual intercourse is prescribed, as well as a special diet with a high protein concentration. Condition control in such cases is carried out at home. If there is a rapid increase in ascites and other dangerous symptoms of the disease, hospitalization is recommended. Infusion therapy is carried out, aimed at replacing the normal volume of circulating blood with the introduction of antiplatelet drugs.

Preventive measures

In order to avoid ovarian hyperstimulation during IVF or spontaneous pregnancy, it is important to take into account all possible risks and the individual characteristics of the patient. Since OHSS is often associated with in vitro fertilization, the most modern and safe protocols and drugs should be used. After the procedure, constant medical supervision is required to prevent a rapid deterioration in the woman's well-being. Even in the absence of complaints about health conditions, patients are advised to visit the doctor periodically to prevent possible complications.

There are several indications for the use of gonadotropins used to stimulate the ovaries. Such protocols minimize the negative consequences of preparing the female body for pregnancy. All of them are aimed at limiting the concentration of follicle-stimulating hormone. This tactic allows for the development of a few dominant vesicles rather than multiple ones. It is the simultaneous maturation of a large number of eggs that provokes the development of symptoms. Recommendations boil down to the following:

1. Stopping the cycle when OHSS occurs, that is, stopping the use of human chorionic gonadotropin. Although this approach often leads to the failure of IVF, in some cases it is the only way to avoid fatal consequences.
2. Reducing the introduction of hCG with the simultaneous use of GnRH agonists is justified in patients with high levels of estradiol and a large number of maturing follicles. This helps to prevent the development of hyperstimulation syndrome.
3. There is evidence that even small doses of human chorionic gonadotropin can lead to ovulation. Therefore, it is recommended to use the minimum amount of the drug to reduce the risk of complications.

The effect of ovarian hyperstimulation is present in women who are susceptible to ovulation during and during in vitro fertilization. During a normal menstrual cycle, one egg is produced in the female body.

Ovarian hyperstimulation syndrome (OHSS) is characterized by the use of drugs to increase the number of eggs. This disease is determined by an increase in the size of the ovaries with the possibility of a breakthrough of cystic formations. The result of ruptured cysts is the accumulation of excess fluid. An important phase in preparing the body for in vitro fertilization is the use of drugs that provoke the formation of eggs in large numbers.

When preparing IVF, a manifestation of hyperstimulation syndrome is possible. Specialists cannot determine the occurrence of HOS, however, according to observations, several reasons have been identified in which hyperstimulation has an increased chance of manifestation:

• Excess content of the female hormone in the body;
• Polycystic disease;
• genetic inheritance;
• Allergy;
• Age categories (less than 35 years old);
• Processes of OHSS in the past.

Symptoms

There are three degrees of hyperstimulation:

- light;

- average;

- heavy.

With a mild degree of hyperstimulation syndrome, the following symptoms appear:

• Pain in the inguinal region of the abdomen, the presence of swelling and heaviness;
• Swelling of integumentary tissues;
• Fatigue, fatigue, drowsiness.

For the average degree, the following symptoms are characteristic:

• Headache, dizziness, fatigue;
• Pain in the groin;
• Vomiting, diarrhea, indigestion;
• Decrease in the amount of urine outflow;
• Rapid weight gain;
• Swelling of limbs and genitals.

In severe form, the following symptoms appear:

• Drowsiness, fatigue, headaches and dizziness;
• Painful spasms in the groin;
• Feeling of fullness in the abdominal cavity;
• Increase in body temperature;
• drop in blood pressure;
• Swelling of external organs;
• Decreased urge to urinate;
• Difficulty in breathing;
• Dysfunction of the rhythm of the heartbeat;
• Vomiting, diarrhea.

Degrees of hyperstimulation syndrome

There are the following degrees of OHSS:

• The mild form is characterized by pain in the groin and an increase in the size of the ovaries, up to about 10 cm;
• Medium degree - an increase occurs up to 12 cm;
• A severe degree manifests itself with an increase in the size of the ovaries over 12 centimeters;
• The critical degree is characterized by the release of a large amount of fluid into the internal cavities of the body and an increase in the ovaries.

Prevention

The use of ovarian stimulation protocols in in vitro fertilization sometimes leads to the formation of hyperstimulation syndrome. There are a number of preventive measures:

1. Violation of the IVF cycle and cancellation of embryo transportation;
2. Freezing embryos and placing them in the uterus using the natural cycle of menstruation;
3. Reviewing the use of hormonal drugs;
4. Cancellation of the in vitro fertilization procedure;
5. Carrying out control measures for the content of hormones;
6. Systematic examination of the patient.

If you feel the above symptoms, you should immediately consult a doctor.

Complications

After the transfer of the disease of ovarian hyperstimulation, the following complications occur:

• The appearance of ascites - the collection of a large amount of water in the tissues of the abdominal cavity;
• Violations of the function of the respiratory and cardiac systems;
• Impaired kidney function;
• Ectopic pregnancy.

Diagnosis of ovarian hyperstimulation

Diagnostics includes the following steps:

• Carrying out an anamnesis of the patient (surveys, examination);
• Physical examination is characterized by determining the general condition of the patient. On examination, the condition of the skin is noted (swelling, pigmentation changes, breathing, palpation of the abdominal cavity);
• Laboratory examinations include biochemical tests of blood, urine, tumor markers;
• Instrumental studies (ultrasound radiation, X-ray, cardiography);
• Differential diagnosis is carried out by an oncogynecologist before the procedure for including a woman in an IVF program.

ovarian hyperstimulation during pregnancy

With ovarian hyperstimulation, the chances of getting pregnant are halved. The IVF process itself is no different from the usual process. Pregnancy has a negative effect on hyperstimulation, that is, this disease becomes severe. The body of a woman undergoes changes in physiological and hormonal levels. These processes lead to a dysfunction of the state and a violation of well-being, approximately at the 14th week of pregnancy.

The development of pregnancy during OHSS disease a woman undergoes complications: in the first periods - the threat of miscarriage, in the later stages - premature birth.

Treatment of hyperstimulation

If mild OHSS occurs, a systematic ultrasound procedure is used to monitor the size of the ovaries. At this stage, it is also necessary to carry out tests to establish the quantity and quality of hormones in the female body. A mild form of ovarian hyperstimulation syndrome does not require specific medications. It is enough to follow a few rules:

• Drink plenty of water every day (mineral water, decoctions, teas, compotes);
• The use of diet food (lean meat, nuts, greens, dairy products);
• Restriction of sexual life, physical work;
• Daily monitoring of weight, stool and urination.

The average degree is characterized by the use of glucocorticoid, antihistamine, antiprostaglandin drugs. The consumption of activated carbon has an effective effect.

The severe form of OHSS requires more thorough treatment. The basis of therapy is the use of drugs aimed at the restoration and functionality of the blood flow. In these cases, injections of solutions are carried out to retain moisture in the bloodstream. Such drugs are used: reopoliglyukin and polyvinylpyrrolidone. With ascites, it is recommended to pump out excess water from the body. The pumping process is carried out under ultrasonic monitoring. If fluid accumulation resumes, re-pumping is carried out.

Operations are carried out in the following cases:

• rupture of ovarian cysts;
• bleeding;
• ectopic pregnancy.

Therapy for moderate to severe ovarian hyperstimulation syndrome is performed in a medical facility under the supervision of specialists. A woman undergoing treatment undergoes a complete examination of the kidneys, liver, heart. The doctor examines the patient and establishes the body structure, weight.

Treatment of ovarian hyperstimulation syndrome with traditional medicine recipes

The following traditional medicine recipes are well known:

• Pour 2 pinches of chopped parsley with boiled water. Set aside for 10 hours. Strain and take 3 times a day before meals. The duration of the course of treatment is about three weeks;
• Pour half a teaspoon of parsley seeds with warm boiled water. Insist for 10 hours and take sips throughout the day;
• Boil the onion peel with two cups of boiling water and insist. The resulting solution is taken 4 tablespoons three times a day before meals;
• Grate lemon or orange zest and mix with sugar. Use one teaspoon;
• Juniper fruits, wormwood, 2 tablespoons of Potentilla pour a glass of boiling water, set aside. Take the resulting mixture in a glass every day.

Video: Ovarian Hyperstimulation Syndrome

Conclusion

If ovarian hyperstimulation syndrome is detected, pregnancy is contraindicated. The manifestation of the symptoms characteristic of this disease, it is necessary to urgently contact your doctor for qualified assistance.

One of the most frequent and most formidable complications that occur during artificial insemination is ovarian hyperstimulation during IVF. Its main reason is the excess of doses of drugs that are administered to stimulate ovulation. In the vast majority of cases, this condition is successfully treated - but only on condition that the necessary measures were taken in time.

Under natural conditions in the female body, one egg cell matures in each cycle. With hormonal stimulation in the process, their number increases several times. This increases the chances of conception, but at the same time increases the production of estradiol, which results in thick blood, impaired capillary permeability, and the appearance of excess fluid.

OHSS can occur in any patient with the wrong choice of drugs and their dosage. However, there are several factors that contribute to its development:

• polycystic ovaries;
• tendency to allergic reactions;
• increased activity of estradiol;
• the use of hCG preparations to support the luteal phase;
• offensive;
• external signs - more often the syndrome develops in thin women under 35 with blond hair.

Symptoms

Most often, signs of hyperstimulation appear after embryo transfer, less often - immediately before it. Very rarely they are found even on the background of stimulation. The strength of their manifestation depends on the degree of development of the syndrome:

1. Mild degree: slight swelling, pain as during menstruation, heaviness in the abdomen, frequent urination. On ultrasound, it can be seen that the ovaries increase in size up to 6 centimeters.
2. Medium degree: bloating, increased swelling, weight gain, vomiting and nausea. The size of the ovaries is 8-12 cm.
3. Severe degree: a noticeable increase in the volume of the abdomen, vomiting, hypotension, shortness of breath, interruptions in the work of the heart. In addition, signs of ascites are noted, the functioning of the liver is disturbed, and accumulation of fluid in the pleural cavity is recorded. The ovaries are enlarged more than 12 cm.

Some of the symptoms the patient describes in her reviews:

Anya: “About a week after the transfer, I began to have severe itching, which lasted 15 days. At the same time, liver enzymes were 10 times higher than normal, I generally keep quiet about hormones. A month after the support was canceled, everything returned to normal, there is no water anywhere, however, I lost a little weight.

Natasha: “I had a very severe hyper. A lot of fluid has accumulated - 10 liters in the stomach and 1.5 liters in each lung. For a month I hardly ate, could not sleep, screamed from pain. For almost a month I lay under a dropper, the pregnancy eventually froze at the eighth week. The fluid went away completely only after four months.

Ira:“It all started on the sixth day after the transfer. At first it was tolerable, kept a diet and drank. Then it twisted so that they called an ambulance, they performed an operation in the hospital. It turned out that a huge cyst had formed, due to which the ovary was twisted. ”

How to treat?

The basis of the treatment of mild hyperstimulation is a protein diet and plenty of fluids.

Methods for treating ovarian hyperstimulation afterward depend on the severity. In all cases, diet is important; at the first degree, it becomes the leading method of treatment, which is carried out at home. OHSS diet and lifestyle suggest:

• drinking plenty of water, except for alcohol and carbonated drinks;
• the use of protein foods;
• in priority - lean white meat, lean veal, boiled fish;
• balanced nutrition with the inclusion of cereals, greens, nuts in the menu;
• refusal of physical activity and sexual relations.

If OHSS has developed to a moderate or severe degree, treatment is carried out in a hospital. As a rule, medications are used:

• designed to reduce vascular permeability;
• aimed at preventing the development of thromboembolism;
• designed to adjust the protein and electrolyte composition of plasma.

In severe cases, treatment of ascites by pumping fluid from the abdominal cavity and surgical intervention may be indicated - for example, if cyst ruptures and internal bleeding occur. In the reviews, the patients talk about the methods of treatment prescribed to them:

Maria:“You need to drink plenty of water and eat protein foods. Nothing salty and no diuretics! You still can’t eat foods that can cause bloating - grapes, black bread, legumes, cabbage. Fish and meat are allowed without restrictions.

Katia:“I started after the puncture - by the evening my stomach ached, it was difficult to breathe, I could not be in an upright position. The next day he was admitted to the hospital, they put refortan droppers. But in the end, the embryos were sent to cryo, and replanting was done only after two cycles.”

Julia: “My hypera started early, two days after the puncture. I was immediately dripped, then for another two days I lay for six hours under droppers. From problems with the intestines, which almost everyone has, I drank Dufalac and Hilak forte.

Eve: “I was covered the next day after the puncture, everything lasted about a week. The abdomen was huge, they wanted to puncture, but everything worked out with droppers - they put refortan and albumin. From the droppers, it only felt worse, it seemed that the stomach was about to burst. But in fact, they are necessary, because it is physically impossible to eat so much protein.

Possible consequences

With OHSS, it occurs almost twice as often. However, if pregnancy still occurs after IVF in the presence of hyperstimulation, then the syndrome significantly complicates its course, especially in the first trimester. In addition, in severe form, the following complications may occur:

• ascites;
• respiratory failure due to the appearance of fluid in the chest cavity;
• kidney failure;
• ovarian rupture;
• torsion of the ovary with subsequent necrosis;
• premature ovarian failure.

How to avoid hyperstimulation?

The main measure for the prevention of ovarian hyperstimulation in IVF is an individual approach on the part of the doctor, for the correct selection of drugs and their dosage. If symptoms have already begun to appear, the following measures can help prevent OHSS:

1. Cancellation of hCG injections.
2. aspiration of follicles.
3. Reducing the dosage of gonadotropic drugs.
4. Cancellation of embryo transfer and their .

In addition, in the reviews of the patient often mention the drug Dostinex and other drugs that are prescribed in small doses for prevention:

Yana: "From the seventh day of stimulation, I drank Dostinex as prescribed to prevent hyperstimulation."

Katia: “I had every chance of getting OHSS, because the male factor became the cause of infertility, and my body worked well even without stimulation. Besides, I'm 30 years old, I'm small and fair-haired. To avoid all this, I drank Dostinex. I know that someone does not tolerate it very well, there are nausea and dizziness. But I didn't see anything like that."

Vika: “The doctor advised me to take protein in capsules for two weeks after the puncture, 80 grams per day, it is sold in pharmacies. It helped me: they took as many as 40 cells, I was very afraid of hyperthermia, but everything worked out.

What is hyperstimulation syndrome and how to avoid it?

Planning to re-attempt IVF is not recommended for 2-3 months after hyperstimulation. This time is necessary to restore the hormonal background and normalize ovarian function. In difficult cases, if complications could not be avoided, preparation for a subsequent pregnancy should be carried out under the strict supervision of a doctor and only after the consequences have been eliminated.