Functional state of the reproductive system in women of late fertility age

The medical community cannot ignore the current trend in increasing childbirth rate at the late fertile age. Over the past decade, attitudes have changed. In the 1990s, if a woman of advanced reproductive age became pregnant, it was considered as a mistake in terms of family planning. Moreover, in many countries there has been a debate about the legal age limit for women of late reproductive age using modern reproductive technologies [1].

The existence of this trend is recognized not only at the medical, but also at the state level. “Late” childbirth is called by scientists a key reproductive problem of our days; however, this phenomenon has become an objective reality in obstetrics in the modern world [1, 2]. According to the World Health Organization, the optimal age for the childbirth ranges from 20 to 30 years, childbirth at the age under 19 years is considered as an early birth, and childbirth at the age over 35 years is a late birth [3].

In Russian and foreign literature a lot of attention is paid to the psychological status of pregnant women of late fertile age. Serious emphasis should be placed on the features of the state of the reproductive system and the impact of extragenital pathology at this age on the gestational process [4, 5, 6].

It is clear that the irregular menstrual cycle and age-related ovarian changes that precede menopause begin to influence the reproductive function of a patient after 35 years, and especially they have a negative effect on the function at the age of 40 years [1, 2, 3, 7].

Among scientists there is no consensus about the main reason for the sharp decrease in the ability of women of advanced reproductive age to conceive. The incidence of anovulatory menstrual cycles between 40 and 50 years ranges from 12% to 15% of the total number, while in women from 26 to 40 years, anovulatory cycles occur in 3 - 7% of patients.

Meanwhile, a significant proportion of premenopausal women maintain systematic ovulatory cycles with approximately the same level of steroid hormones as in the active reproductive period [8, 9]. However, according to the literature data, the ability of women over 35-40 years to conceive a child is 2-3 times lower, and the risk of abortion in such women is 4-7 times higher than the risk in younger ones. Hormone level changing with age affects the folliculogenesis, maturation of the endometrium, and embryonic development. It is also responsible for degenerative changes and apoptosis in the ovarian cells, which, according to some scientists, can cause malignant changes in its tissues with age [10, 11].

It is worth noting that age-related fertility decline is mainly caused by the changes in the level of follicle stimulating hormone (FSH) and estradiol, as well as by the decrease in the concentration of inhibin-B and Anti-Müllerian hormone (AMH). Thus, the main feature of the activity failure period of the female reproductive system is considered to be the change in gonad function. This age-related process is genetically programmed. Aging of the ovary, as an organ, as well as the impairment of other main functions including oogenesis and hormone formation, begins in the antenatal period and continues throughout life. It is known that the average weight of the ovaries begins to decrease after 30 years, and after 40 years the ovary turns into an organ rich in stromal elements and which is characterized by the development of various kinds of regressive processes [10, 11, 12].

Another important factor is the age-related changes in the uterus, which also cause a decrease in fertility. There are a lot of questions about this fact, but the exact answer to what exactly affects fertility decline “age of the ovaries” or “age of the uterus” remains unclear. It is known that the implantation of blastocysts in the endometrium is influenced by the level of hormones and their number varies over the years. This view is supported by Kleyn J. et al. [13], who found the dependence of increase in the frequency of luteal phase insufficiency on the patient’s age. At the same time, the prescription of progesterone drugs in the group of patients of late fertile age with luteal phase insufficiency did not contribute to the growth of the number of pregnancies. It prompted scientists the idea that implantation was influenced not only by the hormonal factor, but also the age-related characteristics of the uterus itself [13]. However, histological examination of the endometrium did not reveal any significant changes that could directly depend on the age of the patients [14]. When comparing two groups of patients in the IVF program with donor oocytes and receiving the same hormonal support with estradiol and progesterone, the histological picture of the endometrium in women over 40 years did not differ from histology of young patients [14].

The study of age-related features of the arterial uterine vessels and the structural elements of the uterine wall revealed sclerotic changes in the vessels of the myometrium, their obliteration and an increase in the number of collagen fibers in all layers of the uterine wall in women of advanced reproductive age, regardless of their parity [11, 15]. This circumstance explains the high frequency of pathology during labor in these patients.

In the group of primiparous women older than 30 years, the study of the sensitivity of myometrial receptors to progesterone detected its significant decrease in the active phase of labor in comparison with younger patients [10, 11]. Along with this research, Srinivas S. K. et al. [16] conducted a study on the reception of sex steroids in women who gave birth with a uterine scar. In the course of this study it was found that isolated sensitivity of receptors does not play a key role in the regulation of labor, but the dynamics of their ratio during childbirth are of critical importance [16].

The studies of the dynamics of age-related fertility decline have made it possible to develop a certain approach to achieve pregnancy in patients of advanced reproductive age using modern medical technology programs [17, 18, 19]. Therefore, a lot of studies are focused on the ovarian reserve, which is an assessment of reproductive potential in women. It is estimated with the help of specific data, including such key indicators as FSH, AMH, ovarian volume, inhibin-B and the number of antral follicles [17, 18, 19]. According to the literature, a significant decrease in these indicators with the age of women is undeniable [17]. For example, the results of a study that was conducted in the United States by Salihu H. M. et al. [20] showed a biexponential relationship between the reduction in the number of antral follicles and age-related changes in all organs and systems of a woman by the end of the 4th decade of her life. This explains the fact that among women over 35 years who were performed in vitro fertilization (IVF), the percentage of successful attempts was not more than 15%, and among patients over 41 years it did not exceed 5-8% [20]. A partial explanation for this can be found in the studies that indicate the presence of age-related changes not only in the nucleus, but also in the cytoplasm of the oocyte [21, 22, 23].

In advanced reproductive age, the necessity of oocyte donation may be explained by a significant age-related increase in the risk of chromosomal mutations in the ova [10, 11, 19]. It is believed that the accumulation of chromosomal abnormal egg cells, which can lead to the development of fetal malformations, may be associated with delayed ovulation and their overripening, which is characteristic of women of late fertile age. The release of a delayed, overripe egg cell usually occurs in the first ovulatory cycle after long-term anovulation. The proof of this theory is a large percentage of premature termination of pregnancy observed in patients older than 35-40 years with frequent anovulatory cycles [17, 19, 24]. On the other hand, it is noted in many studies that the high frequency of chromosomal-abnormal egg formation in patients of late fertile age is due to the gradual accumulation of abnormalities in the egg cells under the influence of various damaging environmental factors [25].

It is also known that the risk of having a baby with Down’s syndrome and other chromosomal abnormalities increases with age. For 20-year-old mothers it is one case per 1923 births, for 35-year-olds it is one case per 365, and for 40-year-olds it is one case per 100 births. Moreover, the non-disjunction of chromosome 21 leading to this genetic disease is associated with the pathology of the mother’s egg cell, but not the father’s sperm [26, 27].

According to some foreign scientists, the percentage of oocytes carrying gene mutations in women over 40 years is 60 - 70% [23, 28].

Other scientists who study the oocytes in women of late fertile age, believe that some of them carrying minor genetic changes (fragmentation of no more than two chromosomes in metaphase), can be normally fertilized and implant, having no morphological difference from healthy embryos. After missed abortion such embryos are subsequently likely to comprise the percentage of “genetically healthy” abortuses, although they all have mutations [24, 27, 28, 29].

In the study of maternal age in the group of children with autism, it was found that women at the age over 35 years are at risk. The age of the father who was over 40 was also of great importance. In cases where both parents were in the advanced reproductive period, the risk of having a baby with autism increased three times in comparison with young parents. Moreover, there are some works where the age of the father over 40 years is indicated as the risk factor of bipolar afferent disorders in a child [30, 31].

Many modern studies are devoted to the problem of preimplantation genetic screening in IVF. This method allows to detect the presence of chromosomal abnormalities and aneuploidy. But until now, the question about the need of conducting this screening in women of late fertile age remains understudied. Some authors consider it impractical because of the reduced number of pregnancies after this procedure [18, 26]. Other scientists believe that preimplantation diagnosis and transfer of certain euploid embryos in the IVF program to patients of late fertile age leads to a decrease in the level of abortion in the early stages [15, 31].

Assisted reproductive technology (ART) programs are the most effective methods to overcome infertility. However, in the group of patients of late fertile age, the effectiveness of ART programs does not exceed 10%, and the probability of pregnancy decreases by 4.7% for each year of life of a woman over 30 years [32].

It was revealed that patients of advanced reproductive age have a low level of AMH, which is a poor prognostic factor in ART programs. To date, AMH is the only proven laboratory criterion for the assessment of ovarian reserve. In clinical practice, the evaluation of AMH level in the blood serum is of great importance for predicting ovarian response, as AMH reflects not only the state of the follicular pool, but also the quality of oocytes [10, 19]. According to the consensus of the European Society of Human Reproduction and Embryology, the level of AMH≤1.2 ng/ml is the criterion for reducing ovarian reserve [32].

Recently, there has been a search for new methods of effectiveness of IVF/ ICSI programs in patients of late fertile age. One of them is the use of a gentle technique of denudation and cultivation of embryos in a gas mixture with a low oxygen level that can reduce the frequency of oocyte degeneration and increase the frequency of obtaining embryos of good quality on the third day of development, and most importantly, increase the frequency of establishing clinical pregnancy. But the use of EmbryoGen in this age group requires further research [17, 19, 32].

There is no consensus among researchers about the adequacy of the usual screening study (evaluation of the thickness of the collar space, AFP level and free beta-HCG) in the first trimester for pregnant patients over 40 years, therefore, it is proposed to develop a special approach and standards, taking into account the age of the woman and the increased risk of genetic abnormalities [17, 27].

It is known that in women of late fertile age, where the risk for genetic fetal abnormalities is especially high, invasive methods of genetic research are most frequent [17, 21, 31]. But clinicians note that prenatal screening and invasive screening techniques are perceived negatively by women in this age group. According to the research conducted in the United States, among 612 pregnant women of late fertile age, a third of them categorically refused to undergo screening because they knew that it is possible to obtain negative results [28]. Of the two thirds screened, only 37.2% of women were found to be at low risk. Among those who received as a result a high risk of genetic abnormalities, only 75% of women agreed to undergo invasive examination [28]. In this regard, the literature highlights the importance of educational work among pregnant women over 40 years and their partners in order to explain the need and feasibility of these procedures.

All these facts indicate that there is a lack of consensus among researchers about the main factor causing a decrease in reproductive function in women of late fertile age. It is possible that neither “age of the ovaries”, nor “age of the uterus”, nor changes in the nucleus and cytoplasm of the oocytes, nor changing hormonal profile of a woman with age can be considered as isolated cause of a decrease in the ability to conceive and bear a child after 40 years. Undoubtedly, the only right decision will be to consider all these factors in a complex.

Extragenital and gynecological diseases in pregnant women of late fertile age

The presence of extragenital pathology during pregnancy is known to lead to an increase in the number of complications of gestation. According to the data of Russian and foreign researchers, extragenital diseases in women aged 30-34 years are detected in 16.9% of cases, at the age of 35-39 years their frequency is 24.8%, at the age of 40 years and older this percentage varies from 44.9% to 79.8% [34].

During pregnancy women are known to experience alterations of the hormonal profile, changes in metabolic processes, a decrease in cellular immunity and tolerance to carbohydrates, an increase in blood cholesterol and triglycerides, an increase in body weight [34]. All these processes enhance during the advanced fertile age period, which undoubtedly complicate the course of gestation [34, 35].

Cardiovascular diseases, impaired lipid metabolism, endocrine disorders are the most common somatic diseases which increase with age. It should be noted that somatic pathology is often encountered in women aged 35-45 years. Frequency of extragenital diseases is considered to be a risk factor for various obstetric complications not only in women of late fertile age [36, 37]. It was found that various diseases of the gastrointestinal tract can increase the frequency of pregnancy-related nausea and vomiting. Also, arterial hypertension can be accompanied by severe preeclampsia which may cause premature birth, premature placental abruption, disseminated intravascular coagulation and HELLP syndrome, perinatal and maternal mortality [3, 34, 38].

Most scientists believe that the age of a woman who is more than 40 years old is an additional risk factor for hypertension in pregnant women [1, 33]. The percentage of hypertension is 6.3-25%, which is significantly higher than in younger pregnant women [1, 3]. As mentioned above, placental abruption in a pregnant woman may also be caused by increased blood pressure. According to Shechtman M.M., placental abruption is likely to occur in the group of women who suffer from hypertension 2.4 times more often than in pregnant women with normal blood pressure [3, 37, 38].

It is also established that endocrine disorders, particularly type 2 diabetes mellitus and gestational diabetes mellitus, increase with age; their highest incidence is observed at the age of 40 years and older. According to various reports, their prevalence in the study age group of patients is 0.6-14% [37].

Over the past ten years, in obstetric practice, hepatoses of pregnant women are increasingly common, different forms of which have many frequent symptoms, but their course, prognosis and complications for the pregnant woman and her fetus may be different [39]. Intrahepatic cholestasis is the most common form of liver disease in pregnant women. At the same time, it is known that the risk of intrahepatic cholestasis in pregnant women who are older than 39 years is 3 times higher than in women younger than 30 years. It is believed that HELLP syndrome and acute fatty hepatosis may be caused by intrahepatic cholestasis [39, 40]. The specific cause of this disease remains a matter for discussion to this day, but genetic and hormonal disorders in the body of a pregnant woman, as well as her age, are considered to be predisposing causes [37, 39].

Among extragenital diseases, more importance in research is given to thrombophilic complications characteristic of pregnant patients of late fertile age. This disease is detected in 37.8% of pregnant women older than 35 years with preeclampsia, 66.7% of pregnant women older than 35 years with fetoplacental insufficiency, 52.9% of pregnant women older than 35 years with fetal growth retardation syndrome. In general, thrombophilia is detected in 40.3% of cases which are accompanied by a severe course of the gestational process [37, 41].

Most often pregnant women over 35 years suffer from acquired thrombophilia. Thus, antiphospholipid syndrome is detected on average in 62.1% of cases, hyperhomocysteinemia - in 36.2%, mutation F V Leiden - in 6.9%. In the structure of multigenic thrombophilia with a severe course of gestational process, the largest share, as a rule, is Pai-1 polymorphism “675 4G/5G”, MTHFR C677T mutation. Also, according to the researchers, a high risk of venous thrombosis is detected in women older than 35-40 years, not only during pregnancy and childbirth, but also in the postpartum period, especially in the first six weeks [36, 37, 41].

Thyroid pathology occurs on average in 5.8% - 32% of women of late fertile age and can result in miscarriage, preeclampsia, labor pathology, chronic intrauterine hypoxia and the syndrome of delayed fetal development [37].

Overweight is revealed in more than 25% of pregnant women of late fertile age. The frequency of obesity ranges from 13.8% in primiparous women over 40 years to 34-62% in multiparous women in this group [41].

Women of late fertile age often suffer from different gynecological pathologies. According to various sources, gynecological diseases in the history were revealed in 48-60% of pregnant women of late fertile age. Endometrial hyperplastic processes dominate and occur in 80% of patients [14]. In this case, the size of the body of the uterus exceeds the normative values of this age group. Among endometrial hyperplastic processes, glandular and glandular – cystic endometrial hyperplasia occur in 51% of cases, endometrial polyps are detected in 45% of women, atypical hyperplasia (adenomatosis) is found in 4% of patients [12, 14].

The next most frequent gynecological disease in women of late fertile age is uterine fibroids, they are identified in 59% of women [14, 42]. Thirty years ago, scientists drew attention to the fact that among pregnant women with uterine myoma were primiparous (58%), and the bulk of these patients were over the age of 30 years [1]. Current data indicate two increasing trends: the rejuvenation of the pathological process on the one hand and the increase in pregnant women with uterine myoma over the age of 35 years on the other hand [1, 11, 14]. The relevance of this pathology in women of late fertile age is justified not only by the increase in its frequency, but also by the increase in the number of complications in the mother and fetus, the need to increase the extent of surgery during childbirth [1, 9].

Foreign and Russian researchers found that every tenth woman in the world has uterine fibroids. The incidence of fibroids depends on the age: 20% of women with fibroids are aged 30 years, 40% of patients with fibroids are women over 50 years. In women older than 40 years, this percentage is on average 24-25% [14, 38, 42]. Probably, this increase in the number of pregnancies in women after 35-40 years with uterine myoma is justified by the current trend towards organ-preserving operations. In the 1990s, radical operations (amputation, extirpation of the uterus) were performed in case of necrosis of myomatous nodes; in the modern world the main method is conservative myomectomy. In the modern literature, the importance of similar operations at any patient’s age of the patient is noted, enabling to preserve her reproductive health, menstrual function and improve the quality of life in the future.

In modern medical literature there are single data on the specific feature of pregnancy in women over 40 years with ovarian tumors. More often, pregnancy can be accompanied by benign ovarian tumors. Among them, dermoid cysts make up 45%, mucinous - 22%, serous cystadenomas - 21% [37]. As it is known, increasing age of women lead to a gradual increase in the incidence of all types of malignant tumors of the genitals [37].

According to various reports, 16-28% of pregnant women of late fertile age have the previous history of inflammatory diseases of the female genital organs. Moreover, the number of diseases is justified by a large number of artificial (39.3%) and spontaneous (15.3%) abortions at this age [3, 43]. With age, the frequency of surgical interventions on the pelvic organs increases, which undoubtedly affect the fertility of women.

Given the above, it is worth noting that the frequency of extragenital and genital pathology in women increases accordingly to the increase in age. Therefore, all women of late fertile age should be included in the group of high risk of perinatal complications. Preconception care, which includes a thorough examination and adequate therapy of somatic diseases and associated gynecological pathology in patients of late fertile age will reduce the number of complications of gestation and improve perinatal outcomes in this group.