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Международный эндокринологический журнал Том 18, №8, 2022

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Вплив ожиріння на репродуктивне здоров’я до та під час вагітності

Вплив ожиріння на репродуктивне здоров’я до та під час вагітності

Авторы: A. Konwisser (1), O. Korytko (2)
(1) — KRH Klinikum Grosburgwel, Frauenklinik, Hannover, Germany
(2) — Danylo Halytsky Lviv National Medical University, Lviv, Ukraine

Рубрики: Эндокринология

Разделы: Справочник специалиста

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Резюме

Більшість жінок з ожирінням є фертильними, хоча ожиріння підвищує ризик безпліддя. В огляді літератури описується вплив ожиріння на репродуктивне здоров’я до та під час вагітності. Також обговорюється міждисциплінарний підхід до лікування ожиріння в репродуктивний період жінки на основі публікацій на цю тему за період із січня 2015 року по березень 2022 року. Ожиріння є фактором ризику гіперплазії ендометрію та раку. Жінки з ожирінням мають меншу реакцію на стимуляцію яєчників. При індукції овуляції існує менша ймовірність овуляції з використанням кломіфену цитрату, потрібні вищі дози гонадотропінів, і розвивається менша кількість фолікулів. Жінки із синдромом полікістозних яєчників (СПКЯ) мають вищу ймовірність розвитку ожиріння (поширеність перебуває в межах від 14 до 75 % залежно від досліджуваної популяції), збільшення маси тіла та абдомінального ожиріння порівняно із жінками без СПКЯ. Ожиріння та СПКЯ є двома станами зі складною патофізіологією, і неясно, яке з них є причиною чи наслідком іншого. Вагітність жінок з ожирінням обумовлює підвищений ризик різних ускладнень, включаючи гестаційний діабет, артеріальну гіпертензію під час вагітності, вади розвитку плода, недоношеність, виникає більша необхідність у кесаревому розтині. Практика первинної медичної допомоги включає заходи зміцнення здоров’я та профілактику ожиріння. Саме на цьому рівні найбільш ефективні профілактичні заходи. Тому лікарі первинної ланки несуть відповідальність за надання якісного допологового догляду з профілактичними заходами до вагітності. На цьому етапі є можливість ефективного спілкування з жінками та їхніми родинами щодо досягнeння цільового рівня маси тіла, важливості зменшення надмірної ваги до вагітності з метою уникнення несприятливих наслідків поточної та майбутніх вагітностей.

Most women with obesity are fertile, although obesity increases the risk of infertility. This review describes the influence of obesity on reproductive health before and during pregnancy and postpartum. It also discusses the multidisciplinary management of obesity during a woman’s reproductive period based on the scientific literature on the subject published from January 2015 to March 2022. Obesity is a risk factor for endometrial hyperplasia and cancer. Women with obesity have a lower response to ovarian stimulation. In ovulation induction treatments, there is less likelihood of ovulation using clomiphene citrate, higher doses of gonadotropins are required and a smaller number of follicles develop. Women with polycystic ovary syndrome (PCOS) have a higher likelihood of obesity (prevalence ranging from 14 to 75 % depending on the population studied), longitudinal weight gain and abdominal obesity compared to women without PCOS. Obesity and PCOS are two conditions with complex pathophysiologies and it is not clear which one of them acts as a cause or as a consequence of the other. The pregnancies of women with obesity are at increased risk of different complications, including gestational diabetes, hypertensive disease of pregnancy (gestational hypertension or preeclampsia), foetal malformations, prematurity, both spontaneous and induced by other complications, Caesarean delivery, postpartum haemorrhage and thromboembolism. Primary care practice includes health promotion and prevention actions, and it is often the first point of contact between a woman and her partner and the healthcare service before they conceive. Primary care is therefore responsible for providing this new family with quality prenatal care with preventive activities prior to pregnancy. In relation to obesity, this situation provides the opportunity for effective communication with women and their families about weight goals at this stage of life, the importance of weight loss prior to pregnancy, maximum weight gain during pregnancy and postpartum weight loss to reduce the risk of adverse outcomes in current and future pregnancies.


Ключевые слова

ожиріння; вагітність; репродуктивне здоров’я; синдром полікістозних яєчників; лікування

obesity; pregnancy; reproductive health; polycystic ovary syndrome; management

doi: http://dx.doi.org/10.22141/2224-0721.18.8.2022.1224
Obesity in pregnancy is a currently a major challenge in obstetric care due to its prevalence, the adverse impact on both mother and foetus and the consequences for the health of present and future generations. This review describes the influence of obesity on reproductive health before and during pregnancy and postpartum. It also discusses the multidisciplinary management of obesity during a woman’s reproductive period based on the English-language scientific literature on the subject published from 2012 to 2022.
Literature search was performed using PubMed Database of the National Library of Medicine, with date limits from January 2015 to March 2022. We used the keywords: obesity, pregnancy, reproductive health, preterm birth, and other related terms. The studies of interest included original papers and review articles on the influence of obesity on reproductive health before and during pregnancy.
In Ukraine, the prevalence of overweight and obesity in women of childbearing age (18–44) is 14.1 % [1, 2], with a similar rate of obesity reported in women during pregnancy [3]. Obesity in this age group is not only important because of its prevalence, but also because it has a negative impact on the different reproductive stages: menstrual cycle and ovulation, achieving pregnancy spontaneously and through assisted reproductive techniques (ART) and in terms of maternal/foetal complications during the pregnancy.
Most women with obesity are fertile, although obesity increases the risk of infertility [4]. A number of elements could explain the negative impact obesity has on fertility: ovulatory dysfunction, altered oocyte quality, endometrial dysfunction [5].
Most studies concur that 35 % of women with obesity experience menstrual cycle irregularity, and the prevalence of oligomenorrhoea and amenorrhoea increases with the degree of obesity [6]. Ovulatory dysfunction is also more common in women with obesity, and anovulatory infertility is more prevalent as body mass index (BMI) increases. Women with obesity and anovulation have greater abdominal obesity than patients with normal ovulation with a similar BMI, so abdominal obesity would therefore be a better predictor of ovulatory dysfunction [7]. However, it is important to note that polycystic ovary syndrome (PCOS) is a confounding factor in determining the effects of obesity on ovulation [8]. Obese patients with regular cycles and no ovulatory disorders also experience subclinical endocrine changes which, when exacerbated, induce menstrual and ovulatory abnormalities. Compared to women of normal weight, the ovulatory cycles of women with obesity have lower total concentrations throughout the cycle of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) and lower concentrations of progesterone in the luteal phase, reduced LH pulse amplitude in the early follicular phase, lengthening of the follicular phase and shortening of the luteal phase [9].
Insulin resistance associated with abdominal obesity increases ovarian androgen production and reduces the liver’s production of sex hormone-binding globulin (SHBG). Increased peripheral aromatization of androgen to oestrogen in adipose tissue, together with altered levels of adipokines such as leptin and IGF-BP, contribute to hypothalamic-pituitary-ovarian axis disruption and menstrual disturbances [10].
Obtaining oocytes surrounded by cumulus cells and follicular fluid in in vitro fertilization (IVF) is a model for studying the intrafollicular endocrinological and metabolic environment. Women with obesity has higher intrafollicular concentration of insulin, inflammatory markers and free fatty acids, and these alterations are correlated with abnormalities in the cumulus-oocyte complex [11]. The results on the fertilization capacity of oocytes from women who are overweight or obese are inconsistent, but obesity influences the development of the resulting embryos, although the proportion of euploid embryos is not reduced when BMI increases [12]. Oocytes from women with BMI  > 35 kg/m2 have a higher prevalence of meiotic spindle and chromosome alignment abnormalities compared to patients with normal BMI [13].
Obesity is a risk factor for endometrial hyperplasia and cancer. From the standpoint of fertility, endometrial immunohistochemistry studies found a correlation between increased BMI and a significant reduction in the glandular expression of oestrogen and progesterone receptors [14]. At molecular level, women with obesity present differences in the gene expression pattern in the implantation window, the period when the endometrium is receptive for embryo implantation, and these differences are more pronounced in women with infertility or PCOS [15]. A combined analysis of the available evidence suggests a potential negative impact of obesity on both the oocyte and the endometrium [16].
Obesity is associated with poorer outcomes in fertility treatments and in ART. Women with obesity have a lower response to ovarian stimulation. In ovulation induction treatments, there is less likelihood of ovulation using clomiphene citrate, they require higher doses of gonadotropins and a smaller number of follicles develop [17]. In IVF cycles, ovarian stimulation takes longer and requires a higher dose of gonadotropins, fewer oocytes are obtained and there is an increased rate of cancelled cycles due to suboptimal or no response to stimulation [18]. A reduction in the expression of the FSH receptor in the granulosa cells of the ovarian follicle and a decrease in the production of oestradiol have been found, which could be mediated by the hyperinsulinaemia associated with obesity [19]. 
According to the results of a recent meta-analysis, women with obesity have a lower likelihood of live birth in IVF compared to women with normal BMI (RR [95% CI] 0.85 [0.82–0.87]), and the prognosis is worse when obesity is associated with PCOS [20]. A woman’s age has a huge influence on fertility and ART outcomes, so as a woman’s age increases, BMI has less of an impact on the live birth rate from IVF [7].
Before an IVF cycle, a couple with obesity should be assessed and advised by a multidisciplinary team, considering BMI, abdominal obesity and comorbidities, not only to establish the potential negative consequences for fertility and maternal foetal health, but also to determine the safety of the technique in the woman, particularly the follicular puncture-aspiration to obtain oocytes under sedation required by IVF techniques.
PCOS is the most common cause of infertility due to anovulation. Women with PCOS have a higher likelihood of obesity (prevalence ranging from 14 to 75 % depending on the population studied), longitudinal weight gain and abdominal obesity compared to women without PCOS [21]. Obesity and PCOS are two conditions with complex pathophysiologies and it is not clear which one of them acts as a cause or as a consequence of the other. Obesity exacerbates different reproductive and metabolic aspects of PCOS, which contributes to increasing the likelihood of menstrual irregularity and oligo-/anovulation, with a negative impact on these patients’ fertility. Once pregnant, women with PCOS have an increased risk of gestational hypertension, preeclampsia, gestational diabetes (GD) and preterm birth [22]. Obesity and PCOS are independent risk factors for several of these gestational complications, and when they present simultaneously their negative effects on pregnancy can be amplified [23]. Weight loss is the first therapeutic step in patients with PCOS and obesity and is known to improve reproductive, metabolic and psychological parameters [24]. Weight loss interventions that achieve a reduction of at least 5–10 % can reverse the negative effects on ovulation and fertility in these women [25].
Obesity is associated with different short-term and long-term adverse consequences. Overweight or obese woman have an increased risk of spontaneous abortion and euploid abortion compared to patients with normal weight [26]. The pregnancies of women with obesity are at increased risk of a different complications, including GD, hypertensive disease of pregnancy (gestational hypertension or preeclampsia), foetal malformations, prematurity, both spontaneous and induced by other complications, Caesarean delivery, postpartum haemorrhage and thromboembolism [27]. Maternal obesity does not only have a negative impact on the health of women, but also on their children’s. Different observational studies indicate a close relationship between maternal weight and obesity and cardiometabolic risk factors in their offspring [28]. Pre-gestational BMI is highly correlated with adiposity not only in the newborn, but also in childhood, adolescence and adulthood, potentially affecting health throughout life [29].
The preconception period is an ideal time to assess and manage conditions that may affect the health of the mother and foetus during the pregnancy, as they can have long-term implications for both. During the periconception period, women are particularly vulnerable to weight stigma, including in the healthcare setting, where some healthcare professionals may evince prejudice and negative attitudes towards them [30]. Education in the health sector through recommendations for maintaining positive communication is essential if this situation is to be improved, for example using person-first language, promoting healthy behaviours rather than focusing solely on weight, and involving obese women in the therapeutic decision-making process [31].
Primary care (PC) practice includes health promotion and prevention actions, and PC is often the first point of contact between the woman and her partner and the healthcare service before they conceive. PC is therefore responsible for providing this new family with quality prenatal care with preventive activities prior to pregnancy. In relation to obesity, this situation provides the opportunity for effective communication with women and their families about weight goals at this stage of life, the importance of weight loss prior to pregnancy, maximum weight gain during pregnancy and postpartum weight loss in order to reduce the risk of adverse outcomes in current and future pregnancies. The ideal role of the PC doctor is to raise the woman's awareness of the importance of maintaining a healthy weight, help them to engage in effective weight loss strategies and to support any initiatives undertaken by the patient. In PC, the intervention strategy of the Five As (Ask, Advise, Agree, Assist and Arrange) has been adopted for the implementation of behavioural interventions and advice on the main risk factors, including weight control [32]. 
The first line of treatment for tackling obesity consists of promoting healthy habits through lifestyle changes, which combine dietary interventions and physical exercise (PE) [33]. Healthy diets encourage the consumption of plant-based foods, rich in fibre, vitamins, minerals and antioxidants (vegetables, fruits, legumes and whole grains), and unsaturated fats (olive oil, nuts and oily fish), together with poultry, dairy products, eggs and red meat eaten in moderation. Eating patterns such as the Mediterranean diet (MD), Atlantic, vegetarian or low glycaemic index (GI) diets could be effective for weight loss [34]. PE should be started gradually, aiming for 150 min of moderate-to-intense aerobic activity such as running, cycling, swimming, aquagym or dancing. In addition, programming strength activities, either with the body alone or using elastic bands, two or more times a week is recommended. At the same time, cognitive-behavioural psychological support should be considered to facilitate adherence to changes and to keep them up. During the peri-gestational stage, alcohol and tobacco, as well as any other toxic substances, should be completely avoided. 
Few studies have been published in this area because the guidelines recommend that any potentially teratogenic medical treatment be discontinued before pregnancy [35]. Some studies have analysed the effect of GLP1 analogues a few weeks before conception. In one of these studies, greater weight loss and an increase in the rate of spontaneous pregnancies were found in a cohort of women with obesity and PCOS who received treatment with exenatide during a short pre-pregnancy period when compared with metformin [36]. Another pilot study in a cohort of women with obesity and infertility due to PCOS compared short-term treatment preconception with low-dose liraglutide combined with metformin to treatment with metformin alone, observing an increased IVF pregnancy rate in the combined treatment group [37].
Weight management in the preconception period may also include advice on surgical treatment for obesity prior to pregnancy. Women who are candidates for BS should be advised and assessed by a multidisciplinary team, highlighting the benefits of weight loss prior to pregnancy, not only in terms of fertility, but also in maternal-foetal complications, without forgetting the potential negative consequences for maternal health (nutritional deficiencies, mechanical complications with restrictive techniques, episodes of intestinal obstruction due to internal hernias or weight regain) and foetal health (SGA and intrauterine growth retardation), as well as the advisability of referral to a specialised centre for management during the pre-pregnancy, pregnancy and postpartum periods [38].

Conclusions

The available evidence collected in this review supports the implementation of strategies for the prevention and integrated management of obesity in women of childbearing age, with the aim of improving their fertility, reducing pregnancy-related risks and benefiting the health of their offspring. Population-based information-providing activities, the design and development of preventive and therapeutic programs and specific training for the different healthcare professionals involved in the management of these patients are all necessary, in addition to the organisation of multidisciplinary teams for the most complex cases. The involvement of the health authorities and scientific societies is essential for the organisation of activities intended to promote research, training and dissemination of information, in scientific forums and in the media, social networks, health centres and other areas in order to address a highly prevalent problem, and at the same time potentially improve the health of the population.
 
Received 08.11.2022
Revised 02.12.2022
Accepted 16.12.2022

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