Diabetes gestacional - ObstetriciaGinecología

ResumenIntroducción: La diabetes gestacional se ha identificado como factor de riesgo a largo plazo para el desarrollo de diabetes mellitus tipo 2, hipertensión arterial crónica, síndrome metabólico y enfermedad cardiovascular.

Objetivos: En base a la evidencia científica actual profundizar en el conocimiento de la transcendencia para la salud futura de la mujer que ha padecido una diabetes gestacional.

Material y métodos: Estudio retrospectivo mediante la búsqueda de artículos originales y revisiones sistemáticas publicados en las bases de datos: PubMed, EMBASE, ScienceDirect y Biblioteca Cochrane entre los años 1999 y 2018. Se incluyeron, en los diferentes motores de búsqueda, las siguientes asociaciones de palabras clave: "Gestational diabetes mellitus and long-term consequences", "previous gestational diabetes mellitus", "Gestational diabetes after delivery" "postpartum followup of women with gestational diabetes", "History of gestational diabetes mellitus", "after gestatio-nal diabetes mellitus", "gestational diabetes and postpartum risk". Se seleccionaron los de mayor nivel de evidencia.

Resultados: Se encontraron 472 artículos que relacionan la diabetes gestacional y sus efectos maternos a largo plazo, se procedió a su revisión y se descartaron los de menor nivel de evidencia científica y todas aquellas referencias duplicadas.

Conclusiones: Existe suficiente evidencia clínica que relaciona la Diabetes gestacional con el desarrollo posterior de diabetes mellitus tipo 2, hipertensión arterial crónica, síndrome metabólico y enfermedad cardiovascular. Todavía no es posible determinar desde la gestación cuales son las pacientes con mayor probabilidad de complicaciones a largo plazo. Existe suficiente evidencia que la diabetes mellitus se puede prevenir, no así de las enfermedades cardiovasculares.

Abstract Background: Gestational diabetes has been identified as a long-term risk factor for the development of type 2 diabetes mellitus, chronic hypertension, metabolic syndrome, and cardiovascular disease.

Objectives: Based on the current scientific evidence, our objective was to increase our knowledge of the importance of gestational diabetes in women’s future health.

Material and methods: Retrospective study by searching for original articles and systematic reviews published in the databases PubMed, EMBASE, ScienceDirect, and Cochrane Library between 1999 and 2018. The key words used for the search were as follows: "Gestational diabetes mellitus and long-term consequences", "previous gestational diabetes mellitus", "gestational diabetes after delivery", "postpartum followup of women with gestational diabetes", "history of gestational diabetes mellitus", "after gestational diabetes mellitus", and "gestational diabetes and postpartum risk". The highest levels of evidence were selected.

Results: We found 472 articles on gestational diabetes and its long-term effects on the mother. The articles were reviewed, and those with the lowest level of scientific evidence and all duplicate references were ruled out.

Conclusions: There is sufficient clinical evidence linking gestational diabetes with subsequent development of type 2 diabetes mellitus, chronic hypertension, metabolic syndrome, and cardiovascular disease. It is still not possible to determine from gestation which patients are most likely to have long-term complications. There is sufficient evidence that diabetes mellitus can be prevented. This is not the case for cardiovascular disease.

Revisión de Conjunto

Palabras clave:

Diabetes gestacional. Diabetes mellitus. Hipertensión arterial. Síndrome metabólico. Enfermedad cardiovascular.

Key words:

Gestational diabetes. Diabetes mellitus. Hypertension. Metabolic syndrome. Cardiovascular disease.

Recibido: 11/10/2017Aceptado: 13/03/2018

Domínguez Vigo P, Álvarez Silvares E. Gestational diabetes: maternal programming. Prog Obstet Ginecol 2019;62(2):168-180. DOI: 10.20960/j.pog.00188.

Gestational diabetes: Maternal programmingDiabetes gestacional: programming materno

Paula Domínguez Vigo, Esther Álvarez Silvares

Servicio de Obstetricia y Ginecología. Complexo Hospitalario Universitario de Ourense. Ourense

Revista Oficial de la Sociedad Española de Ginecología y Obstetricia

P R O G R E S O S D E

O b s t e t r i c i a G i n e c o l o g í ay

Revista Oficial de la Sociedad Españolade Ginecología y Obstetricia

Prog Obstet Ginecol 2019;62(2):168-180

Correspondencia: Esther Alvarez Silvares Servicio de Obstetricia y GinecologíaComplexo Hospitalario Universitario de Ourense C/ Ramón Puga Noguerol, 5432005 Ourensee-mail: [email protected]

169GESTATIONAL DIABETES: MATERNAL PROGRAMMING

[Prog Obstet Ginecol 2019;62(2):168-180]

INTRODUCTION

Gestational diabetes (GD) comprises a heterogeneous group of hyperglycemic metabolic disorders that begin or are first detected during pregnancy (1) and lead to com-plications in 12% of pregnancies (2).

GD has always been discussed by the scientific com-munity in terms of its diagnosis and its clinical manage-ment. It is the most common endocrine-metabolic disease of pregnancy, with a variable prevalence that has been rising in recent decades. If we frame GD in the context of the obesity pandemic faced by an increasingly sedentary society, we paint a picture in which GD is no longer an isolated condition confined exclusively to pregnancy and is now part of cardiovascular disease. If we remove the idea that GD is limited to pregnancy, it takes on a new dimension and can be considered another component of cardiovascular risk that will remain present throughout a woman’s life.

The potential, often underestimated, complications of this disease necessitate regular follow-up of women with a history. Today, we can state that GD is no longer limited to pregnancy.

The importance of these observations in terms of mor-bidity and mortality and in terms of social and health care costs should be considered a warning and lead us to react at all levels of health systems throughout the world so that we can concentrate our efforts on predicting and preventing the problem and thus ensure healthy aging of women.

MATERIAL AND METHODS

We performed a retrospective study based on a search for original articles and systematic reviews published in the databases PubMed, EMBASE, ScienceDirect, and Cochrane Library. Given that there was no single MeSH term for our study, we used the following search terms "gestational diabetes mellitus and long-term consequen-ces", "previous gestational diabetes mellitus", "gestational diabetes after delivery", "postpartum followup of women with gestational diabetes", "history of gestational diabetes mellitus", "after gestational diabetes mellitus", and "ges-tational diabetes and postpartum risk".

We found 472 articles published between 1999 and 2018. We carried out a systematic review of all the arti-cles and excluded those with the least scientific rele-vance (eg, case studies, letters to the editor). The final sample comprised 191 scientific publications, of which 13 were systematic reviews, 7 were meta-analyses, 1 was a Cochrane review, and 3 were clinical practice guidelines. We collected the information with the highest grade of evidence associated with cardiovascular risk in women with a history of GD.

RESULTS

1. Prevalence of gestational diabetes / diabetes mellitus / cardiovascular disease

In its Diabetes Atlas published in 2015 (3), the Interna-tional Diabetes Federation (IDF) estimated that 1 in every 7 births would be affected by GD. Specifically, in 2015, it estimated that 16.2% of women who gave birth had some form of hyperglycemia during their pregnancy, that is, 85% of cases corresponded to GD.

The prevalence of GD is very variable and will always depend on the population analyzed and the diagnostic criteria used.

In its Global Report on Diabetes 2016 (4), the World Health Organization (WHO) estimated the worldwide incidence of hyperglycemia during pregnancy to be 10-25%, with most cases (75-90%) being secondary to GD itself.

The IDF (3) has estimated that the prevalence of GD reached 14.9% in North America and 15.8% in Europe in 2015. Southeast Asia was the most affected according area to 2015 data, with a prevalence of GD of 24.2%.

Irrespective of the estimations, there is no doubt that GD is increasingly prevalent, at least in developed coun-tries. This is probably due to an increase in obesity in the general population and increasingly advanced maternal age (5,6).

It is predicted that in 2030, approximately 552 million people will have type 2 diabetes mellitus (DM) and that this will be the seventh cause of death throu-ghout the world (7). In Europe alone, it is estimated that 66.5 million people will be diagnosed with DM in 2030 (8).

The increased incidence of DM is a reflection of the worldwide increase in obesity, sedentary lifestyle, and aging of the world's population. The greater increase in incidence has been recorded in adults younger than 50 years, including women of childbearing age (9).

Based on these statistics, DM can be classed as a major public health problem that has reached epide-mic proportions.

Furthermore, according to data from the WHO (7), the main cause of death by noncommunicable diseases in 2012 was cardiovascular disease, which was responsi-ble for 17.5 million deaths throughout the world. Today, cardiovascular disease is the main cause of death in women (10) and is responsible for 30% of deaths among women (7).

Cardiovascular mortality is also expected to increase by 2030, reaching 23 million deaths by 2030 (11), mainly because of the current obesity epidemic (7,12), the stress-ful conditions of a fast lifestyle, sedentarism (13-15), and unhealthy diet (16).

170 P. Domínguez Vigo et al.


2. Complications of gestational diabetes

There can be no doubt that GD entails a series of com-plications during pregnancy for both the mother and the child such as macrosomia, a greater risk of preeclampsia and congenital malformations, and an increase in peri-natal morbidity and mortality (17,18), thus necessitating strict control of blood sugar levels during pregnancy.

Considerable attention has always been paid to the influence of GD on perinatal outcome, although in recent decades, research in this field has tended to focus on long-term implications for maternal cardiovascular health. In fact, numerous studies show that these women presented a greater risk of DM (5,19-22) and other cardiovascular events throughout their lives and at earlier stages than other women with normal blood sugar levels during preg-nancy.

The literature provides ample evidence that children who have been exposed to a hyperglycemic metabo-lic environment in utero also develop obesity (23-25), DM (26-29), metabolic syndrome (30), and cardiovascular disease (31-33) more frequently as adults.

Therefore, the key objective of new research lines in this field is to establish pregnancy as the first filter for future complications. Pregnancy per se can be considered to be a "stress test" for the cardiovascular system and maternal metabolism.

Antenatal care is often a stage during which women are closely monitored for the first time and multiple parame-ters are recorded (eg, blood sugar levels, arterial blood pressure, weight gain, and lifestyle habits). When taken into account alongside pregnancy itself, these parameters can help us to identify a group of young, healthy women who may present a considerable degree of cardiovascular morbidity and mortality during their lifetime.

3. Gestational diabetes and subsequent development of diabetes mellitus

While a return to normal tolerance of carbohydrates is expected at the end of pregnancy, as many as 46% of women continue to have some degree of altered glu-cose metabolism during the immediate postpartum period (34).

The exact pathophysiological mechanism of GD con-tinues to be unclear. In her review article from 2014, Kim (35) proposes a hypothetical model in which pregnan-cy (via secretion of a series of hormones produced by the fetus and the placenta) would act as a stressor on mater-nal metabolism that would in turn reveal an underlying deficiency in sensitivity and secretion of insulin by ß cells in the pancreas. This is translated into a state of insuffi-ciently compensated insulin resistance during pregnancy that could persist after pregnancy. This imbalance could

be exacerbated by a series of modifiable factors such as fat accumulation during pregnancy and specific lifestyle habits during the postpartum period.

Thus, the risk of intolerance to carbohydrates and diabetes during this period depends mainly on the following (35):

– The underlying degree of sensitivity to and secretion of insulin by the mother. Compared with pregnant women with normal glucose levels, women who develop GD secrete relatively less insulin with respect to the degree of sensitivity to insulin, thus leading to greater blood sugar levels during pregnancy (36).

– The degree of metabolic stress resulting from fetal-placental hormone production and weight gain during pregnancy.

– Retained adiposity during pregnancy and the postpar-tum period. Pregnancy-associated hormonal changes, which lead to increased weight and redistribution of body fat during pregnancy, have lasting effects on maternal metabolism more than a decade after delivery, and, together with certain lifestyle patterns affecting diet and physical activity, are responsible for retained adiposity after pregnancy (37).

In addition to presenting a series of common risk fac-tors (family history of DM, advanced age, and high body mass index [BMI]), GD and DM share several pathophysio-logical mechanisms. The close association between both entities suggests that the former may represent an early stage of the natural history of the latter and would explain why many of these patients go on to develop DM. There-fore, "diabetes leads to diabetes". In fact, the American Diabetes Association (38) (ADA) currently recognizes GD as a category of DM.

The 2009 meta-analysis by Bellamy et al (21), which was published in The Lancet, estimated that women who have had an episode of GD have a 7-fold greater risk of DM during their lifetime than women whose pregnancy follows a normal course. Up to 50% of these women go on to develop DM within 10 years of delivery; the highest incidence rate is within the first 5 years. These data agree with those of our 2016 study (39), in which we estimated that up to 40% of patients who presented GD went on to develop DM within 5 years of delivery and that up to one-third develop the disease a decade after delivery.

Furthermore, one-third of women with DM have a his-tory of GD (40). Therefore, today, GD is considered a key predictor of DM (41).

Several studies analyze risk factors in an attempt to select a group of patients with a greater tendency to deve-lop DM in the long term. However, the results are highly contradictory.

The traditional risk factors for DM after GD are advan-ced maternal age, family history of DM, pregestational obesity, more than 1 episode of GD, diagnosis of DG with early amenorrhea, multiparity, need for insulin treatment



during pregnancy, and higher blood sugar levels during pregnancy (31,40,42-51).

Of these, BMI is the most modifiable risk factor and one of the most widely studied. Thus, various authors (47,52-55) have associated high pregestational BMI with an increased risk of DM in the long term. A systematic review from 2009 (56) showed weight to be a more important risk factor than age, parity, and family history of DM.

Of all the risk factors associated with DM, the one that most authors agree on is blood sugar levels during preg-nancy. Diagnosis is based on baseline glycemia in the oral glucose tolerance test (OGTT). Blood sugar is one of the most widely studied parameters and is closely associa-ted with postpartum glucose intolerance in most stu-dies (43,57-59).

After 11 years of follow-up, Albareda et al (52) found that having all 4 OGTT values altered was a key predictor of the future development of DM, with a relative risk of almost 4 points.

Hypertensive states of pregnancy (preeclampsia or ges-tational hypertension) are another major complication of pregnancy, and, as with GD, are based on insulin resis-tance, irrespective of BMI and development of glucose intolerance during pregnancy (60). Feig et al (42) analyzed more than 1 million pregnant women and concluded that those who develop gestational hypertension have twice the risk of developing DM within 16 years (HR, 2.08 vs 1.95, respectively); this risk increases considerably if both conditions present simultaneously (HR. 15.75 for GD-as-sociated preeclampsia and 18.49 for gestational hyper-tension with GD).

To date, systematic reviews in this area report on fac-tors associated with DM but do not establish the extent to which each of them increases risk. Furthermore, many studies in which the risk of each individual factor is cal-culated often provide inaccurate data or have a sample that is too small for results to be extrapolated. This could prove to be a basic problem when advising women on the possible implications of having GD in the future, since it does not provide solid and personalized information. This fact, alongside many other causes, could contribu-te to the low rate of attendance at postnatal check-ups among these patients and to their not completing DM screening programs.

However, in their recent systematic review and meta-analysis, Rayanagoudar et al (61) collected data from 39 studies (n=95,750 women) and established the effect of the clinical and biochemical parameters that indicate the greatest risk of developing DM a posteriori. Thus, the statistically significant independent predictors of DM were pregestational BMI >25 kg/m2 (RR, 3.18), family history of DM (RR, 1.70), nonwhite race (RR, 1.49), age >30 years (RR, 1.36), early diagnosis of GD (RR, 2.13), baseline blood sugar values from the OGTT and HbA1C (RR, 2,56), need for insu-lin treatment during pregnancy (RR, 3.66), simultaneous

development of hypertensive disease of pregnancy (RR, 1.38), and multiparity (RR, 1.23). The authors found no association with weight gain during pregnancy, weight of the newborn, fetal macrosomia, or breastfeeding.

It seems reasonable to think that approaches such as measurement of individual risk factors can improve adhe-rence of these patients to postnatal follow-up programs. Undergoing a personalized work-up with more objective data could increase women’s perception of risk. In addi-tion, it is important to remember that pregnancy is a key moment in a woman’s life and, as such, provides us with a unique opportunity to play a role both in her health and in that of her child.

Therefore, we cannot forget to take these factors into account when estimating a women’s risk of developing DM. In this sense, it is interesting to highlight that there are currently few predictive models of DM that include a history of GD, and none of them consider risk parameters present in gestation (62). Nevertheless, it is necessary to develop and validate new models that bring these findings together and do not underestimate the role of an episode of GD in the life of a woman who is initially considered healthy.

4. Gestational diabetes and cardiovascular risk

It is well known that women tend to experience car-diovascular events a decade later than men (63) and that they have a similar risk profile that may worsen after the menopause (65), since the protective role of estrogen during their reproductive life is eliminated.

Nevertheless, women with polycystic ovary syndrome, DM, or a history of GD are at greater risk of cardiovascular disease (65).

Therefore, it seems that diabetes eliminates the cardio-vascular advantages of women of childbearing age and has been associated with an increase in the risk of having cardiovascular disease earlier than men (66,67).

Women who develop GD often have a series of charac-teristics that are typical of metabolic syndrome (68-71). In addition, we know that GD itself can be considered a prediabetic stage, since, over time, women with GD are at greater risk of developing DM, as well as a series of metabolic abnormalities that increase the probability of certain diseases, with greater cardiovascular mortali-ty (6,31,71,72).

Metabolic syndrome (73) is defined as the simultaneous presence of central obesity, hypertriglyceridemia, decrea-sed high-density lipoprotein (HDL) cholesterol, arterial hypertension (AHT), and hyperglycemia (74). Metabolic syndrome is associated with a 2- to 3-fold increased risk of earlier cardiovascular disease and DM (75-77) and is considered a major element in the current epidemic of both conditions, thus making it an important public health



problem throughout the world (74), since it implies increa-sed medical and health care and, thus, considerable social and health costs.

While the etiology and diagnostic criteria of metabo-lic syndrome remain open to debate, the key lies in the pathophysiological characteristics that this condition sha-res with GD, including a background of insulin resistance and endothelial dysfunction (78).

Taking these similarities as a basis, recent decades have seen a growing number of studies (55,78-83) that have investigated the association between GD and metabolic syndrome. In general, the risk of sugar metabolism abnor-malities and metabolic syndrome is greater within the 10 years following an episode of GD.

Women with metabolic syndrome at the start of their pregnancy have a greater risk of developing GD (84); women with GD have a 3- to 4-fold greater risk of meta-bolic syndrome at some point during their lifetime (85), even during pregnancy (86).

A recent meta-analysis (87) of 5,832 women with GD showed that this population had an almost 4-fold greater risk (OR, 3.96; 95% CI, 2.99-5.26) of developing metabolic syndrome than women with a normal pregnancy and that the risk increased in white women (OR, 4.54) and in those with a higher BMI (OR, 5.39).

If we break metabolic syndrome down into its indivi-dual components and analyze its association with GD, we see that compared with women with normal blood sugar levels, women with GD more often have hyperglycemia, insulin resistance, obesity, AHT, and an unfavorable lipid profile (88,89). These conditions create an imbalance in favor of specific proinflammatory factors that prove damaging for the vascular endothelium. Consequently, a prothrombotic state is established. This in turn triggers a process of atherosclerosis, the common denominator in many cardiovascular events.

During pregnancy, diabetic women have a more athero-genic lipid profile, with higher levels of low-density lipo-protein cholesterol, total cholesterol, and triglycerides to the detriment of HDL-cholesterol levels (68,69,90,91).

Various authors (92,93) have focused on the presence of fatty tissue at unusual sites, such as specific muscles or the liver, using nuclear magnetic resonance spectrome-try. They reached the conclusion that women with a his-tory of pregnancy complicated by GD during the previous 4-5 years and subsequent normalization of carbohydrate metabolism have a higher BMI, higher muscle and liver fat, and increased sensitivity to insulin, thus indicating the presence of underlying metabolic abnormalities that could degenerate to cardiometabolic disorders (94-96).

Furthermore, several studies (85,97) consider obesity to be one of the main factors that increase cardiovascular risk in these patients, whether as a result of the greater risk of developing DM or the greater risk of metabolic syndrome.

Independently of BMI, women with GD are more likely to develop hypertensive states of pregnancy, whether in the form of preeclampsia or gestational hypertension. Today, both diseases are known to be associated with a greater risk of AHT in the long term (98). A study carried out at our center (39) showed that the presence of DM in a patient with previous GD is a risk factor for AHT (RR, 4.5). However, Tobias et al (70) studied 1,414 women with a history of GD and 16 years of follow-up and found that GD was a risk factor for AHT (HR, 1.26), irrespective of whe-ther they had had preeclampsia during their index preg-nancy or had concomitant DM. Bentley-Lewis et al (99) reported that white Hispanic women have the greatest risk of AHT (HR, 3.25) within 3-4 years of an episode of GD.

It is plausible that the association between GD and sub-sequent AHT reflects preexisting common risk factors (70). In this sense, hyperinsulinemia may favor AHT, whether as a result of increased retention of sodium in the kidneys, activation of the autonomic nervous system, abnormal transport of cellular electrolytes, or increased activity of growth factors.

Levels of certain inflammatory markers and evidence of endothelial dysfunction have been considered key factors in the development of atherosclerosis, which acts as a substrate in the development of various cardiovascular diseases (100).

Several studies (72,101-105) aimed to measure levels of various markers of inflammation in the postpartum period. Thus, a series of inflammatory markers have been identified (C-reactive protein, IL-6, PAI-1, and TNF-α). The-se substances are secreted by fatty tissue (adipokines), cell adhesive glycopeptides (E-selectin, VCAM-1, ICAM-1), and hormones that regulate the metabolism of carbohydrates and seem to play an important role in the development of DM and eventually cardiovascular disease in women with a history of GD.

Some researchers postulate that both GD and hyperten-sive disorders of pregnancy contribute directly to dama-ge in the vascular endothelium through hyperglycemia and insulin resistance (106-109) (in the case of GD and hypertensive disorders of pregnancy) and development of antiangiogenic factors (110-113) (in the case of hyper-tensive disorders of pregnancy).

Women with a history of GD have higher rates of sub-clinical atherosclerosis (114) and endothelial dysfunc-tion (115,116), both of which occur earlier than in women with a normal pregnancy (6), although it is true that the association between the direct effect of hyperglycemia on vascular function leads to controversial results in many cases.

Carotid intima-media thickness (CIMT) is a parameter that is related to vascular endothelial dysfunction and has been shown to be greater in women who have had GD (117). Gunderson et al (118) show that women with a normal weight who have had GD but did not subsequently



develop DM or metabolic syndrome have increased CIMT, which manifests as subclinical atherosclerosis earlier than in other women, thus increasing the potential risk of coro-nary disease and stroke. CIMT has been shown to be asso-ciated with high levels of various atherothrombotic inflam-matory mediators (E-selectin, ICAM-1, VCAM-1, IL-6, and CRP) 6 years after a pregnancy complicated by diabetes. Many of these inflammatory markers are present in preg-nancies that progress with GD and in pregnancies that progress with normal blood sugar levels, although these only remain high in women who have had diabetes with subsequent normalization of sugar metabolism, indepen-dently of BMI (119).

Homocysteine levels have been directly linked to the development of atherosclerosis, oxidative stress, and endothelial dysfunction. This finding can be considered a marker of cardiovascular disease and is high in women with GD or hypertensive states of pregnancy, even deca-des after the index pregnancy. Furthermore, it is correla-ted with greater CIMT (120).

Therefore, there can be no doubt that GD is currently a risk factor for cardiovascular disease (118,121-125). The controversy lies in establishing the role of developing DM after an episode of GD in the pathogenesis of cardiovas-cular disease.

If we carry out a literature search, we find that it is very difficult to establish a clear distinction between DM and cardiovascular disease, since they both share underlying risk factors, thus suggesting a "common soil" in the pro-gression of both diseases (100,126).

Carr et al (122) found that only women with a fami-ly history of diabetes and a previous episode of GD are at greater risk of developing DM and greater CIMT. In addition, they are more prone to cardiovascular events such as coronary heart disease and cerebrovascular acci-dents (OR, 1.85) and events with an earlier onset than women who have not had GD, independently of whether they subsequently develop DM.

After a mean follow-up of 11.5 years, Shah et al (123) found that young women (20-49 years) with a history of GD have a greater risk of cardiovascular disease (defined as hospitalization for coronary heart disease or cerebro-vascular accident), with an HR of 1.71. Similarly, in their study of almost 450,000 women followed up for a mean of 12 years, Retnakaran et al (124) found that a history of GD confers a greater risk of having a cardiovascular event (defined as hospitalization for acute myocardial infarction, cerebrovascular accident, coronary bypass, angioplasty, or carotid endarterectomy), with an HR of 1.66. In both studies, this risk loses statistical significan-ce after adjusting for DM, suggesting that the risk of car-diovascular disease in these women is due mainly to the subsequent development of DM.

These findings are supported by data from Hopmans et al (71), who, in 2015, carried out a systematic review of more

than 300,000 women and found that women who have had GD were at twice the risk of cardiovascular disease (defined as myocardial infarction or cerebrovascular accident) compa-red with women who had normal blood sugar levels.

Furthermore, a case-control study (127) of 2,639 women concluded that GD was a predictor of cardiovas-cular disease independently of the development of DM only in overweight women (BMI, 25-29) in the absence of other cardiovascular risk factors (smoking, obesity, or AHT). The authors reason that in obese women, the risk of cardiovascular disease itself is already so high that the fact of having had GD does not increase it significantly. In overweight women, on the other hand, having had GD carries an added risk of cardiovascular disease.

However, a study of almost 63,000 women performed in 2016 (128) established that after adjusting for possi-ble confounders such as age, concomitant presence of DM, AHT, and obesity, GD was independently associated with the risk of cardiovascular disease within 3 years of delivery (OR, 1.25). After a separate analysis and adjust-ment for potential confounders, the risk continues to be significant for acute coronary syndrome, acute myocar-dial infarction, and AHT, although not for cerebrovascular accident (defined as stroke, transient ischemic accident, and vascular syndrome). This finding is consistent with a review from 2014 (125).

In general, we can conclude that progression of DM is a strong risk factor for future cardiovascular events; in these patients, the risk is thought to increase 4-fold before a diagnosis of DM (6.129). However, to date, it has not been possible to discover whether the increase in cardiovascu-lar risk these patients are subject to is directly associated with GD itself or, on the other hand, is induced via subse-quent development of DM (125).

We must broaden our research in this field in order to provide more evidence on the pathophysiology of car-diovascular disease after GD or hypertensive states of pregnancy and thus establish strategies to prevent its development.

If we consider pregnancy to be an early filter for future complications, it is worth noting an interesting prospective case-control study performed by Barden et al (79), who followed women with a history of GD for 10 years after delivery. The main objective of the study was to estimate the potential risk of cardiovascular disease and DM based on the identification of cardiometabolic risk factors alre-ady present during pregnancy. Women with GD who fit the profile of "high risk" during pregnancy (greater BMI, hypertension, increased fasting glucose, higher levels of triglycerides and insulin, and lower levels of HDL-choles-terol), have a greater risk of developing cardiovascular disease and DM than women with a "low-risk" profile during pregnancy.

All of these markers of cardiovascular risk that are pre-sent in women who have had complicated pregnancies with



hypertensive states or GD may already be present from the start of pregnancy. In order to clarify the pathophysiolo-gy linking these entities with subsequent development of cardiovascular disease it may be necessary to follow the patient before conception, during pregnancy, and there-after.

The concept of "overall risk of vascular disease" is increasingly important, and, today, we cannot rule out the effect of the main complications of pregnancy when evaluating cardiovascular risk in women. In this respect, in 2011, the American Heart Association first recognized a history of GD or hypersensitive states of pregnancy as mean risk factors for cardiovascular disease in their gui-delines (130) in order to prevent this disease in women. The guidelines consider these risk factors to be equivalent to others such as smoking, obesity, AHT, or dyslipidemia.

Finally, given that the diagnosis of GD could act as a precursor or alarm signal for the potential development of various metabolic and cardiovascular diseases in the near future, we believe that the medical community must recognize this condition as a cardiovascular risk factor in clinical practice.

5. Postpartum follow-up of gestational diabetes and screening for diabetes mellitus and cardiovascular disease

Based on the axiom that GD could be DM that is evol-ving, appropriate screening for potential circumstances stemming from this disease becomes a priority for health systems.

Social and health care costs, morbidity and mortality, and the fact that this problem involves both mothers and children make it worthwhile to do all that is necessary to minimize the potential impact of a diagnosis of GD.

There is considerable potential to prevent or slow the onset of DM in these women, as shown by various studies and randomized clinical trials (131,132).

Data from some prevention studies suggest that early detection and specific intervention strategies in cases of prediabetes can reduce progression of DM in up to 50% of women who have had an episode of GD, with a 35% decrease in the prevalence of DM at 10 years (133-137).

Such simple measures (134,136,138-140), which aim to modify lifestyle (eg, healthy diet, regular physical exercise, maintenance of normal body weight, stopping smoking, breastfeeding, and even treatment with oral antibiotics [in specific cases]), continue to be the cornerstone for over-coming the vicious circle of cardiometabolic disease and have proven cost-effective (133,141).

Weight loss has been proposed as the risk factor with the greatest individual variability in patients who develop DM after GD (35). Weight gain after delivery and during pregnancy are both relevant (142).

A multicenter randomized clinical trial (134) showed that weight loss of 7% can reduce the risk of DM by more than 50%. Hamman et al (143) found that for each kilo-gram of weight lost, the relative risk of DM is reduced by 16%.

The importance of weight loss in preventing DM is further stressed in the composition of the patient’s diet, although any benefit may be mediated by changes in body mass secondary to a healthy diet (144).

The importance of physical exercise is constant in diabe-tes prevention programs. Bao et al (131) estimate that for every 100 minutes of moderately intense physical exerci-se, the risk of DM is reduced by 9%, independently of BMI.

Some authors (145,146) have found evidence of the benefits of breastfeeding for prevention of DM. Long-term studies have shown that breastfeeding for more than 3 months reduces the risk of DM by more than 40% and that if it is for longer than 10 months, then both glucose tolerance and insulin sensitivity improve.

It has been estimated that for each additional year of breastfeeding, the risk of DM can be reduced by 15% (147). Prolonging breastfeeding for more than 3 months can delay the development of DM by up to 10 years (148). Interestingly, this measure can be an inexpensive way of preventing development of DM and one that mothers are usually quite aware of, although generally owing to the benefits it provides with respect to their child’s health as opposed to their own.

The main scientific societies and clinical guidelines have proposed different norms for the postpartum follow-up of women with a history of GD. However, there is currently no consensus on the appropriateness of the diagnostic test to be used (baseline glycemia, OGTT, or glycosylated hemoglobin), not even with respect to the time interval for screening (which usually varies from 1 to 3 years).

During the last 10 years, the ADA itself has sugges-ted measuring baseline glycemia because of its logical advantages (149). However, this test must be performed after at least 8 hours’ fasting. Measurement of glycosyla-ted hemoglobin (HbA1c) may seem to be an interesting approach a priori, given that it does not require fasting and has significantly practical advantages over oral glucose overload. Nevertheless, until more evidence is available, it does not seem that this parameter, whether used alone or together with fasting baseline glucose, can provide a diagnosis of glucose metabolism abnormalities in women who have had a previous episode of GD that is as sensitive and specific as OGTT (34).

The summary of evidence by Uptodate (150) on the management and follow-up of GD, which takes on board the recommendations of the ADA and the American Colle-ge of Obstetrics and Gynecology (ACOG), states that OGTT is the most sensitive test for the diagnosis of diabetes in most publications, but that the determination of fasting plasma sugar is considered a cheaper, more convenient,



specific, and reproducible approach in this group of patients.

Long-term follow-up is clearly essential, and glycemic status should be reevaluated every 3 years, since a nega-tive postpartum test result only rules out diabetes at the time the test is performed. Furthermore, the time since onset of the disease is a parameter that varies with the individual patient (5).

The ADA guidelines "Management of Diabetes in Preg-nancy: Standards of Medical Care in Diabetes-2019" (151), the ACOG (152), and the V International Conference on GD (153) recommend the following:

– Screening for all women diagnosed with GD at 6-12 weeks postpartum based on a test that is not gly-cosylated hemoglobin (grade of recommendation B)

– Women with a history of GD should undergo scree-ning for DM every 3 years (grade of recommendation B). If any test reveals an abnormality compatible with prediabetes, subsequent monitoring should be on a yearly basis.

– Women with a previous history of GD and a diagno-sis of prediabetes should undergo interventions to modify their lifestyle or receive metformin (grade of recommendation A).

The 2015 National Institute for Health and Care Exce-llence (NICE) guidelines on GD (158) recommend the following:

– Baseline glycemia testing at 6-12 weeks postpartum in order to rule out DM. It is not recommended to offer glucose tolerance testing routinely during the late postpartum.

– Annual glycosylated hemoglobin testing for all women with a history of GD.

– Advice on lifestyle, including weight control, diet, and exercise.

Despite all of these guidelines, follow-up programs that facilitate diagnosis and early treatment are genera-lly uncoordinated and lack structural consistency. Once the patient is discharged from hospital, it is not altoge-ther clear who is responsible for subsequent follow-up visits (the patient herself, the primary care physician, the endocrinologist, or the obstetrician) (155).

Most health systems do not currently have strategies to bridge the gap between specialized care of specific obste-tric complications and continuous monitoring in primary care. In addition, it is clear that publication of guidelines on postpartum screening for DM is insufficient. Systematic screening is not being performed at present (156).

The low patient participation in postpartum reevalua-tion is discouraging. Some studies report ≤50% attendance at the postnatal visit at 6-12 weeks. This figure is as low as 40% in the worst cases (157-165).

The low participation reported could be indicative of the low awareness on the part of both health professio-nals and patients of the scope and implications of this

condition for long-term health. In addition, the lack of consensus between organizations on guidelines on the most appropriate postpartum management means that no solution to the problem is provided.

If we are to boost participation, the first thing to do is consider eliminating the barriers and limitations faced by these patients at the time of screening (166).

Some studies have examined this observation (167). Thus, a recent systematic review by Nielsen et al (168) shows that emotional stress, time pressure, and difficul-ties adapting to motherhood are the main barriers faced by women when attempting to fulfill the demands of the postpartum screening program.

Similarly, information on the viewpoint of or barriers perceived by health professionals is scarce; the lack of consensus on the ideal screening method and the fre-quency with which it should be applied seem to be among the main problems (147,169,170).

Improvement in postdischarge guidelines and recom-mendations could be an important first step in solving the problem, since it does not require additional expenditu-re (171).

Early infancy is often a period of great vulnerability for the mother. It is during this period that she invests a con-siderable amount of her time in the care of the newborn and may tend to neglect her own health. Many women do not perceive a greater risk of developing DM after having had GD (160,172,173).

Studies carried out in primary care in patients with DM have shown that health care can improve when risks are transmitted on an individual basis, thus leading to grea-ter adherence to follow-up programs and more favora-ble long-term outcomes. In this respect, it could prove beneficial to provide tools that help to inform about a patient’s individual risk of developing specific DM-related complications (174,175).

Other strategies with the potential to increase adheren-ce to screening programs envisage the need to simplify the detection test (167,176). Similarly, priority should be given to increasing awareness of the importance of follow-up in all areas and of establishing a well-organized system to ensure that the whole process is robust.

Systems for notifying the relevant health care professio-nals and telephone and email reminders for the patient, as well as motivational interviews, have been proposed as useful tools for increasing participation in early detection programs (177-184).

It seems logical to incorporate many of these tools into the public health system and to combine them with, for example, routine infant examinations and the vaccination schedule, which most mothers are aware of and adhere to (41).

While early detection of cardiovascular risk fac-tors (hyperglycemia, AHT, obesity, and hypercholestero-lemia) and their treatment have proven useful in healthy



persons (185,186,187), interventional studies are neces-sary to determine whether screening for cardiovascular disease is cost-effective in women who have had GD. What is clear is that despite the hormonal effects of pregnancy, measurement of typical risk factors for car-diovascular disease during pregnancy complicated by GD, together with a detailed family history, can offer a unique opportunity to identify women with GD who are at greater risk of DM and other cardiovascular events in the future (79).

CONCLUSIONS

There is sufficient scientific evidence to demonstrate that experiencing an episode of GD is associated with a greater risk of DM, AHT, metabolic syndrome, and car-diovascular disease at a younger age than women with normal blood sugar levels during pregnancy.

Gestation is a physiological situation that provides us with a unique opportunity to identify a group of women at future risk of cardiovascular morbidity and mortality.

Today, it is not possible to objectively select from among patients with GD a group that is at greater risk of cardio-metabolic complications.

In the case of a diagnosis of GD, the patient should be informed of the need for preventive measures (regular physical exercise, healthy diet) and systematic screening.

More research is necessary to shed light on the most appropriate types of intervention in this group of patients.

Obstetricians, endocrinologists, and primary care physi-cians should be made aware of the need for appropriate control of GD at the end of pregnancy.

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