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Abstract

Progression of retinopathy and nephropathy in women with diabetes occurs, at least temporarily, during pregnancy and postpartum. However, normotensive pregnancy seems to have no detrimental effects regarding the long-term progression of any microvascularcomplication. Increased risk from pregnancy induced hypertension without proteinuria and with proteinuria (pre-eclampsia) relates mainly to the association with kidney disease in diabetes, and poor glycemic control. A history of pre-eclampsia or pregnancy induced hypertension is an important prognostic factor for micro- and macro-vascular complications later in life. Data regarding the long-term effects of hypertensive pregnancies on late complications of diabetes suggest that women with diabetes should be monitored regularly and nephroprotective treatment initiated early.

Keywords

gestational diabetes gestational hypertension hypertensive disorder nephropathy pre-eclampsia retinopathy Type 1 diabetes Type 2 diabetes

Pregnancy, being characterized by hypervolemia, a hyperkinetic circulation, acquired thrombophilia, insulin resistance and low-grade inflammation, can induce gestational diabetes and, in women with pregestadonal diabetes, increases the risk of microangiopathic complications [1]. However, uncomplicated pregnancy in women with diabetes seems to have no long-term detrimental effects as regards the development of nephropathy or retinopathy [2,3]. This good outcome was shown in the Eurodiab Prospective Complication Study which had a mean follow-up of 7.3 years [3].

On the contrary, pregnancy in women with diabetes and complicated by hypertension with or without proteinuria seems to enhance the risk of subsequent microangiopathy development and progression [1]. The aim of this review is to focus on pregnancy as a window to the development of micro- and macro-angiopathic complications in women with diabetes.

Literature search

We searched MEDLINE, the Cochrane Database of Systematic Reviews and Clinical Evidence online using the search terms ‘pre-eclampsia’ (PE), ‘gestational hypertension’, ‘pregnancy-induced hypertension’, ‘hypertensive pregnancy’ and ‘diabetes’, as well as reviewing recent conference proceedings. We limited studies to those conducted in adults and focused on systematic reviews, meta-analyses and high-quality randomized controlled trials whenever possible.

Hypertensive pregnancy

Complications of pregnancy have the potential to be effective cardiovascular disease (CVD) risk ‘stress tests’ or ‘markers’, identifying women who may most benefit from primary prevention in order to reduce CVD risk [4,5]. Among women with diabetes, PE, the combination of hypertension and proteinuria, affects ∼2–5% of pregnancies, but the prevalence is higher (around 10%) among first pregnancies [6] and 20–25% in women with a history of hypertension prior to the pregnancy [7]. Estimates of the prevalence of gestational hypertension (new-onset hypertension without proteinuria) in women with diabetes vary from 3 to 14% [6,8]. Many risk factors for gestational hypertension have been recognized in the general population. Compared with those who have had normal pregnancies, a woman who has had PE in the past carries an sevenfold risk of recurrent disease. CVD risk factors such as antiphospholipid antibodies, diabetes, elevated BMI, hypertension and kidney disease are also known to increase the risk of PE [9]. But women with diabetes carry a two- to fourfold elevated risk of a hypertensive pregnancy and up to a sixfold increased risk of PE compared with women without diabetes. The risk is especially high in patients with diabetes and kidney disease [10,11].

This is important as hypertensive pregnancy seems to predict the short-term and long-term outcomes in the mother with diabetes. Women with gestational diabetes are at an increased risk of subsequently developing Type 2 diabetes, hypertensive pregnancy and sustained hypertension [12].

Different types of hypertensive pregnancy

Probably the most commonly used definition of PE is a blood pressure level of ≥140/90 mmHg accompanied by proteinuria after 20 weeks of pregnancy [13], while gestational hypertension is defined as an elevated blood pressure without the presence of proteinuria. Gestational hypertension in patients with diabetes was defined by the American Diabetes Association as a systolic blood pressure of ≥130 mmHg or a diastolic blood pressure ≥80 mmHg based on evidence from randomized controlled trials of treatment benefits in nonpregnant patients with diabetes [14,15]. When blood pressure is elevated prior to pregnancy or before 20 weeks of gestation, the hypertension is considered to be ‘chronic’.

In patients with diabetes, albuminuria is considered significant when the albumin excretion is >300 mg in a 24-h urine collection or >200 µg/min in an overnight collection, or the albumin-to-creatinine ratio is >35 mg/mmol in a single spot urine sample. Microalbuminuria is a marker of incipient kidney disease and is defined as an albumin excretion rate of 30 to <300 mg/24 h or 20 µg/min to <200 µg/min in an overnight collection, or 3.5–35 mg/mmol in a single spot urine sample [16]. Importantly, the albumin excretion rate can increase up to three-times during pregnancy due to increased kidney perfusion and glomerular filtration. Accordingly, microalbuminuria alone cannot be used to make a diagnosis of PE.

Health during pregnancy in women with Type 1 diabetes

Compared with women without diabetes, patients with Type 1 diabetes but without nephropathy have a two- to three-times increased risk of developing gestational hypertension [11]. A woman with Type 1 diabetes carries a 10–20% risk of suffering from PE during her first pregnancy. This risk increases with the presence of kidney disease: 42% of women with Type 1 diabetes and microalbuminuria, and 64% of those with macroalbuminuria develop PE during pregnancy [17,18].

Good blood glucose control has been shown to protect women with Type 1 diabetes from PE but not from gestational hypertension [11]. Similar findings were observed in a randomized controlled study [19] in which women with moderate glucose control (HbA_lc 6.1–6.9 %, 43–52 mmol/mol) in early pregnancy had a three-times increased risk of PE compared with those with good glucose control (HbA_lc <6.1%, 43 mmol/mol). The risk was eight-times increased in those with poor glycemic control (HbA_lc >8.0%, 64 mmol/mol).

Somewhat in contrast, Klemetti et al. reported that between 1989 and 2008 an increase in BMI and worsening of glycemic control did not affect the prevalence of PE, gestational hypertension or chronic hypertension in women with Type 1 diabetes [20]. It should be noted, however, that the proportion of patients with Type 1 diabetes patients with a blood pressure > 130/80 mmHg but <140/90 mmHg increased during the same time period [21].

Although, kidney disease is by far the most important risk factor for the development of PE in women with Type 1 diabetes, other risk factors have also been shown to play a role. These factors are similar to those in the general population and include nulliparity, previous PE, chronic hypertension, retinopathy and duration of diabetes [11,22].

Impact of hypertensive disorders of pregnancy on later life in women with diabetes

Kidney diseases

As early as 1936, PE had been shown to have adverse effects on the kidneys both during pregnancy and later in life [23]. Since then our knowledge in this area has increased considerably. A meta-analysis (involving women with and without diabetes), published in American journal of Kidney Diseases in 2010 [24], reported that after a follow-up of 7 years, incipient kidney disease (microalbuminuria) developed in 31% of the women who had had PE compared with 7% of those who did not [24]. The estimated glomerular filtration rate upon completion of the study did not differ between the groups but this was probably due to the relatively short follow-up time. A large register study recently showed that women who had had PE had a five- to 16-times elevated risk of subsequently developing end stage renal disease (dialysis or transplantation) (Table 1) [25].

Table 1.

Long-term effects of uncomplicated and complicated (hypertension with or without proteinuria) pregnancy on micro- and macro-vascular complications in women with diabetes.

Baseline status	During pregnancy	After pregnancy	Ref.
Uncomplicated: microangiopathies	Transient worsening of retinopathy and nephropathy	No effects	[1 –3]
Hypertension: microangiopathies
Without proteinuria induced of retinopathy and hypertension)	Transient worsening of retinopathy and nephropathy	Increased risk for development and progression retinopathy	[26]
With proteinuria (pre-eclampsia)	Transient worsening of retinopathy and nephropathy	Increased risk for development and progression of nephropathy	[27]
Hypertension: macroangiopathies
With or without proteinuria	No effect if younger age (<40 years) and no other risk factors	Increased risk for coronary artery disease and stroke	[12,27–28]

There is a shortage of data regarding PE as a risk factor for kidney disease in patients with Type 1 diabetes. However, we observed that the risk of developing nephropathy in those with Type 1 diabetes was eight-times elevated in women with a prior PE compared with those with normal blood pressure during pregnancy [27]. Although the presence of gestational hypertension did not appear to change this risk [27], microalbuminuria was not quantitatively measured hence the possibility that microalbuminuria was present prior to pregnancy cannot be ruled out.

Eye diseases

Retinopathy worsens temporarily during pregnancy in 17–70% of women with Type 1 diabetes (Table 1) [29,30]. Duration of diabetes, poor glycemic control and high blood pressure increase this risk. These retinal changes may relate to endothelial dysfunction, and to inflammation since markers of inflammation are increased in women whose eye disease worsens during pregnancy [31].

Pregnancy itself seems not to affect the development or progression of microvascular complications in diabetes later in life [3,32]. However, a Swedish study of women with Type 1 diabetes with PE reported a deterioration of retinopathy 6 months after pregnancy compared with women without PE [33]. When analyzing patients with Type 1 diabetes with PE and gestational hypertension separately and following them for 16 years, we observed that severe retinopathy was more common not only in patients with PE but also in those with gestational hypertension compared with women with a history of normal blood pressure during pregnancy [26].

Cardiovascular disease

Compared with women who have had uncomplicated pregnancies, women with prior PE have a roughly fourfold higher incidence of subsequent hypertension and twofold elevated risk of heart disease, stroke and venous thromboembolism [12,28]. Two systematic reviews, one of cohort studies (n = 25) and the other of both cohort (n = 10) and case–control (n = 5) studies, have both reported a doubling of risk for different measures of CVD comparing women with PE with normotensive women over a median of 10–12 years follow-up [12,28].

Our cohort of women with Type 1 diabetes and a history of a hypertensive pregnancy (PE or gestational hypertension) more often subsequently developed a hypertensive pregnancy (42–50%) during a mean follow-up of 11 years, compared with women with Type 1 diabetes and normal blood pressure in pregnancy (10%) (Table 1) [27].

Some critical evaluations of the data

The above data suggest that PE may serve as a window into the future vascular health of women with Type 1 diabetes. It may be that pregnancy itself, as a state of hypervolemia, acquired thrombophilia, insulin resistance and low-grade inflammation, can induce PE as the first manifestation of vascular disease, which then progresses to clinical CVD after only a few years postpartum [1,4]. It is also possible that some women with diabetes may have had signs of incipient kidney disease (microalbuminuria) already before pregnancy, and in such cases the pregnancy encouraged and enhanced the development of glomerulopathy in the years post partum. In any event, PE and nephropathy in women with diabetes appear to share factors such as endothelial dysfunction and associated CVD risk factors (dyslipidemia, insulin resistance, hypertension, subclinical inflammation, increased oxidative stress and chronic hyperglycemia), that are likely to be intimately involved in the pathophysiology of both, and ultimately in the development of CVD itself [4].

Type 2 diabetes

There is an urgent need of data regarding risk factors for PE in Type 2 diabetes considering the increasing number of such patients [34]. Not surprisingly, chronic hypertension is more common in childbearing women with Type 2 diabetes compared with childbearing women with Type 1 diabetes [35]. Furthermore, nulliparity, duration of diabetes, poor glycemic control, elevated BMI and CVDs increase the risk of PE. In contrast, the pregnant mother's age seem to affect the risk of PE in women with Type 2 but not Type 1 diabetes [35].

Gestational diabetes

The prevalence of gestational diabetes mellitus (GDM) is 5–13% and is a increasing. Women with history of GDM have a sevenfold increase in the risk of later developing Type 2 diabetes [12]. As is well known, Type 2 diabetes is an important CVD risk factor, having a markedly higher relative and absolute association with CVD in women than in men [36].

GDM is associated with an increased the risk of developing hypertension during pregnancy [36]. Known risk factors for gestational hypertension are overweight, impaired glucose tolerance, high fasting plasma glucose and, above all, insulin resistance. Insulin sensitivity is known to decrease during the third trimester in many pregnancies whereas serum triglyceride concentrations increase. Intriguingly, PE is a state of sympathetic overactivity which in the short-term elevates insulin resistance and, in the long term, is likely to increase the risk of CVD [7,37]. This increased risk of CVD in those with a history of GDM has been reported in a number of recent studies [38 –41].

Clinical implications

Based on the available data we suggest that women with diabetes plan their pregnancies early in order to avoid complications in both themselves and their offspring. Obese women with Type 2 diabetes and those at risk of gestational diabetes (family or personal history of GDM) should loose weight and increase physical activity. All pregnancies in women with diabetes should be planned with right control of blood glucose (HbA_lc <7%, 53 mmol/mol), blood pressure (>140/90 mmHg) and body weight combined with measurements of proteinuria in order to lower the risks of complications during and after pregnancy. Subsequent to the pregnancy, all women with history of hypertension should be followed for the possible development of microangiopathies, chronic hypertension and dyslipidemia, and treated appropriately. Angiotensin-converting enzyme (ACE) inhibitors/ angiotensin II receptor (ATR) blockers are the medications of choice for renal and retinal protection after a hypertensive pregnancy.

Conclusion

The physiologic changes of pregnancy can induce the onset or exacerbate chronic diseases including diabetes mellitus. Among women with diabetes, recent data regarding the long-term effects of hypertensive pregnancies on subsequent complications in women with diabetes indicate that these women should be followed carefully during and after pregnancy and appropriate protective treatment started early. In this review we have summarized data on risk factors and the long-term effects of hypertensive pregnancies on complications in diabetes that may be of clinical relevance in prevention. After pregnancy, all women with diabetes and with a history of hypertension should be followed for the development of microangiopathies, chronic hypertension and dyslipidemia and treated early and appropriately. ACE inhibitors/ATR blockers are the drugs of choice for renal and retinal protection after a hypertensive pregnancy women with diabetes.

Future perspective

In future, pregnancies in women with diabetes will be better planned to screen those with early signs of nephropathy (microalbuminuria) and/or preproliferative retinopathy and treated to get optimal diabetes control and improvement in microangiopathies. Special attention will be paid in blood pressure and in the presence of mild nephropathy ACE inhibitor/ATR blocker treatment will be started. This treatment will be stopped during pregnancy, these women will be followed closely after (as well as during) pregnancy and nephron/retinoprotective treatment (with ACE inhibitors or ATR blockers in particular) will be started soon after delivery in women with history of hypertensive pregnancy. With this procedure the onset and progression of microangiopathies in women with diabetes will be delayed and pregnancy serves as a window to woman's life.

No writing assistance was utilized in the production of this manuscript.

Executive summary

Health during pregnancy in women with Type 1 diabetes

Women with diabetes carry a two- to four-fold elevated risk of a hypertensive pregnancy and up to a sixfold increased risk of pre-eclampsia (PE) compared with healthy women. The risk is especially high in patients with kidney disease.

Impact of hypertensive disorders of pregnancy in later life

The prevalence of nephropathy is eight-times elevated in women with diabetes and with a prior PE compared with those with normal blood pressure during pregnancy. Gestational hypertension does not change this risk. For patients with diabetes, severe retinopathy is more common not only in patients with PE but also in those with gestational hypertension compared with women with a history of normal blood pressure during pregnancy.

Gestational diabetes mellitus & risk of cardiovascular disease

Women with history of gestational diabetes mellitus have a sevenfold increased risk of later developing Type 2 diabetes. Type 2 diabetes is an important cardiovascular disease risk factor, having a markedly higher relative and absolute association with cardiovascular disease in women than in men.

Conclusion

For women with diabetes, the well-documented long-term effects of hypertensive pregnancies on late complications dictate that such women should be followed regularly and protective treatment started early.

Footnotes

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Health after Pregnancy in the Mother with Diabetes

Abstract

Keywords

Literature search

Hypertensive pregnancy

Different types of hypertensive pregnancy

Health during pregnancy in women with Type 1 diabetes

Impact of hypertensive disorders of pregnancy on later life in women with diabetes

Kidney diseases

Eye diseases

Cardiovascular disease

Some critical evaluations of the data

Type 2 diabetes

Gestational diabetes

Clinical implications

Conclusion

Future perspective

Footnotes

References