Gestational Diabetes During and After Pregnancy

12. Blood Pressure in GDM

Baha Sibai  and Mounira Habli

(1)

Department of Obstetrics and Gynecology, University of Cincinnati College of Medicine, Cincinnati, OH, USA

Baha Sibai

Email: sibaibm@ucmail.uc.edu

Abstract

Hypertensive disorders of pregnancy are common medical complications and are also associated with insulin resistance during pregnancy. While physiologic mechanisms are not completely elucidated, hypertension and gestational diabetes (GDM) have overlapping etiologies and adverse effects on outcomes. Several treatment strategies aimed at normotension may be effective for reduction in perinatal morbidity, with some treatments more optimal in glucose intolerance than others.

12.1 Gestational Diabetes and Hypertension During Pregnancy

There is a strong association between insulin resistance and hypertensive disorders in pregnancy,1 both of which are associated with higher risk of cardiovascular disease later in life.1 Because of recent trends in advanced maternal age at time of conception and the growing rate of obesity, the incidences of both chronic hypertension as well as gestational diabetes (GDM) are also increasing.2 Therefore, the rate of pregnancies complicated by both hypertensive disorders and GDM are expected to rise. In this chapter, we discuss the classification of hypertensive disorders of pregnancy; pathophysiology of hypertension and insulin resistance; outcomes of pregnancies affected by hypertension and GDM and prevention and management strategies of hypertensive disorders with and without GDM.

12.2 Classification of Hypertensive Disorders

Hypertensive disorders are the most common medical complications of pregnancy, affecting 5–8% of all pregnancies.23 Categories of hypertensive disorders in pregnancy include chronic hypertension and the group of hypertensive disorders unique to pregnancy, including gestational hypertension, with and without preeclampsia. Approximately 30% of hypertensive disorders in pregnancy are due to chronic hypertension and 70% are due to gestational hypertension.23 The spectrum of disease ranges from mildly elevated blood pressures with minimal clinical significance to severe hypertension and multi-organ dysfunction. The incidence of disease is dependent upon multiple demographic parameters including maternal age, race, and associated underlying medical conditions. Understanding the disease process and the impact of hypertensive disorders on pregnancy is of utmost importance, because these disorders remain a major cause of maternal and perinatal morbidity and mortality worldwide.

Hypertension is defined as a systolic blood pressure (SBP) of 140 mm Hg or greater, or a diastolic blood pressure (DBP) of 90 mm Hg or greater.24 These measurements must be present on at least two occasions at least 4 h apart, but no more than a week apart.24 Abnormal proteinuria in pregnancy is defined as the excretion of 300 mg or more of protein in 24 h. The most accurate measurement of proteinuria is obtained with a 24-h urine collection, but in certain instances, semiquantitative dipstick measurement may be the only test available to assess urinary protein. A value of 1+ or greater correlates with 30 mg/dL. Proteinuria by dipstick is defined as 1+ or more on at least two occasions at least 4 h apart but no more than 1 week apart in the absence of urinary tract infection. The accuracy of semiquantitative dipstick measurements on spot urine samples as compared with 24-h urine collections is highly variable.24 Care should be taken when obtaining urine protein measurements to use a clean sample for dipstick measurement, because blood, vaginal secretions, and bacteria can increase the amount of protein in urine. In addition, protein excretion is influenced by posture and exercise.

Edema is a common finding in the gravid patient, occurring in approximately 50–80% of normal pregnancies. Lower extremity edema is the most typical form. Pathologic edema is usually seen in nondependent regions such as the face, hands, or lungs. Excessive, rapid weight gain of five pounds or more per week is another sign of pathologic fluid retention.24

The recent classification system of hypertension in pregnancy by the American College of Obstetricians and Gynecologists Committee adopted the criteria proposed by the National High Blood Pressure Education Program Working Group in 2000. This system offers simple, concise, and clinically relevant features for each of the four major categories of hypertension24 in pregnancy – gestational hypertension, preeclampsia or eclampsia, chronic hypertension, and preeclampsia superimposed on chronic hypertension.

Gestational hypertension is the most frequent cause of hypertension during pregnancy.4 The rate ranges between 6 and 17% in healthy nulliparous women and between 2 and 4% in multiparous women based on the population studied.4 Gestational hypertension is considered severe if there is sustained SBP to at least 160 mmHg and/or DBP to at least 110 mmHg for at least 6 h without proteinuria. Treatment generally is not warranted, because most patients have mild hypertension. However, approximately 40–50% of patients diagnosed with preterm mild gestational hypertension will develop proteinuria and progress to preeclampsia.4 In general, the majority of cases of mild gestational hypertension are diagnosed at or beyond 37 weeks and have a pregnancy outcome similar to term normotensive pregnancies.4

The incidence of preeclampsia is reported to be from 5 to 8%, depending upon the population.24 Preeclampsia occurs more frequently in primigravidas. The reported rate of preeclampsia ranges from 6 to 7% in primigravidas and from 3 to 4% in multiparous patients.24 Advanced maternal age (≥35 years) is another risk factor especially if conception was secondary to assisted reproductive technology.24Obesity is another important factor.24

The symptoms of preeclampsia are headaches, visual changes, and epigastric or right upper quadrant pain plus nausea or vomiting.24 In the absence of proteinuria, preeclampsia should be considered when gestational hypertension is associated with persistent cerebral symptoms, epigastric or right upper quadrant pain with nausea or vomiting, fetal growth restriction, thrombocytopenia or abnormal liver enzymes.24

Preeclampsia may be subdivided further into mild and severe forms. The distinction between the two is made on the basis of the degree of hypertension and proteinuria and the involvement of other organ systems.24 Close surveillance of patients with either mild preeclampsia or gestational hypertension is warranted, because they may progress to fulminant disease. A particularly severe form of preeclampsia is the HELLP syndrome, an acronym for hemolysis (H), elevated liver enzymes (EL), and low platelet count (LP).5 The acronym may be deceptive, because hypertension or proteinuria might be absent in 10–15% of women who develop HELLP and in 20–25 % of those who develop eclampsia.5 A patient diagnosed with HELLP syndrome should be classified as having severe preeclampsia. Another severe form of preeclampsia is eclampsia, which is the occurrence of seizures not attributable to other causes.5

Hypertension complicating pregnancy is considered chronic if a patient was diagnosed with hypertension before pregnancy, if hypertension was present prior to 20 weeks gestation, or if it persists longer than 12 weeks after delivery.3 Women with chronic hypertension are at risk of developing superimposed preeclampsia. The reported rate of superimposed preeclampsia ranges from 15% to 35%.3 Superimposed preeclampsia is defined as an exacerbation of hypertension with new onset of proteinuria or symptoms of headache or epigastric pain or laboratory abnormalities as elevated liver enzymes.3

12.3 Pathophysiology

The etiologic agent responsible for the development of preeclampsia remains unknown.24 Theories as to the causative mechanisms include placental origin, immunologic origin, abnormal angiogenesis, endothelial cell injury, alterations in nitric oxide levels, increased oxygen free radicals, abnormal cytotrophoblast invasion, dietary deficiencies, and genetic predisposition.24

Insulin resistance has long been implicated in the pathogenesis of preeclampsia. Insulin resistance and preeclampsia share several biomarkers that vary over the course of pregnancy, and both insulin resistance and cardiovascular disease share similar biomarkers with preeclampsia.6 For example, levels of triglycerides, small dense low density lipoprotein particles, free fatty acids, plasminogen activator inhibitor-1, vascular cell adhesion molecules, and leptin normally increase in normal pregnancy with advancing gestational age and with progression of insulin resistance.79 Pregnancies complicated with preeclampsia are characterized by low sex hormone binding globulin1012 and low serum adiponectin levels,13,14 which are also risk factors for GDM (Table 12.1).

Table 12.1

Risk factors for GDM and hypertensive disorders in pregnancy

Multifetal gestation

Chronic vascular disease (renal disease, rheumatic disease, connective tissue disease)

Age ≥25 years

Body mass index (BMI) ≥25 kg/m2

Ethnicity (Native American, Asian)

Type 1 or type 2 diabetes or GDM in a first degree relative

Previous history of GDM

Previous macrosomic baby

Mother’s own weight <2,500 g or 10th percentile

Multiple gestation

Polycystic ovary syndrome

Family history of preeclampsia or eclampsia

Metabolic syndrome

GDM itself may increase risk for hypertension. Suhonen et al15 reported that women with GDM (n = 81) as compared with controls (n = 327) have a higher frequency of chronic hypertension (2.5 vs. 0.3%, p<0.05) and preeclampsia (19.8 vs. 6.1%, p <0.001). Hyperinsulinemia has been prospectively diagnosed before the clinical diagnosis of preeclampsia.16 However, in the Toronto Tri-Hospital Gestational Diabetes Project, Naylor et al17 found only a 9% incidence of preeclampsia in untreated GDM, which is comparable to the incidence reported in treated women with GDM and in women treated for type 1 or type 2 diabetes mellitus. Therefore, treatment of GDM apparently does not reduce the incidence of hypertensive disorders in pregnancy. No treatment studies1827 have corrected for age or maternal BMI, which are well established risk factors for hypertensive disorders in pregnancy. There are also no prospective observational studies or randomized trials evaluating the benefits of treating mild hypertension for prevention of GDM. Thus, whether GDM shares a common causal pathway with hypertensive disorders or is a cause of hypertensive disorders is unknown (Table 12.2).

Table 12.2

Percent of hypertensive disorders in pregnancies complicated with GDM

Author

N

% Gestational hypertension

% Preeclampsia

Prospective studies

Yogev et al (2008)18

Metzger B et al (HAPO) (2008)19

1,319

25,505

5.9

11.7

4.8

Retrospective studies

Svare JA et al (2001)20

Yogev et al (2004)21

Jacobson et al (2005)22

Shand AW et al (2008)23

Stella C et al (2008)24

323

1,813

504

16,727

14,880

6.9

21.4

7

9.6

8.7

6.7

Randomized clinical trials

Langer O et al (2000)25

Crowther CA et al (2005)26

Rowan JA et al (2008)27

404

1,030

733

5.04

6

15.1

6.3

12.4 Pregnancy Outcomes

Maternal and neonatal outcome in patients with preeclampsia with or without GDM depends on the following factors: the gestational age at delivery, severity of disease, quality of management, and presence of preexisting disease. Perinatal mortality is increased in those who develop hypertensive disease at <34 weeks. Risk to the mother can be significant and includes the possible development of disseminated intravascular coagulation, intracranial hemorrhage, renal failure, retinal detachment, pulmonary edema, liver rupture, abruptio placentae, and death.28

At least one study has shown an association between GDM and preexisting chronic hypertension and subsequent impact on perinatal outcomes. Schaffer found that the coexistence of chronic hypertension and GDM is associated with a higher rate of induction of labor (36.7 vs. 6.6%, p <0.05) but not with increased incidence of small- or large- for gestational age deliveries or low Apgar scores as compared with nonhypertensive GDM women.29

12.5 Prevention of Preeclampsia

Preventive interventions for preeclampsia could impact maternal and perinatal morbidity and mortality worldwide. As a result, during the past decade several randomized trials reported methods to reduce the rate and/or severity of preeclampsia. Several trials assessed protein or low-salt diets, diuretics, bed rest, zinc, magnesium, fish oil, vitamin C and E supplementation, and heparin to prevent preeclampsia, but results showed minimal to no effects of these therapies.28 Of note, none of these strategies were evaluated among women with coexisting GDM per se.

12.6 Management of Hypertension and GDM

There are no proven benefits of treating mild chronic hypertension or mild gestational hypertension during pregnancy, regardless of GDM.30 On the other hand, there is general agreement regarding treatment of severe hypertension during pregnancy (chronic or gestational).4 Informed by guidelines in persons without diabetes, the American College of Obstetricians and Gynecologists recommends that maternal blood pressure be aggressively treated to levels below 130/80 mm Hg (both systolic and diastolic) in women with type 1 and 2 diabetes mellitus.31 While some authors recommend treating GDM women with antihypertensive medications to keep SBP <140 mm Hg and DBP <90 mm Hg, the benefits and neonatal impact of such therapy remain unclear.

Women with GDM should be evaluated for superimposed preeclampsia as soon as the diagnosis is suspected. There are no data to guide physicians regarding the proper management of chronic hypertension in patients with GDM. As such, our recommendations are empiric.

The development of superimposed preeclampsia or mild preeclampsia/gestational hypertension is an indication for hospitalization in order to maintain close observation of maternal and fetal conditions. This evaluation should include 24 h urine for protein, platelet count, liver enzymes, and attention to new onset symptoms, such as severe headaches, visual disturbances, epigastric pain, and shortness of breath. In addition, patients should receive fetal testing (ultrasound for fetal growth and amniotic fluid index, and non-stress test or biophysical profile) at the time of diagnosis. If the patient was a candidate for outpatient management, fetal testing should be performed weekly and ultrasound for fetal growth every 3 weeks. We recommend that urine and blood tests be obtained at least once every week.

If there is proteinuria (≥300 mg/24 h), thrombocytopenia (platelet count <100,000/mm3), or elevated liver enzymes (AST or ALT >2x upper limit of normal), or signs or symptoms of severe preeclampsia, patients should be considered to have severe preeclampsia and be managed accordingly. Management strategies upon diagnosis should include intravenous magnesium sulfate, antihypertensive medications to control blood pressure in labor and delivery, and steroids for fetal lung maturity. Subsequent management will depend on response to this therapy, results of fetal and maternal evaluation, and gestational age at time of diagnosis.

Delivery is recommended for all patients with mild preeclampsia and gestational age of ≥37 weeks or in the presence of fetal or maternal indications. The presence of any of the factors listed in Table 12.3 is an indication for delivery. In addition, once the diagnosis of severe preeclampsia is established, women with gestational age greater than 24 weeks and less than 34 weeks should receive corticosteroids to accelerate fetal lung maturity and then be delivered within 48–72 h,32 likewise, delivery at gestational age >34 weeks is the treatment of choice after maternal stabilization.

Table 12.3

Indications for delivery in patients with GDM and severe preeclampsia

Gestational age >34 weeks

Preterm labor or rupture of membranes

Vaginal bleeding/suspected abruption

Persistent symptoms after magnesium sulfate

Eclampsia or persistent cerebral symptoms

Thrombocytopenia (platelet count less than 100,000) or elevated liver enzymes (HELLP syndrome)

Serum creatinine of 1.5 mg/dL or more or oliguria (<0.5 mL/kg/h)

Uncontrolled severe hypertension (SBP≥160 mmHg, DBP≥110 mmHg) despite maximum doses of antihypertensive (intravenous labetalol, hydralazine, and oral nifedipine)

Non-reassuring fetal heart rate testing

Congestive heart failure or pulmonary edema

Fetal growth restriction (<5‰ for gestational age)

Oligohydramnios (fluid index of <5 cm on at last two occasions >24 h apart)

Biophysical profile <4 on two occasions at 4 h apart

Repetitive late deceleration or severe variable deceleration or loss of variability

Reverse end diastolic flow or persistent absent diastolic flow in umbilical artery Doppler studies

For patients with essential chronic hypertension (absent target organ damage), we recommend using a calcium channel blocker such as nifedipine or diltiazem extended release (see doses in Table 12.4) with a target goal of SBP <140 mm Hg and DBP <90 mm Hg based on the recommendations for type 2 diabetes with hypertension in nonpregnant individuals. For patients with mild gestational hypertension (absent chronic hypertension), we do not recommend antihypertensive therapy because of the concern that such therapy may mask the development of severe gestational hypertension-preeclampsia. However, if the physician elects to use antihypertensive therapy to control mild hypertension, we recommend that such patients be managed in-hospital under close medical evaluation.

Table 12.4

Antihypertensive drugs commonly used in pregnancy

Drug

Starting dose

Maximum dose

 

Comments

Acute treatment of severe hypertension

   

Hydralazine

Labetalol

Nifedipine

5–10 mg IV every 20 min

20–40 mg IV every 10–15 min

10–20 mg oral every 30 min

30 mga

220 mga

50 mga

 

Avoid in women with asthma or congestive heart failure

Long term treatment of hypertension

Half life

 

Methyldopa

Labetalol

Nifedipine

Diltiazem

Thiazide diuretic

250 mg twice a day

100–200 mg twice a day

10 mg twice a day

120–180 mg daily

12.5 mg twice a day

4 g/day

2,400 mg/day

120 mg/day

540 mg/day

50 mg/day

2 h

5–8 h

2 h

2 h

3 h

Rarely indicated

First choice

To be used in women with diabetes

To be used in women with diabetes

Use in salt-sensitive hypertension and/or congestive heart failure

May be added as second agent

Not to be used if preeclampsia develops or intrauterine growth retardation present

Not to be used except post partum

Angiotensin converting enzyme inhibitors or angiotensin receptor blockers

       

aIf desired blood pressure levels are not achieved, switch to another drug

It is important to note that the recommendation for achieving this target goal is empiric and is not based on validated scientific data. Indeed, our target goal for patients without GDM is to keep systolic BP below 160 mm Hg and diastolic BP below 105 mm Hg.33 If the target goal BP is not achieved with maximum dose of nifedipine, we then add a combined β-and α- blocker such as labetalol starting with a dose of 100–200 mg twice daily for a maximum dose of 2,400 mg/day (800 mg three times daily). Failure to achieve the target blood pressure goal with maximum doses of these drugs is considered an indication for delivery except in cases where gestational age is <30 weeks, where a third drug can be added, such as oral hydralazine.

12.7 Conclusions

While the pathophysiology and risk factors for GDM and hypertension during pregnancy overlap, the implications of this overlap for clinical management remain uncertain. Currently, management of these conditions remains separate, with hypertension and preeclampsia guidelines nearly identical in women with and without glucose intolerance during pregnancy. Future studies exploring the effects of concurrent treatment of mild hypertension and glucose intolerance are needed. Of particular importance would be studies of the impact of lifestyle interventions for both hypertension and glucose intolerance on incidence of GDM and preeclampsia. Elucidation of the common pathways of glucose intolerance and hypertension during pregnancy would address the adverse outcomes associated with these two increasingly common conditions.

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