Recent Advances in Management of Gestational Diabetes and Pre-Eclampsia

RECENT ADVANCES IN MANAGEMENT OF GESTATIONAL
DIABETES AND PRE-ECLAMPSIA

1. GESTATIONAL DIABETES
INTRODUCTION
Treatment of gestational diabetes mellitus (GDM) aims to reduce hyperglycaemia and in turn
reduce the risk of adverse perinatal outcomes including large for gestational age (LGA),
macrosomia, shoulder dystocia, neonatal hypoglycemia and the need for caesarean section. Diet
modification is often used as first-line treatment; pharmacological treatments (metformin,
glibenclamide (glyburide) and/or insulin) are offered. Although results from these reviews
generally indicate that treatment reduces the risk of adverse perinatal outcomes. Several trials
have been published and recommended criteria for GDM diagnosis have changed.
Diabetes mellitus (DM) is one of the most common medical complications
of pregnancy; gestational diabetes mellitus (GDM) accounts for approximately 90-95% of all
cases. GDM is defined as carbohydrate intolerance of variable severity with onset or first
recognition during pregnancy. The prevalence of GDM varies from 1 to 14%, in direct
proportion to the prevalence of Type 2 diabetes in a given population or ethnic group. The
incidence of gestational diabetes is also increasing as a result of higher rates of obesity in the
general population and more pregnancies in older women. The concerns of diabetes are mainly
due to the maternal and fetal complications if the glycemic control during pregnancy is not
adequate. There is a linear relationship between maternal hyperglycemia and adverse fetal
outcomes. Two types of risk factors are identified in GDM. Unmodifiable risk factors are age,
genetic background, ethnicity, number of previous pregnancies and recently a short stature has
been identified as an independent variable. Modifiable known risk factors are obesity, lack of
exercise, dietary fat and lifestyle habits like smoking and certain drugs.
GDM is a major cause of maternal, fetal and neonatal morbidities like pre-eclampsia, birth
trauma, cesarean section, stillbirth, respiratory distress, hypoglycemia, hyperbilirubinemia, and
polycythemia.
DECCAN SCHOOL OF PHARMACY Page 1

Figure 1.EFFECTS OF DIABETES ON PREGNANCY
HIGH RISK PATIENTS
 GDM during previous pregnancy.

 High weight babies born from a previous pregnancy.
 A history of stillbirth or infants with congenital abnormalities.
 Poor obstetric history including recurrent fetal wastage, hypertension, eclampsia,
hydramnios, etc.
 A history of repeated or persistent urinary tract infection
 Age >30 years
RISKS FOR CHILD
 Stillbirth
 Birth Defects
 Respiratory Distress syndrome
 Becoming obese as children or adults
 Developing Diabetes

FETAL COMPLICATIONS
 MACROSOMIA
In this condition, the baby’s body is larger than normal. Large-bodied babies may be injured
during natural delivery through the vagina, so the baby may need to be delivered through
cesarean section.
 HYPOGLYCEMIA
In this condition, the baby’s blood glucose is too low. Breastfeeding may need to be started
right away to get more glucose into the baby’s system. If breastfeeding is not possible, then the
baby may need to get glucose put directly into the blood through a thin, plastic tube in his or
her arm.
 JAUNDICE
In this condition, the baby’s skin turns yellowish. The white parts of the eye may also change
color slightly. If treated, this is not a serious problem.
 RESPIRATORY DISTRESS SYNDROME (RDS)
In this condition, the baby has trouble breathing. The baby may need oxygen or other help
breathing if he or she has this condition.
 LOW CALCIUM AND MAGNESIUM LEVELS IN BABY’S BLOOD
In this condition, spasms in the hands and feet, or twitching and cramping of muscles can
occur. The condition can be treated through supplementation with magnesium and calcium
supplements.
NOTE: Keep in mind that just because you have GDM it does not mean that these problems
will occur.
 Gestational diabetes usually does not cause birth defects or deformities.
 Most developmental or physical defects happened during the first trimester of pregnancy,
between the 1st and 8th week, and gestational diabetes typically develops around the 24th week
of pregnancy.
 The fact that you have gestational diabetes will not cause diabetes in your baby. However, your
child will be at a higher risk for developing type 2 diabetes in adulthood and may get it at a
younger age (younger than 30).

Figure 2. (Left) A macrosomic baby born to a mother with diabetes.

(Right) A normal baby born to a mother without diabetes
MATERNAL COMPLICATIONS
PREECLAMPSIA
It is more common than in non-diabetic pregnancies (10% vs. 4%) and increases to 30% in the
presence of vascular disease. In women without pre-existing hypertension or nephropathy,
preeclampsia becomes apparent when the classical signs of hypertension and proteinuria
develop. At this time, the only curative treatment is delivery of the baby. In women with
nephropathy in whom the diagnosis is unclear, delivery is usually indicated when renal function
deteriorates and blood pressure becomes difficult to control, or if fetal compromise occurs.
PRETERM LABOR
The most common cause is still iatrogenic for the management of preeclampsia (9%).
Spontaneous rupture of membranes (6%) and spontaneous onset of labor (3%) possibly due to

polyhydramnios also contribute to this high incidence (48). Conventional management of

preterm labor in the absence of obstetric contraindications is with an intravenous infusion of
beta-adrenergic agonist such as salbutamol or ritodrine, which inhibit uterine contractivity,
usually given for 24 h. This is combined with high dose glucocorticoids (typically two doses of
12 mg dexamethasone given intramuscularly at 12 h apart) to encourage fetal lung maturation.
The two doses of dexamethasone are repeated at weekly intervals while the risk of preterm
delivery remains.
MAGNETIC RESONANCE IMAGE OF PREGNANCY

COMPLICATED BY DIABETES
NORMOGLYCMIA HYPERGLYCMIA

SCREENING AND DIAGNOSTIC INVESTIGATION
Diagnosis
 The oral glucose tolerance test (OGTT) was the gold standard for making the diagnosis of type 2
diabetes. It is still commonly used during pregnancy for diagnosing gestational diabetes. With an
oral glucose tolerance test, the person fasts overnight (at least 8 hours, but not more than 16
hours). The next morning, the fasting plasma glucose is tested. After this test, the person receives
a dose of oral glucose (the dose depends upon the length of the test). There are several methods
employed by obstetricians to do this test, but the one described here is standard. Usually, the
glucose is in a sweet-tasting liquid that the person drinks. Blood samples are taken up to four
times at different time points after consumption of the sugar to measure the blood glucose.
 Oral glucose tolerance test (OGTT)
Procedure:
 Carbohydrate intake of at least 150 g/day 3 days prior to test, then fast for 10 to 16 hours.

 100 grams or 75 grams of anhydrous dextrose powder

• Drink within 5 minutes (first swallow is time zero)
• Terminate test should nausea and vomiting occur
 Abstain from tobacco, coffee, tea, food and alcohol during test
 Sit upright and quietly during the test , Slow walking is permitted but avoid vigorous exercise
 Collect samples at 0, 1 ,2 and 3 hours.
Table 1.Diagnostic criteria for the 75-g OGTT

Plasma or Serum Level Plasma Level NDDG
Carpenter and Coustan
Fasting blood glucose ≥5.3 mmol/L (95 ≥5.8 mmol/L (105 mg/dL)
mg/dL)
One hour ≥10.0 mmol/L (180 mg/dL) ≥10.6 mmol/L (190 mg/dL)
Two hours ≥8.6 mmol/L (155 mg/dL) ≥9.2 mmol/L (165 mg/dL)
Three hours ≥7.8 mmol/L (140 mg/dL) ≥8.0 mmol/L (145 mg/dL)
PATHOPHYSIOLOGY
1. Pathophysiology of Gestational Diabetes

GDM is usually the result of β-cell dysfunction on a background of chronic insulin resistance
during pregnancy and thus both β-cell impairment and tissue insulin resistance represent critical
components of the pathophysiology of GDM. In most cases, these impairments exist prior to
pregnancy and can be progressive—representing an increased risk of T2DM post-pregnancy. A
number of additional organs and systems contribute to, or are affected by, GDM. These include
the brain, adipose tissue, liver, muscle, and placenta.

Figure 3. Organs involved in the pathophysiology of GDM
1.1 β-Cell Dysfunction

The primary function of β-cells is to store and secrete insulin in response to glucose load. When
β-cells lose the ability to adequately sense blood glucose concentration, or to release sufficient
insulin in response, this is classified as β-cell dysfunction. The exact mechanisms underlying β-
cell dysfunction can be varied and complex. Defects can occur at any stage of the process: pro-
insulin synthesis, post-translational modifications, granule storage, sensing of blood glucose
concentrations, or the complex machinery underlying exocytosis of granules. Indeed, the
majority of susceptibility genes that are associated with GDM are related to β-cell function,
including potassium voltage-gated channel KQT-like 1 (Kcnq1) and glucokinase (Gck). Minor

deficiencies in the β-cell machinery may only be exposed in times of metabolic stress, such as
pregnancy.
β-cell dysfunction is exacerbated by insulin resistance. Reduced insulin-stimulated
glucose uptake further contributes to hyperglycemia, overburdening the β-cells, which have to
produce additional insulin in response. Thus, once β-cell dysfunction begins, a vicious cycle of
hyperglycemia, insulin resistance, and further β-cell dysfunction is set in motion.
Insulin resistance
Figure 4. Pathophysiology of insulin resistance

A diagram of the relationship between β-cell dysfunction, insulin resistance, and GDM is
provided in Figure 5.
Figure 5. β-cell, blood glucose, and insulin sensitivity during normal pregnancy and GDM.
During normal pregnancy, β-cells undergo hyperplasia and hypertrophy in order to meet the
metabolic demands of pregnancy. Blood glucose rises as insulin sensitivity falls. Following
pregnancy, β-cells, blood glucose, and insulin sensitivity return to normal. During gestational
diabetes, β-cells fail to compensate for the demands of pregnancy, and, when combined with
reduced insulin sensitivity, this results in hyperglycemia. Following pregnancy, β-cells, blood
glucose, and insulin sensitivity may return to normal or may remain impaired on a pathway
toward GDM in future pregnancy or T2DM.

1.2 Placental Transport

The placenta contributes to insulin resistance during pregnancy via its secretion of hormones and
cytokines. As the barrier between the maternal and fetal environments, the placenta itself is also
exposed to hyperglycemia and its consequences during GDM. This can impact transport of
glucose, amino acids, and lipids across the placenta:
Glucose—Glucose is the primary energy source for the fetus and the placenta, and therefore must
be readily available at all times. For this reason, insulin is not required for the placental transport
of glucose. Instead, glucose transport occurs via GLUT1, by carrier-mediated sodium-
independent diffusion . However, the placenta still expresses the insulin receptor, and insulin
signaling can influence placental metabolism of glucose. The receptiveness of the placenta to
glucose uptake means that it is particularly sensitive to maternal hyperglycemia, and this directly
contributes to increased fetal growth and macrosomia.
Protein—Amino acid transport across the placenta is also an important determinant of fetal
growth.
GDM is associated with increased System A and L activity. These can also be modulated by pro-
inflammatory cytokines, such as TNF-α and IL-6. Altered amino acid transport may also be one
mechanism by which excess protein intake contributes to GDM.
Lipids—finally, while GDM has traditionally been described as a disease of hyperglycemia, the
rise in obesity-associated GDM has prompted a greater focus on the role of hyperlipidemia in
GDM. The majority of placental gene expression alterations in GDM occur in lipid pathways
(67%), as compared with glucose pathways (9%). Preferential activation of placental lipid genes
is also associated with GDM compared with T1DM. These data correlate with the results of the
HAPO Study, which revealed independent effects of maternal obesity and glucose on excessive
fetal growth. Therefore, it appears that GDM influences the placental transport of glucose, amino
acids, and fatty acids, and that all three must be considered when discussing the impact of GDM
on placental function and fetal growth.

MANAGEMENT OF GDM
Recent data provide strong evidence that proper treatment of GDM reduces adverse maternal and
perinatal outcomes. The Australian Carbohydrate Intolerance Study in Pregnant Women
randomized women to receive routine care or treatment for gestational diabetes. Primary fetal
outcomes included death, shoulder dystocia, bone fracture, and nerve palsy. Primary maternal
outcomes were induction of labor and caesarean delivery.
A. Diet
First-line therapy for women with gestational diabetes is dietary modification, often referred to
as medical nutritional therapy (MNT). This is best done in consultation with an experienced
nutritionist, and should take cultural preferences into account. The ADA also recommends
nutritional counseling, if possible by a registered dietitian, with individualization of the nutrition
plan based on height and weight. For normal-weight women (BMI: 20-24 kg/m2) 30 kcal/kg.
B. Exercise
In the management of Type 2 DM in non- pregnant condition, physical exercise is advocated.

Very few studies or reports on the effects of physical activity for the prevention or treatment of
gestational diabetes are available at present. Dempsey et al.; in a prospective study and in a case-

control study showed that lean as well as overweight women who were physically active before
and/or during pregnancy experienced statistically significant reduced risks of GDM (48% risk
reduction). In 2006, Zhang et al. found that vigorous physical activity before pregnancy and
continuation of activity during early pregnancy may reduce the risk of developing abnormal
glucose tolerance and GDM.
Dietary strategies are the mainstay of therapy for patients with GDM. However, some women
suffering from GDM cannot be managed with diet alone and need to use insulin. But insulin
corrects hyperglycemia without affecting peripheral insulin resistance. Thus, the most
appropriate intervention would be exercise, which affects insulin resistance and, in the absence
of either medical or obstetric complications, is certainly the most suitable intervention for GDM
women. ADA has endorsed exercise as 'a helpful adjunctive therapy' for GDM wheneuglycemia
is not achieved by diet alone.
C. Monitoring Blood Glucose
In non-pregnant individuals, pre-prandial blood glucose is generally monitored. A randomized

trial comparing pre-prandial to 1-h postprandial glucose measurements showed that
glycohemoglobin levels, macrosomia, neonatal hypoglycemia and cesarean deliveries were
significantly lower among those who had postprandial monitoring. Regarding the frequency of
glucose monitoring it is stated that pregnant women who are on multiple daily insulin injection,
will test their pre-meal, 1-hour post-meal and bedtime blood glucose levels daily. But if they are
on diet and exercise or taking oral therapy (with or without diet and exercise therapy) or single-
dose intermediate-acting or long-acting insulin, they will test their fasting and 1-hour post-meal
blood glucose levels daily. Although daily self- glucose monitoring has not been demonstrated to
reduce perinatal mortality in women with GDM, it appears to be useful in reducing potentially
adverse outcome such as macrosomia.
Recently the new technology of continuous glucose monitoring (CGM) is available.

The CGM measures interstitial glucose levels in subcutaneous tissue within a range of 50-400
mg/dl every 5 min [1]. CGM can accurately detect high postprandial blood glucose levels and
nocturnal hypoglycemic events that may go unrecognized by intermittent blood glucose

monitoring. However, CGM is not recommended to replace self-monitoring of blood glucose,

but the intermittent application of CGM could be used who have problematic severe
hypoglycemia (with or without impaired hypoglycemic awareness) or who have unstable blood
glucose levels (to minimize variability) or to gain information about variability in blood glucose
levels.
D. Target Blood Glucose
Pregnant women with pre-gestational or gestational DM are advised to keep their fasting blood
glucose level 5.3 mmol/L and 1-hour and 2-hour postprandial level 7.8 and 6.7 mmol/L
respectively [5]. HbA1c(hemoglobin that is bound to glucose)levels are measured in all women
with gestational diabetes at the time of diagnosis to identify those who may have pre-existing
type 2 diabetes. HbA1c is lower in normal pregnancy than in normal non pregnant women. Other
alternate new measure of glycemic control—fructosamine test has been proposed. The
fructosamine measures glycemic levels over a period of 2-3 weeks. However, it is less widely
used due to lack of standardization.
E. Insulin treatment
Insulin is started at a dosage of 0.7 units per kg per day (based on pre-pregnancy weight), given
in divided doses. A commonly used dosing regimen includes two thirds of the total insulin dose
to be given in the morning, with the remainder before dinner.
Regular insulin, which is often used in pregnancy for the treatment of diabetes, has some
drawbacks: it starts its action from 30 to 60 min after subcutaneous injection and it peaks too late
(2-3 hour after injection) to be very effective in postprandial control; in addition, its action also
lasts about 8-10 hour with an increased risk of postprandial hypoglycemia [31]. For this reason,
insulin analogue started to be used in the last few years. Two types of insulin analogues are used,
rapid acting like lispro and aspart (bolus) and long acting (basal) like glargine and detemir.
Combining these two types of insulin, basal-bolus therapy (BBT) is planned which most closely
simulates physiological insulin profiles and already in use in non-pregnant patients. Now this
BBT is also used in pregnant patients. Compared to regular insulin, rapid acting insulin analogue
is associated with lower rate of 1- and 2- hour postprandial hyperglycemia. This is important for

perinatal outcome as post prandial hyperglycemia is more predictive of neonatal complications

than is elevated fasting blood glucose level. Rapid acting analogues also reduce the risk of late
postprandial hypoglycemia, helping to minimize daily glucose excursion. Use of insulin
analogue in pregnancy is associated with decrease in HbA1c, less maternal and neonatal
hypoglycemia when compared to conventional insulin (regular and NPH).
F. Oral Anti-diabetic agents
Traditionally insulin is considered as the gold standard for management of GDM .But it can be
problematic for some women as it is expensive and invasive.. For this a safe and effective oral
agent for the treatment of gestational diabetes is highly desired. The sulfonylurea glyburide is
close to meeting these goals, with prospective and retrospective studies .
ANTENATAL CARE(the care you get from health professionals during your pregnancy.)
Management of the pregnant diabetic is a complex issue and a single provider cannot take care of
all aspects of the care. It is a team work consisting of obstetrician, diabetologist, nutritionist,
perinatologist, nurse and a social worker or counselor
Fetal surveillance consists of screening for congenital anomalies, monitoring for fetal well-being,
and ultrasound assessment of fetal growth. The ADA recommends screening for congenital
anomalies in women with gestational diabetes who present with evidence of preexisting
hyperglycemia, such as an HbA1c level greater than 7 percent. Monitoring for fetal well-being is
generally based on local practice. The frequency of antenatal monitoring depends on the patient’s
degree of metabolic control, the type of therapy she is receiving and the presence of other risk
factors (hypertension). This typically consists of twice-weekly non stress testing, with amniotic
fluid determinations beginning early in the third trimester.
INTRAPARTUM MANAGEMENT (the care of women and their babies during labour and
immediately after the birth.)
As women with pre gestational diabetes, the goal ofintrapartum management of women with
GDM is to avoid maternal hyperglycemia and thus minimize the risk of neonatal hypoglycemia
after delivery. Patients controlled by diet will not require intrapartum insulin and may simply

need glucose level monitoring on admission for delivery. During labor, patients with insulin-
requiring diabetes need capillary hourlymonitoring of blood glucose levels. Target values are 80-
110 mg/dl. Published protocols recommend low-dose insulin infusion for intrapartum
management of patients with insulin requiring diabetes. A study suggests 5% dextrose infusion
in active labor when maternal blood glucose is below 100 mg/dl. For blood glucose
concentrations exceeding 100 mg/dl, no dextrose is included in the intravenously administered
solution.Continuous fetal monitoring is used. If fetus is compromised expeditious delivery is
done by method depending upon the stage of labor.
Postpartum Management
Contraception should be discussed and a commitment sought to a program of planned

pregnancies. Low-dose oral contraceptive (OC) can be prescribed to GDM patients with careful
monitoring of their serum lipids and glucose concentrations. If OCs is contraindicated barrier
methods can be used. Though there is limited experience with long-acting progesterone in these
patients, but in the absence of serum lipid abnormalities, there are good results.
NEW APPROACHES IN THE MANAGEMENT OF GESTATIONAL DIABETES
The main elements of the therapy include education, nutritional therapy, exercise, and medical
treatment.The recommended daily calorie intake is 30 kcal/kg for women with a BMI of 22-25,
24 kcal/kg for women with a BMI of 26-29, and 12-15 kcal/kg for women with a BMI of >30.
The recommended diet composition contains 33%-40% complex carbohydrates, 35%-40% fat,
and 20% protein. This calorie intake may turn 75%-80% of women with GDM into
normalglycemic state.
The pregnant women in whom blood glucose control cannot be achieved with exercise and diet
regulation must be switched to insulin or oral anti-diabetics.There is also no consensus on when

to initiate insulin therapy, which has been reported to reduce the risk of macrosomia and other
complications during infancy. There are two approaches for the initiation of insulin therapy one
of which requires measurement of fasting glucose concentration >90 mg/dl with two weeks
intervals and other approach requires postprandial 1-hour glucose measurement >120 mg/dl. The
insulin preparations used in GDM include neutral protamine Hagedorn (NPH) and regular
insulin.
The use of oral anti-diabetics (OAD) during pregnancy is a relatively new practice. In a review
of the literature regarding this topic, 12 randomized studies were evaluated, and the effects of the
use of oral anti-diabetic agents was investigated on pregnant women with a known diabetes and
those with impaired glucose tolerance in the current or previous pregnancy.
MAJOR ORAL ANTI-DIABETIC AGENTS
Biguanides:Metformin falls into this group. These agents enhances peripheral glucose uptake,
inhibit gluconeogenesis and reduce plasma triglyceride concentrations. Metformin can pass
across the placenta. In a study that compared the use of insulin versus metformin during
pregnancy, use of metformin did not result in an increase in perinatal complications, and it was
even less prone to cause severe neonatal hypoglycemia and it resulted in lesser maternal weight
gain and provided better patient compliance. However, metformin was used between 20 and 34
weeks of gestation in this study.In a recent randomized study, 47 pregnant women with GDM
who received metformin or insulin therapy were evaluated, and metformin group had better daily
glycemic control, lesser weight gain neonatal hypoglycemia.
 Safety:
 Maternal:The average weight gain and pregnancy-induced hypertension rates in

women after enrollment was significant lower in the metformin group than in
insulin group in meta-analysis.
 Fetal:Metformin has been shown to pass freely across the placenta. Two in
vivo studies measured maternal and cord blood samples in women taking

metformin throughout pregnancy.In meta-analysis, the average birth weight of

neonates was slightly lower in the metformin group as compared with the insulin
group
Sulfonylureas:Glyburide (glibenclamide) and Glimepiride fall into this group. These drugs
increase insulin secretion and peripheral sensitivity to insulin and decrease hepatic clearance of
insulin. Glyburide is a second generation oral sulfonylurea hypoglycemic agent. It acts by
enhancing the release of insulin from the pancreatic beta cells, therefore for its action, some
degree of pancreatic insulin-releasing function is required. It is well-absorbed following oral
administration and is metabolized by the liver. The initial dose of glyburide is 2.5-5.0 mg once or
twice a day with a maximum dose of 20 mg/day.The rate of maternal hypoglycemia in the
women who received insulin was higher (20%) as compared to glyburide (4%) in one study.
 Safety:
 Maternal:The rate of maternal hypoglycemia in the women who received

insulin was higher (20%) as compared to glyburide (4%) in one study.
 Fetal:The maternal-to-fetal transport of second generation sulfonylureas

(glyburide) is significantly lower than the first-generation drugs
(chlorpropamide and tolbutamide).In the randomized study of glyburide versus
insulin in gestational diabetes, glyburide was not detected in the cord blood of
any infant.In a meta-analysis (10 studies on 471 exposed women to
sulfonylureas and biguanides in first trimester), no significant difference was
found in the rate of major malformations or neonatal death among women with
first-trimester exposure to oral anti-diabetic agents compared with non-exposed
women.
 NOTE:These drugs aren't approved for gestational diabetes by the Food and Drug
Administration.
CASE STUDIES
Gestational Diabetes Mellitus

Case study #1: Mrs. C
 Mrs. C is a 22 year old primigravida coming for her first antenatal checkup at 12 weeks
of gestation.
 On examination, she is 152 cm tall and weighs 69 kg. BMI, 30 kg/m2
 She does not have a family history of diabetes
 Mrs. C had a fasting blood glucose done
 Her results are as follows.
Time 0 hr fasting
Glucose mmol/L(mg/dL) 4.7 (86)
 Mrs. C undergoes repeat testing at 26 weeks’ gestation.

Her results on the 75 gm glucose load (fasting) are as follows.
Time 0 hr (Fasting) 1 hour 2 hour
Glucosemmol/ 4.8 (88) 10.3 (186) 8.9 (161)

L(mg/dL)
After 2 weeks, her results were as follows

Fasting blood glucose mmol/L(mg/dL) 5.2 (93)
2 hour postprandial bloodglucose mmolL 8.6 (156)

(mg/dL)
Breakfast

Mrs. C is put on 4 units of rapid acting insulin before breakfast and

advised to monitor her blood glucose daily. She does well.
After 2 weeks, her reports are as follows.
Fasting blood glucose mmol/L (mg/dl) 6.5 (118)
2 hour postprandial blood 7 (126)

glucosemmol/L(mg/dl) breakfast
Mrs. C is now on 6 units of NPH (neutral protamine Hagedorn) insulin at bedtime

in addition to 4 units of rapid acting insulin before breakfast. She starts
complaining of excess hunger during the early hours of the morning.
Her reports are as follows.
Fasting BGmmol/L (mg/dL) 3.3 (61)
2 hour postprandial BG 5.6 (102)
Her insulin dose has stabilized
NPH 8 units at bedtime
rapid acting insulin 6 u before breakfast, 4 units before lunch and 4 units
before evening meal.
Mrs. C goes into labour at 39 weeks.

Following delivery, blood glucose levels normalised and she was able to stop
insulin.
After 6 weeks, she underwent an OGTT, the results of which are

as follows.
Time 0 hour (Fasting) 2 hours
Glucose mmol/L(mg/dl) 4.5 (82) 7.0 (127)
2. PRE-ECLAMPSIA
INTRODUCTION
Pre-eclampsia is a multisystem disorder of pregnancy that forms an integral part of the spectrum
known as hypertensive diseases of pregnancy. The National High Blood Pressure Education
Program (NHBPEP) Working Group1classifies hypertensive /diseases in pregnancy into 4
groups:
1) Gestational hypertension
 New onset hypertension in pregnancy presenting after 20 weeks
 No proteinuria
 BP returns to normal less than 12 weeks postpartum
 Final diagnosis made only postpartum
2) Chronic hypertension

 BP >140/90 mm Hg before pregnancy or diagnosed before 20 weeks gestation not

attributable to gestational trophoblastic diseaseor
 Hypertension first diagnosed after 20 weeks gestation but persistent after 12 weeks
postpartum.
3) Pre-eclampsia/eclampsia
 BP > 140/90 mm Hg after 20 weeks gestation in a women with previously normal blood
pressure
 Proteinuria (>0.3 gm urine protein in 24 hr).
 Eclampsia is defined as seizures that cannot be attributed to other causes in a woman with
pre-eclampsia
4) Superimposed pre-eclampsia (on chronic hypertension)
 New onset proteinuria (>300 mg/24 hr) in a woman with hypertension but no proteinuria
before 20 weeks gestation
 A sudden increase in proteinuria or blood pressure, or platelet count less than 100,000 in
women with hypertension and proteinuria before 20 weeks gestation
Pre-eclampsia (disease of theories) is a controversial and complicated disease which needs active
involvement of both the obstetrician and the anesthesiologist. It is one of the important causes of
maternal morbidity and mortality characterized by hypertension and multiorgan system
involvement. It complicates about 4-7 % of pregnancies. The pathogenesis is still controversial.
Intracerebral haemorrhage, eclamptic seizures, placental abruption, acute pulmonary edema,
organ failure and coagulation abnormalities leads to maternal morbidity and mortality in severe
preeclampsia. It is, however, a preventable condition with a multi-disciplinary team management
approach. Current scientific evidence should be incorporated in institutional clinical practice.
Hypertensive disorders of pregnancy are responsible for over 60,000 maternal deaths worldwide
annually and complicate 5% of all pregnancies. Pregnancies complicated by pre-eclampsia show

an increase in maternal and perinatal morbidity and mortality. The definition of pre-eclampsia
was revised in 2014 and is defined as hypertension developing after 20 weeks’ gestation with
one or more of the following: proteinuria, maternal organ dysfunction (including renal, hepatic,
hematological, or neurological complications), or fetal growth restriction. It is important to note
that this definition does not require proteinuria to meet the diagnostic criteria. Diagnosing pre-
eclampsia remains a challenge. Women may present with late-onset hypertension and
proteinuria, with an absence of fetal growth restriction near term. This appears to have few long-
term consequences for mother or infant. Conversely, early onset, severe maternal disease is often
associated with fetal intrauterine growth restriction. Even in the presence of severe preterm
disease, a woman can be asymptomatic.
DEFINITION
Pre-eclampsia can be defined as ‘a blood pressure ≥140/90 mmHg after 20 weeks of gestation
and involvement of one or more organ systems with previously normal blood pressure’.
The American College of Obstetricians and Gynecologists defines preeclampsia as ‘the

development of hypertension with proteinuria, edema or both (the traditional triad) induced by
pregnancy after the 20th week of gestation’.
The International Society for the Study of Hypertension (ISSH) in its definition of preeclampsia
does not include edema because it may be detected in 80% of normotensive pregnant women
most of whom are healthy. Severe pre-eclampsia includes severe hypertension and proteinuria
with one or more of the following signs/symptoms e.g. severe headache not responding to
treatment, seizures, pulmonary edema, vision disturbances with papilledema, liver tenderness,
vomiting, elevated liver enzymes, thrombocytopenia, hyper reflexes, absent or reversed
umbilical/uterine artery end diastolic blood flow.

EPIDEMIOLOGY
Pregnancy induced hypertension complicates about 10% of pregnancies, but there is a
widespread geographic variation in its incidence. The incidence is higher in developing
countries. Estimates of maternal mortality from the developing countries (in Asia, Africa, Latin
America and the Caribbean) suggest that 10-15% of maternal deaths are associated with
hypertension in pregnancy, while eclampsia is associated with 10% maternal mortality10.
Severe pre-eclampsia is also associated with significant maternal morbidity, including eclamptic
seizures, intracerebral haemorrhage, pulmonary edema due to capillary leak or heart failure,
acute renal failure, liver dysfunction, and coagulation abnormalities.
Fetal complications include placental abruption, intrauterine growth restriction, premature

delivery, and intrauterine fetal death. The incidence of stillbirths and neonatal deaths in mothers
who suffered eclampsia was 22.2/1000 and 34.1/1000, respectively, in the UK with a higher
incidence in developing countries.

Pathophysiologic concepts in Pre-eclampsia
The exact mechanism of pre-eclampsia is unclear. However, most current theories attribute pre-
eclampsia to poor placental perfusion, secondary to abnormal placentation.
In normal placentation, the trophoblast invades the myometrium and the spiral arteries of the
uterus, destroying the tunica muscularis media. This renders the spiral arteries dilated and unable
to constrict, providing the pregnancy with a high flow, low resistance circulation.
In pre-eclampsia, the remodelling of spiral arteries is incomplete. A high resistance, low-flow

uteroplacental circulation develops, as the constrictive muscular walls of the spiral arterioles are
maintained. The resultant increase in blood pressure, combined with hypoxia and oxidative
stress from inadequate uteroplacental perfusion, leads to a systemic inflammatory
response and endothelial cell dysfunction (resulting in leaky blood vessels).

Figure 6. Abnormal placentation in pre-eclampsia
New developments in prediction
An important focus for improving the antenatal management of pre-eclampsia is to develop

accurate prediction models that identify women at high risk of disease. This would enable more
appropriate targeting of prophylaxis from the first trimester as well as increased surveillance of
those at high risk of dis-ease. Lack of recognition of risk contributes to substandard care
associated with maternal deaths. Early administration of prophylactic aspirin in high-risk women
prior to 16 weeks’ gestation appears to reduce the risk of pre-eclampsia by 17%. Furthermore,
there is an 8% relative risk reduction of preterm birth and a 14% reduction in fetal and neonatal
death.
Risk Factors
The National Institute for Health and Care Excellence (NICE) recommends a list of maternal risk
factors that can be used to identify women at high risk for pre-eclampsia in whom aspirin should
be started from 12 weeks’ gestation. Strong risk factors include previous pre-eclampsia or
hypertension in pregnancy, chronic kidney disease, chronic hypertension, diabetes (type 1 or 2),
and autoimmune disorders such as systemic lupus erythematous or anti phosphospholipid
syndrome. Women should also be advised to take aspirin if they have more than one of the
following moderate risk factors : first pregnancy, age of 40 years or more, a pregnancy interval
of greater than 10 years, body mass index of 35 kg/m2 or more, family history of pre-eclampsia,
and multiple pregnancy.
Maternal Considerations
Inherent
 Age < 20 or 35–40 years
 Nulliparity

 Prior or family history of PE or cardiovascular disease
 Woman born small for gestational age Medical conditions
 Obesity
 Chronic hypertension
 Chronic renal disease
 Diabetes mellitus (insulin resistance, type 1, and gestational)
 Connective tissue diseases
 Stress
Figure 7. Ankle Edema in pre-eclampsia
Paternal Considerations
 Limited sperm exposure
 Barrier contraception
 First-time father
 Donor insemination

 Partner who fathered a pre-eclamptic pregnancy in another woman
What exactly happens in Pre-eclampsia?
The triad of physiological derangements in pre-eclampsia include
1. Vasospasm
2. Plasma volume contraction
Local or disseminated intravascular coagulation
Although the cause of pre-eclampsia is unknown, we have already discussed that the placenta is
largely implicated. The sequence of events starts with vasospasm caused by increased production
or sensitivity to vasoconstrictors (angiotensin II, serotonin and endothelin) and/or decreased
production or sensitivity to vasodilators (prostacyclin and nitric oxide). Redistribution of fluid
occurs from the intravascular to interstitial fluid spaces causing peripheral tissue edema. Along
with this, intravascular coagulation may occur due to platelet activation, thrombocytopenia and,
often, reduced production of anti-thrombin III.
Commonly affected systems are kidney (manifested by reduced GFR, proteinuria,

hyperuricaemia and occasionally oliguria), liver (manifested by elevated transaminases with or
without epigastric and right upper quadrant pain), and the brain (manifested by headaches,
transient visual disturbances due to occipital lobe ischaemia and rarely convulsions, i.e.
eclampsia). This leads to increased maternal morbidity.
In spite of major advances in understanding the pathophysiology of the disease in

recent years, interventions to prevent hypertensive disorders in pregnancy have had
disappointing results, hence early detection, continued surveillance and timely intervention still
remains the key towards decreasing the inherent maternal and fetal morbidity and mortality
associated with severe pre-eclampsia and eclampsia.

Figure 8. Pre-eclampsia with severe features: Effects on the Heart
Assessing pre-eclampsia
Pre-eclampsia is elusive to diagnose. Hypertension is classified as a blood pressure of at least

140/90 mmHg. Those with a background of chronic hypertension are at higher risk of developing
pre-eclampsia and remain a challenge to diagnose, as conventional blood pressure thresholds are
not always applicable. There is evidence of accuracy, increased surveillance, and acceptability of
home blood pressure monitoring in pregnancy in small studies. However, a systematic review of
ambula-tory versus conventional monitoring of blood pressure in pregnancy found no evidence
to support its routine use. OPTIMUM (optimizing titration and monitoring of maternal blood
pressure) is an ongoing randomized controlled study assigning women with high blood pressure
to self-monitoring in addition to ante-natal care versus usual antenatal care to identify rising
blood pressure sooner, which could lead to an earlier diagnosis and treatment of subsequent
complications. Also under way is the BUMP trial (Blood Pressure monitoring in High-Risk

Pregnancy to Improve the Detection and Monitoring of Hypertension). This randomized

controlled trial compares routine antenatal care with self-monitoring in high-risk women to
determine whether self-monitoring can lead to earlier diagnosis of hypertension and lower blood
pressure in those with hypertension and pre-eclampsia.
DIAGNOSTIC CRITERIA
CONSERVATIVE MANAGEMENT OF PRE-ECLAMPSIA
Risk of mortality decreases by reduction of severe hypertension.With the help of

antihypertensive drugs peripheral resistance decreases and perfusion of uterus increases, which
in turn help in decreasing fetal complications.
For systolic BP between 140-159 mmHg and diastolic BP 90-109 mmHg, oral labetalol is the
drug of choice. Methyl dopa and nifedipine are safe alternatives. For systolic BP ≥ 160 mmHg
and diastolic BP ≥ 110 mmHg, the choice of drug should depend upon experience with that
particular agent.15 The preferred drugs include oral or intravenous labetalol, oral nifedipine
(sublingual not recommended) and intravenous hydralazine (5-10 mg boluses every 20 min up to
a cumulative dose of 30 mg). Cautious preloading with 500 ml crystalloid is recommended to
avoid maternal hypotension. Labetalol is not suitable for asthmatics. Nifedipine may cause
profound muscle weakness and maternal hypotension with fetal distress in patients receiving
magnesium sulphate. Labetalol and nifedipine are better choices than hydralazine as recent
evidences suggests. In all cases blood pressure should be monitored carefully along with fetal
heart rate monitoring. In patients with pre-eclampsia and acute pulmonary edema, the preferred
drug is glyceryltrinitrate as an intravenous infusion at the rate of 5µg/min which can be increased
every 3-5 min to a maximum dose of 100µg/min.
Eclampsia is associated with a mortality rate of 3.1%.2,19 Drug of choice for eclampsia is
magnesium sulphate. The risk of seizure recurrence is significantly reduced by the use of
magnesium sulphate in comparison to diazepam, phenytoin and lytic cocktail (chlorpromazine +
promethazine + pethidine).20,21 Intensive care unit admission and morbidity related to mechanical
ventilation and pneumonia is significantly reduced with magnesium sulphate compared with
phenytoin.22 Collaborative Eclampsia Trial regimen is 4-5 gm magnesium sulphate intravenously
over 5 minute followed by infusion of 1 gm of magnesium sulphate every hour for 24
hours.23 When magnesium sulphate is used in conjunction with other clinical parameters infusion
may be stopped earlier (12 hours post-partum).
Prevention of pre-eclampsia
Till date there is no well-established measure for prevention of pre-eclampsia in the general
population. Calcium is clearly of benefit amongst high risk women in communities where low
dietary calcium intake is prevalent. A Cochrane systematic review in 2010 concludes that
calcium supplementation approximately halves the risk of pre-eclampsia, reduces the risk of
preterm birth and the rare occurrence of the composite outcome 'death or serious morbidity.
Low dose aspirin (antiplatelet agent) therapyefficiently reduces the development of pre-
eclampsia in women with abnormal uterine artery Doppler studies. If started in early gestation (<
16 weeks), it also causes a significant reduction in the incidence of severe pre-eclampsia
MANAGEMENT

Antenatal Care
These patients should be under consultant led care with multidisciplinary input from the
anesthetic and neonatal teams as necessary.
Women with risk factors for developing pre-eclampsia may be considered for uterine artery
Doppler velocimetry at 20-24 weeks to look for increased impedance to flow (resistance
index>95th centile or early diastolic notch), which is predictive of developing pre-eclampsia in
late gestation, however the specificity and sensitivity varies widely between different studies.
At diagnosis of pre-eclampsia, the best practice is to offer initial hospital admission for
assessment and formulation of follow-up care. Assessment of proteinuria should be done by
automated reagent strip reading device. If the automated reagent strip reading of urine yields a
result of 1+ or more, this should be followed up with a spot urinary protein: creatinine ratio or a
24 hour urine collection to quantify the proteinuria. Significant proteinuria is diagnosed if the
urinary protein: creatinine ratio is more than 30mg/mmol or the validated 24 hr. urine sample has
more than 300 mg of protein. Baseline blood investigations should include full blood count, liver
function (bilirubin and transaminases), electrolytes and kidney function tests.
Antihypertensive medications may need to be commenced with the aim of maintaining the
systolic blood pressure below 150 mm Hg, and the diastolic pressure between 80 - 100 mm Hg.
Labetalol is the first line treatment. However, in patients in whom labetalol cannot be used (e.g.
in patients with bronchial asthma), alternatives include nifedipine (contraindicated before 20
weeks of gestation), methyldopa, atenolol and metoprolol. 4-6 hourly blood pressure, daily
assessment of proteinuria, along with haematological and biochemical monitoring are also
carried out. Inpatient management is required till the blood pressure stabilises.
Fetal monitoring:
Ultrasound assessment of fetal growth and amniotic fluid volume along with umbilical artery
Doppler velocimetry needs to be done at initial diagnosis of pre-eclampsia to exclude IUGR and
then every 2 weeks if the pregnancy is managed conservatively and the results remain normal

CTG monitoring is commonly done at diagnosis, along with the ultrasound assessment. If
normal, further CTG should be performed weekly unless otherwise clinically indicated.
Delivery
In pre-eclampsia with mild or moderate hypertension, women may be delivered between 34 and
37 weeks of gestation, depending on maternal and fetal condition, presence of risk factors and
availability of neonatal intensive care facilities. If severe pre-eclampsia develops, refractory to
treatment or fetal wellbeing delivery may need to be done earlier.
Pre-eclampsia is considered to be severe in case of
1) Severe hypertension with proteinuria or
2) Mild / moderate hypertension and proteinuria with one or more of the following signs /
symptoms:
 Severe headache , not responding to medications
 Visual disturbance (blurring or flashing of light)
 Severe pain in upper abdomen or vomiting
 Papillo-oedema
 Signs of clonus (³ 3 beats)
 Liver tenderness
 HELLP syndrome
 Decrease in platelet count to less than 100 x 109 per litre
 Abnormal liver enzymes (ALT or ASTrising to above70 iu/litre).
Blood pressure

The NICE recommends keeping systolic blood pressure below 150 mmHg and diastolic blood
pressure below 80–100 mmHg 7 and using labetalol as first-line treatment for hypertension over
this threshold. The results of the Control of Hypertension In Pregnancy Study (CHIPS) were
reported in 2016. This trial compared “tight” (target diastolic blood pressure of 85 mmHg)
versus “less tight” (target diastolic blood pressure of 100 mmHg) control of hypertension in
women with non-severe, non-proteinuric maternal hypertension at 14–33 weeks 46. The results
demonstrated that those with “tight” control achieved a lower blood pressure (by 5 mmHg) and
there was no increase in adverse perinatal outcome (adjusted OR 0.98, 95% CI 0.74–1.3) and
birth weight less than the tenth percentile (1.3, 0.93–1.8). However, there were reduced rates of
severe maternal hypertension ( p<0.001) with tighter control. In this trial, 48.9% of the women
developed pre-eclampsia in the “less tight” group and 45.7% in the “tight” control group
(adjusted OR 1.14, CI 0.88–1.47). While results from this study can only be extrapolated to pre-
eclampsia with caution, it may be concluded that in these women who are at high risk of the
complications of severe hypertension, seizures, and intracerebral hemorrhage, there may be
benefit in tighter control of blood pressure.
Oral antihypertensives
Traditionally, severe hypertension has been treated with short-acting parenteral antihypertensive
agents, most frequently intravenous hydralazine or labetalol. This is because of the speed of
onset of action but means that they require more intensive monitoring and can affect the fetus if
large shifts in blood pressure occur. A systematic review showed that, in most women, nifedipine
achieved treatment success similar to that of hydralazine or labetalol. Less than 2% of women
who received nifedipine experienced hypotension. There were no differences in adverse maternal
or fetal outcomes. Thus, the authors suggest that oral nifedipine is a suitable treatment for severe
hypertension in pregnancy and post-partum.
A meta-analysis by Shekhar et al. confirmed these findings, providing further evidence that oral
nifedipine is a reasonable antihypertensive for the treatment of severe pregnancy hypertension of
any classification. These treatments are widely available, even in middle- and lower-income
countries, so these findings can be implemented globally and reduce costs.

Table 2: Management strategies for chronic hypertension and gestational hypertension
Preconception Antenatal Delivery Postpartum Further follow-

up
Chronic Optimiseantih Continue At 37 Aim to maintain BP Medical review

Hypertens ypertensives, treatment to weeks, if BP <140/90 at 6-8 weeks
ion is with
change ACE maintain BP
controlled. antihypertens
inhibitors, diet <150/100. Offer
ives
and lifestyle uterine artery
modification dopplers to
detect risk of
developing pre-
eclampsia/IUGR
Gestation Assessment of Hospital admission Titrate Medical review
al risk factors if severe antihypertensives at 6-8 weeks, or
Hypertens hypertension. At 37 weeks, to keep BP earlier if need
if BP
ion Antihypertensive <140/90 to continue
<160/110,with
if BP >150/100. /without antihypertensiv
Test for antihypertensiv es
proteinuria at s
each visit,blood
tests as indicated
Pre- Assessment of Hospital Delivery Initial monitoring Medical
eclampsi risk factors. admission at between as inpatient, to be review at 2
a diagnosis. 34-37 discharged to the weeks, if
Antihypertensivesto weeks, community when continuing
be started if depending BP antihypertensi
BP>150/100. on <149/99 ves. Otherwise
with/without
Regular blood maternal/ treatment and blood at 6-8 weeks
investigations (2- foetal results are stable
3/week) condition
Magnesium sulphate
Magnesium sulphate is recommended in severe preeclampsia to prevent eclamptic seizures in

the mother. This is established in clinical practice for women with severe hypertension or
proteinuria or with mild to moderate hypertension or proteinuria with the addition of clinical or

biochemical signs. A review by the Cochrane Collaboration from 2009 found that magnesium
sulphate is also neuroprotective for the preterm infant (<37 weeks) in preventing cerebral palsy
(relative risk 0.68, 95% CI 0.54-0.87) [34]. The number of women needed to be treated with
magnesium sulphate to benefit one baby by avoiding cerebral palsy is 63 (95% CI 43-155), and
magnesium sulphate should now be part of established practice. There is a cohort of women with
mild to moderate pre-eclampsia who do not meet maternal indications for magnesium sulphate
but in whom, for fetal reasons, preterm delivery is necessary. It is appropriate now to give those
women magnesium sulphate for fetal neuroprotection.

Recent Advances in Management of Gestational Diabetes and Pre-Eclampsia

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RECENT ADVANCES IN MANAGEMENT OF GESTATIONAL

DIABETES AND PRE-ECLAMPSIA

RECENT ADVANCES IN MANAGEMENT OF GESTATIONAL

DECCAN SCHOOL OF PHARMACY Page 1

Figure 1.EFFECTS OF DIABETES ON PREGNANCY

HIGH RISK PATIENTS

 GDM during previous pregnancy.

RISKS FOR CHILD

DECCAN SCHOOL OF PHARMACY Page 2

DECCAN SCHOOL OF PHARMACY Page 3

Figure 2. (Left) A macrosomic baby born to a mother with diabetes.

DECCAN SCHOOL OF PHARMACY Page 4

polyhydramnios also contribute to this high incidence (48). Conventional management of

MAGNETIC RESONANCE IMAGE OF PREGNANCY

DECCAN SCHOOL OF PHARMACY Page 5

SCREENING AND DIAGNOSTIC INVESTIGATION

DECCAN SCHOOL OF PHARMACY Page 6

 100 grams or 75 grams of anhydrous dextrose powder

Table 1.Diagnostic criteria for the 75-g OGTT

1. Pathophysiology of Gestational Diabetes

DECCAN SCHOOL OF PHARMACY Page 7

Figure 3. Organs involved in the pathophysiology of GDM

1.1 β-Cell Dysfunction

DECCAN SCHOOL OF PHARMACY Page 8

Figure 4. Pathophysiology of insulin resistance

DECCAN SCHOOL OF PHARMACY Page 9

DECCAN SCHOOL OF PHARMACY Page 10

1.2 Placental Transport

DECCAN SCHOOL OF PHARMACY Page 11

In the management of Type 2 DM in non- pregnant condition, physical exercise is advocated.

DECCAN SCHOOL OF PHARMACY Page 12

C. Monitoring Blood Glucose

In non-pregnant individuals, pre-prandial blood glucose is generally monitored. A randomized

Recently the new technology of continuous glucose monitoring (CGM) is available.

DECCAN SCHOOL OF PHARMACY Page 13

monitoring. However, CGM is not recommended to replace self-monitoring of blood glucose,

D. Target Blood Glucose

DECCAN SCHOOL OF PHARMACY Page 14

perinatal outcome as post prandial hyperglycemia is more predictive of neonatal complications

F. Oral Anti-diabetic agents

DECCAN SCHOOL OF PHARMACY Page 15

Contraception should be discussed and a commitment sought to a program of planned

NEW APPROACHES IN THE MANAGEMENT OF GESTATIONAL DIABETES

DECCAN SCHOOL OF PHARMACY Page 16

MAJOR ORAL ANTI-DIABETIC AGENTS

 Maternal:The average weight gain and pregnancy-induced hypertension rates in

DECCAN SCHOOL OF PHARMACY Page 17

metformin throughout pregnancy.In meta-analysis, the average birth weight of

 Maternal:The rate of maternal hypoglycemia in the women who received

 Fetal:The maternal-to-fetal transport of second generation sulfonylureas

Gestational Diabetes Mellitus

Case study #1: Mrs. C

Glucose mmol/L(mg/dL) 4.7 (86)

 Mrs. C undergoes repeat testing at 26 weeks’ gestation.

Glucosemmol/ 4.8 (88) 10.3 (186) 8.9 (161)

After 2 weeks, her results were as follows

2 hour postprandial bloodglucose mmolL 8.6 (156)

DECCAN SCHOOL OF PHARMACY Page 19