Pattern and Treatment of Pregnancy Associated Diabetes

1. Introduction

1.1 Pregnancy:

Pregnancy is the term used to describe when a woman has a growing fetus inside of her. In most cases, the fetus grows in the uterus. Human pregnancy lasts about 40 weeks or just more than 9 months, from the start of the last menstrual period to childbirth.[ Robinson, Victor, Ph.C., M.D.1939]

According to NCI, Pregnancy is the state or condition of having a developing embryo or fetus in the body (uterus), after union of an ovum and spermatozoon, during the period from conception to birth.

Incidence (annual) of Pregnancy more than 4 million; 1 million adolescent U.S. females become pregnant every year and 399 female deaths for "pregnancy and childbirth" in the USA 2001. (NCHS, 2003)

1.2 Signs of pregnancy:

The primary sign of pregnancy is missing one or more consecutive menstrual periods.  However, because many women experience menstrual irregularities that may cause missed periods, women who miss a period should see their health care provider to find out whether they are pregnant or whether there is another health problem. .[ Robinson, Victor, Ph.C., M.D.1939]

Others signs and symptoms of pregnancy may include:

Nausea or vomiting, Morning sickness. Sore breasts or nipples. Fatigue. Headaches. Food cravings or aversions. Mood swings. Frequent urination.

1.3 Pregnancy Test:

There are two way for pregnancy testing-

1) Diagnostic testing2) Misdiagnosis

A pregnancy test is the best way to determine if you are pregnant. Home pregnancy test kits are available over-the-counter and are considered highly accurate.  A health care provider can also do a pregnancy test.

NICHD research in the 1970s found that high levels of the hormone human chorionic gonadatropin (HCG) in the urine were associated with pregnancy.  This research led to the development of the home pregnancy test that is commercially available today.If you think you may be pregnant, or have a positive home pregnancy test, see a health care provider. [ Robinson, Victor, Ph.C., M.D.1939]

1.4 Types of Period:

There are three types of period

1.4.1 Prenatal period:

Prenatal defines the period occurring “around the time of birth", specifically from 22completed weeks (154 days) of gestation (the time when birth weight is normally 500 g)to7 completed days after birth. Legal regulations in different countries include gestation age beginning from 16 to 22 weeks (5 months) before birth.

1.4.2 Postnatal period:

The postnatal period begins immediately after the birth of a child and then extends for about six weeks. During this period, the mother's body returns to pre-pregnancy conditions as far as uterus size and hormone levels are concerned.

1.4.3 Perinatal period:

The perinatal period is immediately before to after birth. Depending on the definition it starts between the 20th to 28th week of gestation and ends between 1 to 4 weeks after birth (the word "perinatal" is a hybrid of the Greek "peri-" meaning 'around or about' and "natal" from the Latin "natus" meaning "birth.").

1.5 Duration:

The expected date of delivery (EDO) is 40 weeks counting from the first day of the last menstrual period (IMP), and birth usually occurs between 37 and 42 weeks. The actual pregnancy duration is typically 38 weeks after conception. Though pregnancy begins at conception, it is more convenient to date from the first day of a woman's last menstrual period, or from the date of conception if known. Starting from one of these dates, the expected date of delivery can be calculated using the Naegele's rule for estimating date of delivery. [Robinson, Victor, Ph.C., M.D.1939]

1.6 Prenatal Stages of Development:

There are 3 stages of prenatal development –

1) Pre-embryonic or conception development stage2) Embryonic development stage3) Fetal development stage.

Stage Duration Development

Pre-embryonic 17 days post conception Fertilized ovum consolidates (becomes dense/harden/solid).

Embryonic 18 days to 8 weeks (56 days). The major organ systems are formed.Fetal 8 weeks to 38 weeks. Maturation, development and growth of

all organ systems

1.6.1 Embryonic and fetal development:

Prenatal development is divided into two primary biological stages. The first is the embryonic stage, which lasts for about two months. At this point, the fetal stage begins. At the beginning of the fetal stage, the risk of miscarriage decreases sharply, all major structures including hands, feet, head, brain, and other organs are present, and they continue to grow and develop. When the fetal stage commences, a fetus is typically about 30 mm (1.2 inches) in length, and the heart can be seen beating via sonograph; the fetus bends the head, and also makes general movements and startles that involve the whole body. [ Robinson, Victor, Ph.C., M.D.1939]

Fig- 1.1: Embryonic and fetal development

1.7 Physiology:

Pregnancy is typically broken into three periods, or trimesters, each of about three months. While there are no hard and fast rules, these distinctions are useful in describing the changes that take place over time.

1.8 There are three trimesters:

1) First Trimester2) Second Trimester3) Third Trimester

1.8.1 The First Trimester:The first pregnancy trimester is the stage of pregnancy from conception to 12 weeks. Hormonal changes cause frequent nausea, vomiting, increased fatigue and heightened

emotional sensitivity. Food aversion and cravings, heartburn and indigestion, tender and swollen breasts, change in complexion, frequent urge to urinate, constipation, dizziness are all the 'gifts' of pregnancy. Changes in habits, like frequent but small meals, nutritive diet, no smoking or alcohol, light exercise, drinking plenty of water, and taking adequate rest will mitigate the problems of first trimester.

1.8.1 The Second Trimester:

The second pregnancy trimester starts from the 13th week to the 28th week. Initial nausea and fatigue abates and the baby grows rapidly and shows movements; the umbilical cord thickens to carry oxygen and nourishment to the fetus. Light exercise, good personal hygiene, nutritive diet adds to the healthy growth of the baby at this stage.

1.8.1 The Third Trimester:

This is the last trimester from the 28th week till the birth of the baby. The fetus continues to grow in size, bringing in changes in physical appearance. Deep breathing helps in providing good oxygen supply to the baby. Take adequate rest, diet and exercise, avoid carrying heavy weights and standing for long periods. The fetus will be growing the most rapidly during this stage, gaining up to 28 g per day

1.9 High-risk During Pregnancy:

All pregnancies involve a certain degree of risk to both mother and baby.  But, factors present before pregnancy or that develop during pregnancy can place the mother and baby at higher risk for problems. Women with high-risk pregnancies may need care from specialists or a team of health care providers to help promote healthy pregnancy and birth.[ Li, D; Liu, L; Odouli, R ,2009]

1.9.1 Factors present before pregnancy that can increase risk are:

Young or old maternal age Being overweight or underweight Having had problems in previous pregnancies, such as miscarriage, stillbirth, or

preterm labor or birth Pre-existing health conditions, such as high blood pressure, diabetes, or HIV/AIDS During pregnancy, problems may also develop even in a woman who was previously

healthy.  These may include (but are not limited to) gestational diabetes or preeclampsia/eclampsia.

Getting good prenatal care and seeing a health care provider regularly during pregnancy are important ways to promote a healthy pregnancy.

1.10 Complications of pregnancy:

Each year, according to the WHO, ill-health as a result of pregnancy is experienced (sometimes permanently) by more than 20 million women around the world. Furthermore, the "lives of eight million women are threatened, and more than 500,000 women are estimated to have died in 1995 as a result of causes related to pregnancy and childbirth".[ Reproductive Health and Research Publications 2009]

The following are some of the complaints that may occur during and/or after pregnancy due to the many changes which pregnancy causes in a woman's body:

1. Anemia 2. Diabetes3. Hypertension4. Back pain: A particularly common complaint in the third trimester when the patient's

center of gravity has shifted. 5. Constipation: A complaint that is caused by decreased bowel mobility secondary to

elevated progesterone (normal in pregnancy), which can lead to greater absorption of water.

6. Braxton Hicks contractions: Occasional, irregular, and often painless contractions that occur several times per day.

7. Edema (swelling): Common complaint in advancing pregnancy. Caused by compression of the inferior vena cava (IVC) and pelvic veins by the uterus leads to increased hydrostatic pressure in lower extremities.

8. Haemorrhoids: Complaint that is often noted in advancing pregnancy. Caused by increased venous stasis and IVC compression leading to congestion in venous system, along with increased abdominal pressure secondary to the pregnant space-occupying uterus and constipation.

9. Round Ligament Pain: Pain experienced when the ligaments positioned under the uterus stretch and expand to support the woman's growing uterus

10. Regurgitation, heartburn, and nausea. [ Robinson, Victor, Ph.C., M.D.1939]

1.11 Importance of drugs during Pregnancy:

Drug use cannot be always avoided during pregnancy. For women with certain chronic medical conditions such as epilepsy, diabetes, inflammatory bowel disease and asthma, the use of drugs is essential, and benefits for mother and child may well outweigh the teratogenic risk of the drug. Other nonchronic diseases related or unrelated to the pregnancy may require medical treatment [Bakker et al 2006].Most women use a number of different medications during pregnancy, many of which are self-administered. It is essential to consider the following factors before prescription of drugs during pregnancy.

A) Dose and duration of drug exposure is important. The larger the dose is more likely the effects. The longer the duration of drug exposure is greater chance of susceptible periods of organogenesis and developmental problem.

B) Timing of exposure is very crucial. Certain organ systems may have only limited period of susceptibility for damage.

C) Pathogenetic mechanism, teratogen produces their adverse effect by specific mechanism.

D) Host susceptibility, variability in the genetic factors related to mechanism of certain drugs. All drugs can affects the health of the mother and fetus, therefore any drugs should be administer with care during pregnancy [Bakker et al 2006].

Sometimes drugs are essential for the health of the pregnant woman and the fetus. In such cases, a woman should talk with her doctor or other health care practitioner about the risks and benefits of taking the drugs. Before taking any drug (including over-the-counter drugs) or dietary supplement (including medicinal herbs), a pregnant woman should consult her health care practitioner. A health care practitioner may recommend that a woman take certain vitamins and minerals during pregnancy [Bakker et al 2006].

Drugs taken by a pregnant woman reach the fetus primarily by crossing the placenta, the same route taken by oxygen and nutrients, which are needed for the fetus's growth and development. Drugs that a pregnant woman takes during pregnancy can affect the fetus in several ways:

They can act directly on the fetus, causing damage, abnormal development (leading to birth defects), or death.

They can alter the function of the placenta, usually by causing blood vessels to narrow (constrict) and thus reducing the supply of oxygen and nutrients to the fetus from the mother. Sometimes the result is a baby that is underweight and underdeveloped.

They can cause the muscles of the uterus to contract forcefully, indirectly injuring the fetus by reducing its blood supply or triggering preterm labor and delivery.

How a drug affects a fetus depends on the fetus's stage of development and the strength and dose of the drug. Certain drugs taken early in pregnancy (within 20 days after fertilization) may act in an all-or-nothing fashion, killing the fetus or not affecting it at all. During this early stage, the fetus is highly resistant to birth defects. However, the fetus is particularly vulnerable to birth defects between the 3rd and the 8th week after fertilization, when its organs are developing. Drugs reaching the fetus during this stage may have no effect, or they may cause a miscarriage. Drugs taken after organ development is complete are unlikely to cause obvious birth defects, but they may alter the growth and function of normally formed organs and tissues [Bakker et al 2006]

1.12 Physiological changes during pregnancy:

Responses to drugs are influenced by many factors including age, ethnic background, metabolic phenotype, body fat content and distribution, body size, the effect of hormones and concomitant therapies (Benet et al. 1984; Evans et al. 1986). In addition, physiological changes during pregnancy influence further features like absorption, distribution and clearance of the medicinal product (Given below table). Many of these changes can be observed in the first trimester of pregnancy, but the physiologic effects change throughout pregnancy and continue through the postpartum period.

1. Cardiovascular system:50 % increase in plasma volumeIncrease in cardiac outputIncreased blood flow to uteroplacental unit

2. Respiratory system:Respiratory alkalosisChanges in lung volumes and capacities

3. Changes in activity of enzyme systems involved in medicinal product metabolism

4. Decrease in serum albumin filtration rate – leads to alteration in protein binding

5. Increased glomerular filtration rate – leads to clearance changes

6. Gastrointestinal system:

Delayed gastric emptying Increased transit time Decreased stomach acidity Another important factor is the placental-fetal organ which is actively involved in the

amount of drug crossing the placenta, the fraction of drug being metabolized by the placenta and the distribution and elimination of a drug by the fetus [Loebstein et al. 1997].

1.13 The effects of drugs during pregnancy:

All the drugs should be avoided if possible during the 1st trimester1. During the 1 st trimester drugs may produce congenital malformations teratogenesis), and the greatest risk is from the 3rd to 11th week of pregnancy (stage of organogenesis). Wilson’s six general principles of teratogenesis are:

1) Genotype and interaction with environmental factors, 2) Timing of exposure, 3) Mechanisms of teratogenesis, 4) Manifestation, 5) Agent, and 6) Dose effect

1.13.1 Pharmacokinetics:

Maternal pharmacokinetics:

Absorption: 1) Pregnancy can alter the absorption of oral drug; hyper-emesis gravid arum does not retain the drug. 2) Gastrointestinal transit is prolonged owing to slow emptying of the stomach and reduced gut motility.

Distribution: 1) Lipid solubility and protein binding affect the distribution of drugs. 2) Plasma drug concentration is greatest for drugs with low lipid solubility that are highly bound to plasma protein.

Drug metabolism: 1) Water soluble drugs are eliminated unchanged. 2) Lipid –soluble drugs are metabolized by oxidation, or conjugated in the placenta and fetal liver before being excreted in bile or urine.

Drug excretion:

1) Renal plasma flow (RPF), 2) Glomerular filtration rate (GFR), 3) Creatinine clearance are all increased in pregnancy; drugs excreted unchanged and more quickly

Fetal pharmacokinetics:Distribution, metabolism, and fetal excretions occur in the fetus and placenta.

Placental Transfer of Drugs: 1) The human placenta allows bi-directional transfer of most molecules below molecular weights of 1500. 2) The great majority crosses the placenta by simple diffusion. 3) Highly fat-soluble molecules that are uncharged reach the fetus more rapidly than drugs with a low fat solubility, which are ionized. Teratogenic agents usually affect organ systems at very specific points in development. The heart, central nervous system, palate, and ear are most commonly affected.

Teratogenic period:

1) The pre-implantation and presomatic stages, from “0 to 31 days” following conception, drugs exert an “all –or- none effect”. 2) If a toxic exposure occurs between day 31 and 81, the pregnancy either survives the insult without harm, or terminates. 3) After 81, organs growth continues, but malformation due to a maternally ingested medication is less likely. The pre-implantation and pre-somatic stages, from “0 to 18 days” following conception, drugs exert an “all –or- none effect” [Harita, N.; Hayashi, T,2008]

1.14 How Drugs Cross the Placenta:

The nutritive component of the placental arm of foeto-maternal communication system is responsible for the transfer of oxygen and nutrients from the mother to the foetus, and transfer of carbon dioxide and metabolic wastes in the other direction. Substances crossing the placental barrier must traverse the capillary walls of the mother and foetus, the trophoblast and stroma of intervellous space, collectively known as s~ncytio-trophoblast. Passage may be by active or passive process, and it usually takes over 40 minutes for equilibrium to occln acmss the placenta. There is no direct communication between maternal and foetal blood, except when occasional breaks occur in the chorionic villi which permit leakage of foetal blood cells into maternal circulation. This is responsible for development of Rh isoimmunisation.

Fig-1.2: drug transferring mechanism from mother to fetus across the placenta. Some of the fetus's blood vessels are contained in tiny hair like projections (villi) of the placenta that extend into the wall of the uterus. The mother's blood passes through the space surrounding the villi (intervillous space). Only a thin membrane (placental membrane) separates the mother's blood in the intervillous space from the fetus's blood in the villi. Drugs in the mother's blood can cross this membrane into blood vessels in the villi and pass through the umbilical cord to the fetus [Loebstein et al. 1997].

1.15 Categories of Drugs:

During pregnancy, some medications are safe and some are not. Some require a higher than usual dose, and some doses change with the advancing pregnancy. Physicians responsible for providing care to pregnant women are aware of these different medications and their restrictions.The U.S. Food and Drug Administration has generated a grading system for medications used during pregnancy. The categories are A, B, C, D, and X. The significance of these categories is:

  Definitions Clinical ApplicationA "Controlled studies in women fail to

demonstrate a risk to the fetus in the first trimester (and there is no evidence of a risk in later trimester), and the possibility of fetal harm appears remote."

For all practical purposes, there is no Category A drugs. Such as, folic acid.

B "Either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of a risk in later trimesters)."

Category B drugs include prenatal vitamins, acetaminophen and several other medications used routinely and safely during pregnancy. If there is a clinical need for a Category B drug, it is considered safe to use it. Such as, metronidazole, sulbutamol etc.

C "Either studies in animals have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the fetus."

Category C drugs have not been shown to be harmful to fetuses (if they had been, they wouldn't be Category C drugs). However, there are some reasons to be more concerned about these drugs than Category B drugs. If the pregnant patient will benefit from a Category C drug, it is generally used, although most obstetricians would prefer a Category B drug if it will give equivalently good results. Such as, diclofenac, metformin etc.

D "There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective.)"

Category D drugs have some significant risks. They should be used during pregnancy only when the alternatives are worse. Such as, doxycyclin, metformin etc.

X "Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant."

Category X drugs should not be used during pregnancy. Such as, misoprosole, captopril etc.

1.16 Diabetes mellitus

Diabetes mellitus is a metabolic disorder characterized by persistent hyperglycemia (raised blood glucose) resulting from defects in insulin secretion or insulin action (resistance) or both

due to genetic and/or environmental factors acting alone or together.The foods we eat turn into simpler components. Glucose is one of these components; it is mostly derived from carbohydrates. Glucose is carried to the cell by blood stream. It is one of the main substances needed by the cells to make energy. Our body uses a hormone called insulin (secreted from the beta cells of pancreas) to deal this glucose. In diabetes something goes wrong in the body so that insulin production and/or function becomes impaired. Due to this impairment body cells cannot handle glucose properly and blood glucose goes up/This condition is called diabetes mellitus. Glucose passes into urine if blood glucose goes above a particular limit. [ Ripsin, CM; Kang, H, et al, 2009]

Lack of insulin secretion or action

Fig:1.3 Development of diabetes mellitus

1.17 Classification of diabetes mellitus

Diabetes mellitus is usually divided into following types

• Type l diabetes mellitus • Type2 diabetes mellitus • Other specific types • Gestational diabetes mellitus

Food Intake

Protein FatCarbohydrate

Glucose in Blood

Body cell

Increased glucose in blood

Glucose in urine

Diabetes mellitus

1.17.1 Type 1 Diabetes:

Type 1 Diabetes (also known as insulin-dependent diabetes, juvenile diabetes or simply type 1 DM) develops when the pancreas is unable to produce insulin. When type 1 diabetes appears, it is usually in children or young adults, before the age of 40. The normal treatment for Type 1 diabetes is regular insulin injections and appropriate diet. Regular exercise may also be recommended. This type accounts for only 5-10% of diabetes.

Fig- 1.4: Pictorial presentation of Type 1 Diabetes

1.17.2 Type 2 Diabetes:

Type 2 Diabetes (also known as type 2 diabetes mellitus, adult-onset diabetes or type 2 DM) accounts for about 90% of diabetes cases, and develops when the body itself is able to create some, but not enough insulin, or if the insulin produced can't work properly ("insulin resistance" or "impaired insulin sensitivity"). When type 2 diabetes occurs, it is usually after the age of 40, and is often linked with being overweight. In certain people, such as South Asian and African-Caribbean, Type 2 diabetes may appear earlier, even at age 25. Increasingly, Type 2 diabetes is being diagnosed in children.

Fig-1.5: Pictorial Presentation of Type 2 Diabetes

This form of diabetes is usually treatable with life style changes such as weight loss, healthier diet and an increase in physical activity. Type 2 diabetes may also require that normal blood glucose levels be maintained by taking tablets and sometimes insulin. Some with Type 2 diabetes may need to take insulin a twice a day, but it can often be controlled with tablet medication and diet. Type 2 diabetes is sometimes referred to as "non-insulin-dependent diabetes" because many with this type of diabetes do not need to take insulin

[ Ripsin, CM; Kang, H, et al, 2009].

1.17.3 Gestational Diabetes Mellitus (GDM):

Brought on by metabolic changes during pregnancy, is similar to type 2 diabetes in that it is caused by insulin insensitivity or resistance and occurs in up to 6% of women during pregnancy. Gestational diabetes can be successfully treated but if ignored, it poses health risks for mother and baby, even if you show no symptoms. After pregnancy, gestational diabetes usually goes away. If a woman who already has type 1 diabetes becomes pregnant, she should be monitored very closely.[ Metzger BE, Coustan DR et al, 1998]

1.17.4 Other specific types

This type covers a group of diabetes where hyperglycemia is caused by some specific factors. Some: examples areHormonal diseases - Gushing's syndrome, thyrotoxicosis, acromegaly, pheochromocytoma Drugs/chemicals - glucocorticoid, diuretics, vacorPancreatic diseases - chronic pancreatitis, FCPDClinically this type of diabetes shows features of both diabetes and underlying causes.

1.18 Development of Diabetes

The carbohydrate we eat is converting into glucose in the intestine and goes into blood. Glucose is then filtered from the blood in kidneys. Normally all the filtered glucose is reabsorbed in the renal tubules. Thus no glucose appears in urine. In diabetes, when glucose is present in high concentration in blood, large amount of glucose filters through renal tubules but the tubules are unable to reabsorb glucose beyond a certain limit called the 'renal threshold'. When extra amount of glucose is not reabsorbed, it passes through urine. Being an osmotically active particle it carries extra water along with it. This results in increased urination (Polyuria).

Excessive loss of water in the urine causes intercellular dehydration and in turn stimulates the thirst centre called the osmoreceptor located in the hypothalamus, which in turn leads to increased water intake (Polydipsia).

Glucose is important source of energy. In diabetes mellitus, there is excessive loss of glucose in the urine. Due to the excessive loss, there is increased food intake (Polyphagia).

Due to total lack of insulin, the circulating glucose in the blood is not utilized for metabolic processes of the body. Under these circumstances, the fat and protein stores are mobilized for energy (Weight loss and general weakness).[Buchanan TA, Xiang AH et al, 2005].

1.19 Diagnosis

Diagnosis is based on raised blood sugar with or without clinical symptom. Diabetes cannot be diagnosed by urine testing.

a. OGTT (oral glucose tolerance test)

b. Fasting blood glucose levelc. Random or casual blood glucose level

1.19.1 Oral glucose tolerance test (OGTT)

This is the standard procedure throughout the world where two samples of glucose values, at fasting and 2 hours after 75 gm oral glucose drink , classify a person either to be a diabetic, or impaired glucose tolerance (IGT), impaired fasting glucose (IFG) or non-diabetic. [Buchanan TA, Xiang AH et al, 2005].

OGTT report reading:Inference Fasting blood sample 2hrs after glucose loadNormal <6.1 mmol/L <7.8mmol/LIFG (Impaired Fasting Glucose)

≥6.1 to < 7.0 mmol/L < 7.8 mmol/L

IGT (Impaired Glucose Tolerance)

< 7.0 mmol/L ≥7.8to < 11.1 mmol/L

DM (Diabetes Mellitus) ≥7.0 mmol/L ≥ 11.1 mmol/L

1.19.2 Fasting blood glucose (FBG)

It is an easy procedure, less expensive, less time consuming, with no disturbance of daily activities and can be performed in large population at a time. After 8-14 hours of overnight fast, blood is drawn early in the morning.

Inference FBG levelNormal < 6. 1 mmol/L

IFG ≥6.1 to < 7.0 mmol/LDM ≥ 7.0 mmol/L

1.19.3 Random blood glucose (RBG)

REG value should be interpreted to diagnose when typical symptoms are present. Results may be likely or unlikely to be DM and most of the times require OGTT to confirm the diagnosis.

Inference RBG levelDM is unlikely <5.5mmol/LDM uncertain 5.5-11.1mmol/LDM is likely ≥11.1mmol/L

Casual or random is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria. polydipsia, polyphagia, general weakness and unexplained weight, loss.

1.20 Signs and Symptoms of Diabetes

Awareness of these signs and symptoms High blood levels of glucose can cause several problems, including:

1. Blurry vision2. Excessive thirst3. Fatigue4. Frequent urination5. Hunger6. Weight loss

However, because type 2 diabetes develops slowly, some people with high blood sugar experience no symptoms at all.[ Metzger BE, Coustan DR, 1998]

Symptoms of type 1 diabetes:

1. Fatigue2. Increased thirst3. Increased urination4. Nausea5. Vomiting6. Weight loss in spite of increased appetite

Patients with type 1 diabetes usually develop symptoms over a short period of time. The condition is often diagnosed in an emergency setting.

Symptoms of type 2 diabetes:

1. Blurred vision2. Fatigue3. Increased appetite4. Increased thirst5. Increased urination

1.21 Testing of Diabetes:

Basically there are two tests to aid in diabetes diagnosis: one is blood test, the other a urine test. In a urine test, chemicals are added to the urine, and a test stick inserted into the fluid. How the stick changes color indicates the presence or non-presence of glucose? But the most accurate test is a blood test, which gives a very good indication of blood glucose level.

Fig -1.6: Diabetes testing.

1.22 Management of Diabetes:

Diabetes mellitus is a serious disorder in respect to its potentiality of complications. Absolute insulin deficiency is the major feature of type! diabetes mellitus. On the other hand, insulin deficiency_and_insulin resistance in different combinations are responsible for type2 diabetes mellitus So treatment is directed on the basis of predominant contributing factor. Management of diabetes mellitus varies not only from one person to another but also in the same person from time to time. [ Ripsin, CM; Kang, H, et al, 2009]

There are two major modalities of treatment of diabetes:

1. Non-pharmacological (lifestyle modification) and2. Drug therapy, either oral drugs or insulin

Lifestyle modification can be sufficient in some type2 diabetics; but most of them need both modalities in course of time.

Pharmacological agents are of following types based on basic effect

1. By increasing insulin availability in blood, either endogenously (by secretagogues) or exogenously (by insulin)2. by increasing insulin action and sensitivity in the body3. Other various agents-newer oral and injectable agents

1.22.1 Oral anti-diabetic drugs (OADs):

Classification of OADs:

Three categories of drugs are available:Improve insulin secretion (Insulin secretagogues) - Sulphonylurea (SU)

Glibenclamide Gliclazide Glipizide Glimepiride

(These are all second generation SUs)

Non- sulphonylurea paglinide Nateglinide

Improve insulin action or reduce insulin resistance (Insulin sensitizers) Biguanide Thiazolidinedione

Reduce glucose absorption from GI tract Alpha- glucosidase inhibitors

No drug is yet available to act at all these sites simultaneously. [Eurich; McAlister et al, 2007]

1.22.2 Insulin

1.22.3 Diet Control and Exercise

1.23 Gestational diabetes mellitus (GDM):If a woman gets diabetes when she is pregnant, but she never had it before pregnancy, then she has gestational diabetes.

1.24 Why is not insulin doing its normal function:

The placenta, a system of vessels that passes nutrients, blood, and water from mother to fetus, makes certain hormones that prevent insulin from working the way it is supposed to. This situation is called "insulin resistance. To keep metabolism normal, body has to make three times its normal amount of insulin or more to overcome the hormones made by the placenta. For most women, the body's extra insulin is enough to keep their blood glucose levels in the healthy range. But, for about 5 percent of pregnant women, even the extra insulin is not enough to keep their blood glucose level normal." [ Ripsin, CM; Kang, H, et al, 2009]

1.25 Whom to screen:

Ideally all pregnant women should undergo screening for glucose intolerance at least once between 24th-28th weeks of gestation. In high-risk patients screening should be done at 12-14 weeks/earlier.

1.25.1 High risk:

Age >25yearsFamily history of diabetesMember of high prevalence ethnic groupObesity (pre-pregnancy BMI >25)Previous Bad Obstetric History (BOH)History of GDM, IFG or IGT

1.25.2 Low risk:

Age < 25 yearsNo h/o diabetes in familyMember of a low prevalence ethnic groupNormal weight before pregnancyNo h/o poor obstetric outcomeNo h/o abnormal glucose tolerance

1.26 Screening and diagnosis of gestational diabetes:

If no risk factor for GDM is present- perform at 24-28 weeks of gestation If there is one or more risk factor present perform earlier and for negative cases repeat at 24-28 weeks of gestationScreen at 1st prenatal visit if history of previous GDMGlucose Challenge Test (GCT) is done with 50 gm oral glucose load regardless of the last mealOGTT with 75 gram glucose is done in all GCT positive case

1.27 Interpretation of results:

Screening TestGlucose Challenge Test (GCT)

Diagnostic TestGlucose Tolerance Test (OGTT)

Glucose loadFasting plasma glucose1 hour plasma glucose2 hour plasma glucose

50 grams (not applicable) ≥ 7.8 m mol/L (not applicable)

75 grams≥6.1 m mol/L (not applicable)≥7.8 m mol/L

1.27.1 Prognosis:

Risk of developing diabetes mellitus in the futureIf they require insulin for their pregnancy, there is a 50% risk of diabetes within 5 yearsIf dietary control has been! Sufficient, a 60% risk of developing diabetes mellitus within 10-15 years still persistsFetal and maternal complications affect prognosis Two-thirds of women with type l and type2 diabetes are delivered by caesarean section

1.27.2 Management of pregnancy with diabetes: Pre-pregnancy counseling- understanding the need for tight diabetic control before conception Tight control of diabetes through pregnancy Management of diabetic complications during pregnancyObstetric requirements and monitoring during pregnancy Management of diabetes in labour Management of the neonate. [Ripsin, CM; Kang, H, et al, 2009]

1.27.3 Pre-pregnancy counseling:

Understanding the need for tight glycemic control before conceptionHbAlc should be < 6.5 % before conceiving and shouN. Be on insulin instead of OAD

1.27.4 Tight control of diabetes through pregnancy:Diabetic control should be optimal throughout pregnancy; if it is not, admission to hospital, even for a short period should be arranged without delay.

1.27.5 Targets:

Blood glucose levels - Premeal <6.0 mmol/L - 2h Postmeal <6.0 mmol/L -HbAlc <6.5%Weight change should be positive in pregnancy - Overweight: 7-10 kgs - Normal: 10-12 kgs - Underweight: 10-14 kgs

Blood pressure - < 130/70 mmHgKetones – negative

1.27.6 Good control can be achieved by:

Proper dietary adviceRegular physical activity Frequent monitoring of blood glucose and urine ketonesMedication if neededThose who are on oral drugs should be changed to insulin, preferably before conception.

1.27.7 Dietary advice:

Eat meals and snacks (as allowed on meal plan) on a regular schedule throughout the day. Researchers recommend that women with gestational diabetes eat at least three small-to-medium meals and two-to-four snacks every day.

1.27.8 Daily total calories: 30 kcal/kg of ideal body weight in first trimester 38 kcal/kg of ideal body weight thereafterFrom carbohydrate: 50-60%; protein: 20-30% and fat:30%Protein: 1.5-2 gm/kg of IBW dailyIron, calcium, folic acid

1.27.9 Meal plan:

Meals: Breakfast, lunch, dinnerSnacks: Mid-morning, mid-afternoon and bedtimeBedtime snack is essential to prevent fasting ketonuria

1.27.10 Physical activity:

Choose light to moderate exercise that can be maintained throughout the pregnancy Exercise 30 minutes per day at least 5 days per week High intensity activity, stress in lower trunk, jerky/bouncy movement should be avoided A consultation and approval by a health care provider is needed before beginning any physical activity during pregnancy

1.28 Drugs treatment during gestational diabetes:

Avoiding controversy about OAD, insulin therapy in different schedules should be given with the aim of good glycemic control throughout pregnancy.

1.29 Insulin use during pregnancy:

Human insulin was shown to achieve improved pregnancy and infant outcomes compared with highly purified animal insulins.Commencing in 1999, the safety and efficacy of the rapid-acting analogue insulin lispro has been demonstrated in pregnancy in pre-existing

diabetes and GDM,and it was found not to cross the placenta.The second rapid-acting analogue, insulin aspart, has also been shown to be safe and effective in pregnancy in type 1 diabetes and GDM . [Eurich; McAlister et al, 2007]

1.29.1 Classification of insulin:

Insulin Onset of Action Peak Action

Duration of action

Color Trade name

Rapid acting analogueLisproAspartGlulisine

5-15min5-15min5-15min

1-1.5hrs1-1.5hrs1-1.5hrs

3-5hrs3-5hrs3-5hrs

ClearClear Clear

HumalogNovoRapidApidra

Short acting insulin

30-60min 2-4hrs 6-8hrs Clear Actrpid-HMInsuman-RapidHumulin-R

Intermediate acting insulinNPH or Isophane IZS or Lente

2-4hrs 6-8hrs 12-18hrs Cloudy

Insulatard-HM Insuman-BasalHumulin-n

Long acting analogueGlargineDetermir

2-3 hrs2-3 hrs

No peak 24 hrs24 hrs

ClearClear

LantusLevemir

PremixedBiphasic insulinPremixed analogue

Conventional Premixed- short acting and intermediate acting inproportions of 30/70 % , 50/50 % , 25/75 %Rapid acting (analogue) 30%, intermediate acting (protaminated analogue) 70%

1.29.2 Indications of insulin administration:

Type l DMAcute illnesses (DKA, HONK, severe infection, etc)Chronic illnesses (CKD, heart failure, etc)Pregnancy, lactationOAD failureMajor surgery

1.29.3 Insulin regimens:

The aim of different insulin regimens is to achieve adequate glycamic control with maximum compliance of the patient, which mimics normal physiological insulin secretion.

The choice of insulin regimen should depend on age, lifestyle, targets of metabolic control specially blood glucose, associated conditions, etc.

Some patients may achieve their target blood glucose with basal insulin only at night and metformin and/or secretogouges in the day time.

Some patients (particularly elderly) may require only thrice daily short acting insulin.

Most regimens include a proportion of short/rapid acting insulin 2-3 times a day as bolus and intermediate/long acting insulin once or twice daily as basal.

For type 1 DM basal-bolus insulin regimen is the standard treatment (with one basal and three or more bolus insulin).

Insulin pumps are gaining popularity with a fixed or variable basal and bolus doses with meal.

Premixed insulin is widely used for convenience of use.

1.29.4 Side effects of insulin:

Hypoglycemia Insulin allergy Lipodystrophy- at injection site Weight gain [Eurich; McAlister et al, 2007]

1.30 Management of diabetic complications during pregnancy

Full clinical assessment is needed; blood pressure, renal and retinal complications should be looked for; ophthalmoscopy and testing for urinary albumin should be repeated during pregnancy. ACE inhibitors, beta blockers and thiazide diuretics should be avoided in hypertension during pregnancy or in women planning to conceive. [Ripsin, CM; Kang, H, et al, 2009]

1.31 Obstetric requirements and monitoring during pregnancy

Fetal well being is monitored by ultrasonography at 18-20 weeks to exclude abnormality. Thereafter monthly scans document the rate of fetal growth. Assessment of fetal size and weight is important in determining the timing and mode of delivery.

Follow up at clinic (office) - once in every 2 weeks up to 30th gestational weeks and thereafter once in every week

1.32 Management of diabetes in labour:

Delivery should be monitored and planned. It can take place at term without surgical intervention but earlier induction or caesarean section may be needed for obstetric reasons. It is important to keep blood glucose between 4-5.5 mmol/L in order to prevent neonatal hypoglycemia. It is best achieved by continuous insulin-glucose infusion. The infusion is stopped after the delivery of the baby. During this time regular insulin in small dose is given before meals. Pre-pregnancy regular schedule of insulin may be started within a week (in case of pre-gestational diabetes). [Ripsin, CM; Kang, H, et al, 2009]

1.32.1 Post delivery follow-up for GDM:

Arrange for 75gm OGTT at 6 weeks postpartum. If it is normal an OGTT is to be done yearly.

1.32.2 Management of the neonate:

The newborns of diabetic mother have risk to develop hypoglycemia. Blood glucose levels must be checked within 30-60 minutes of birth and continued at regular intervals until one is sure that there is no risk for hypoglycemia. Neonatal hypoglycemia is defined as blood glucose levels less than 40 mg/dl in full term babies and less than 30 mg/dl in premature babies. Management is by feeding 10% dextrose, or if necessary by intravenous dextrose. [ Ripsin, CM; Kang, H, et al, 2009]

1.32.3 Breast feeding:

This is encouraged in diabetic as well as in non-diabetic mothers. The mother's calorie should be increased with ample fluid. Breast feeding mothers should not use oral hypoglycemic agents.

1.32.4 Contraception and diabetes:

Low dose oral contraceptive pills can be given to young women Intra Uterine Contraceptive Device (IUCD) for older womenSterilization if the patient doses not wish to have further pregnancies

1.33 Education tips:

1.33.1 What to do before planning pregnancy: Inform your doctor and diabetes care team so that you can be referred to the designated diabetes clinic for women planning pregnancy at your local hospitalHave your medication reviewed and start insulin if requiredMonitor your blood glucose control more frequently (at least 4 times a day) as advised by your team Aim to keep good blood glucose control; not to conceive until HbAlc <6.5%If you smoke, ask for help stopping

1.33.2 What to do after being pregnant:

Inform your doctor and diabetes care team as soon as possible so that you can be referred to the designated diabetes antenatal clinic at your local hospital Monitor your blood glucose control at least 4 times a dayAim to keep good blood glucose control: not higher than 6 mmol/L before meals or 6 mmol/L two hours after mealsAttend the diabetes antenatal clinic regularly as advised by your diabetes antenatal clinic team

1.33.3 What to do after delivery:

Ensure breast feeding

Use effective and reliable contraception to avoid an unplanned pregnancyAttend the clinic approximately 6 weeks after delivery; among other things your medication will need to be reviewedAim to continue to keep good blood glucose control to protect your long term health.

3.1. ResultsTable 3.1.1Age of the patients:Age Number of patientsBelow 20 121-25 5026-30 4931-35 6Above 35 0Total 106

Figure 3.1.1 Ages of various pregnant Patients

The above graph and table represents the frequency and percentage of age of various pregnant patients. From the above graph we can say that, in between the age of 21-25the women become more pregnant than that of other age women and the percentage is 47%. The women become less pregnant above the age of 35 year and the percentage is 0%. Other percentages are 1%, 6%, 46% respectively.

Table 3.1.2Body weight of the patients:Body weight of the patients Number of patients41-44 145-48 4449-52 4753-56 1057-60 4Total 106

Figure 3.1.2 Body weight of patients

The above table and the graph represent the frequency and percentage of body weight (Kg) of pregnant patient. From this above graph we can say that, in between the range of 49-52 body weight is highest in case of most of the pregnant patient and the percentage is 44%. The lowest body weight lies in between the range of 41-44 and the percentage is 1%. Other percentages are 4%, 9%, 42% respectively.

Table 3.1.3 Height of the patients:Height of the patients Number of patients

Below 5’ 155-5.4’ 85 5.5-5.9’ 6

Figure 3.1.3 Height of patients

The above table and the graph represent the frequency and percentage height of patient (inches) of pregnant patient. From this above graph we can say that, the maximum patient height in between the range of 61-64 inches and the percentage is 80%. Other percentages are 6% and 14% respectively.

Table3.1.4 Sufferings from diabetes patients: Suffering from gestational diabetes Number of patientsYes 54No 52Total 106

Figure 3.1.4 Patients suffering from gestational diabetes

The above table and the graph represent the frequency and percentage of patient suffering from gestational diabetes. From this above graph we can say that, the maximum patients answer is yes. It indicates the gestational diabetes presents 57.24%.

Table 3.1.5 Which trimester patients are suffering from gestational diabetes :Trimester Number of patients1st 332nd 193rd 2

Figure 3.6 Which Trimester Patient are Suffering from Gestational Diabetes

The above table and the graph represent the frequency and percentages which trimester patients are suffering from gestational diabetes. From this above graph we can say that, the maximum patients are suffering in 1st trimester. Also in 2nd trimester patients are suffering lot but not more than 1st trimester.

Table 3.1.6 Sugar level at first diagnosed:

3.1.6 (A) Fasting value:Fasting value of patients(mmol/L) Number of patientsBelow 6.5 66.6-10.5 42Above 10.6 6

Figure 3.1.6(A) Fasting Value when first Diagnosis

The above table and the graph represent the frequency and percentages of fasting value when first diagnosis of patients. From this above graph we can say that, the maximum patients fasting Value in between the range of 6.6-10.5 mmol/L and the percentage is 78%. In case of below 6.5mmol/L and above 10.6 mmol/L the percentage is same. The percentage is 11%.

3.1.6 (B) Non fasting condition:Non fasting value of patients(mmol/L) Number of patients6.5-8.5 268.5-10.5 13Above 10.5 15

Figure 3.1.6(B)Non fasting value when first diagnosis

The above table and the graph represent the frequency and percentages of non fasting value when first diagnosis of patients. From this above graph we can say that, the maximum patients non fasting value in between the range of 6.5-8.5mmol/L and the percentage is 48%. Other percentages are 28% and 24% respectively. Table 3.1.7 Sugar level at present diagnosis:3.1.7(A) Fasting value:Fasting value of patients(mmol/L) Number of patientsBelow 6.5 326.5-10.5 20Above 10.5 2

Figure 3.1.7(A) Fasting value at present diagnosis

The above table and the graph represent the frequency and percentages of fasting value at present diagnosis of patients. From this above graph we can say that, the maximum patients fasting value below 6.5 mmol/L, and the percentage is 59%. The patients fasting value is lowest in the range of above 10.5mmol/L and the percentage is 4%.

3.1.7 (B) Non fasting value:Non fasting value of patients(mmol/L) Number of patients6.5-8.5 408.6-10.5 8Above 10.5 6

Figure 3.1.7(B) Non fasting value at present diagnosis

The above table and the graph represent the frequency and percentages of non fasting value at present diagnosis of patients. From this above graph we can say that, the maximum patients non fasting value in between the range of 6.5-8.5 mmol/L, and the percentage is 74%. The patients non fasting value is lowest in the range of above 10.5 and the percentage is 11%.

Table 3.1.8 History of the patients:

3.1.8 (A) Diabetes in family members:Diabetes in family members Number of patientsParents 27Not applicable 24Grand parents 0Others 3

Figure 3.1.8 (A) Previous History of Diabetes of patient family Members

The above table and the graph represent the frequency and percentages Previous History of Diabetes of patient family Members. From this above graph we can say that, in 50% patients there have diabetic parents in their family are suffering from Diabetes. The percentage of parents not suffering from diabetes is 44%.

3.1.8 (B) Diabetes during previous pregnancy:Diabetes during previous pregnancy Number of patientsYes 0No 24Not applicable 30

Figure 3.1.8 (B) Diabetes during Previous Pregnancy

The above table and the graph represent the frequency and percentages of the history of diabetes in their previous pregnancy. From this above graph we can say that, their was no patients who had diabetes in their previous pregnancyand the percentages is 25.44%

Table 3.1.9. Taken any type of medicine:Taken medicine Number of patientsYes 46No 8

Figure 3.1.9 Take any type of medicine when suffer from diabetesThe above table and the graph represent the frequency and percentage of about their medication pattern .From this above graph we can say that, 48.76% patients said they take any type of medicine during pregnancy,only 8.48% patients they were not taken any type of medication.

Table 3.1.10 Drug have been prescribed to treat gestational diabetes:Prescribed drugs to treat diabetes Number of patientsInsulin 46Diet control & exercise 8

Figure 3.1.10 Medicine consume for treatment of Diabetes

The above table and the graph represent the frequency of the patients who were taken medicine for the treatment of gestational diabetes. From this above graph we can say that, 48.76% patients were taken insulin to treat the diabetes during pregnancy. And 8.48% patients was treated by diet control and exercise.

3.2 Discussion:

The extent of the prescribing and the area of greatest concern regarding the occurrence potential prescribing errors in pregnant mothers require further definition. We evaluated the recent medication prescribing experience.The maximum 106 number of prescriptions were collected from Chittagong Medical Collage Hospital. The mean age of the patients found in Chittagong under study was between 20-35 years. The highest body weight of patients was found about 49- 52 kg, which is near about 44% among all. The height of patients was surveyed about 60- 64 inch, which is near about 80%. On the other hand, only 54 gestational diabetic patients were found in 106 pregnant women. The highest number of prescriptions were collected from patients in their 1 st trimester of pregnancy (34.98%), followed by 2nd trimester (20.14%) and 3rd trimester (2.12%). When patients first diagnosis for gestational diabetes had occured, the fasting value was measured about 6.6-10.5mmol/L (78% patients), and non fasting value was about 6.5-8.5mmol/L (48% patients). Parents of 50% patients have a history of gestational diabetes, not applicable 44% and others 6% were observed by the patient previous family history. In previous pregnancy, diabetes was not responded for 25.44% patients.While analyzing the prescription of gestational diabetic patients, it was found that 48.76% patients were taking insulin as a drug. And some physicians suggested there patients to control diet & keeping regular exercise (8.48%).

4. Conclusion:

Information on the use of drugs during Gestational Diabetes is not available in Bangladesh. Reducing medication errors and improving patient safety are the important areas of discussion. The use of drugs during Gestational Diabetes calls for special attention because in this case in addition to the mother, the health and life of her unborn child is also at risk. Prescribing drugs during pregnancy presents a challenge for the physicians. Most drugs cross placenta and expose the developing embryo and fetus to their pharmacological and teratogenic effects of pregnant women. Pregnant women very commonly use OTC drugs. Although most OTC drugs have an excellent safety profile, some have unproven safety or are known to adversely affect the fetus.

The main objective of this study was to obtain information about the use of prescription drugs among Gestational Diabetic mother in Bangladesh. Only 54 gestational diabetic patients were found in 106 pregnant women and the highest number of prescriptions were collected from patients in their 1st trimester of pregnancy (34.98%), followed by 2nd trimester (20.14%) and 3rd trimester (2.12%). When patients first diagnosis for gestational diabetes had occured, the fasting value was measured about 6.6-10.5mmol/L (78% patients), and non fasting value was about 6.5-8.5mmol/L (48% patients). Parents of 50% patients have a history of gestational diabetes, not applicable 44% and others 6% were observed by the patient previous family history. In previous pregnancy, diabetes was not responded for 24 patients.

While analyzing the prescription of gestational diabetic patients, it was found that 48.76% patients were taking insulin as a drug. And some physicians suggested there patients to control diet & keeping regular exercise (8.48%).Oral anti-dibetic drug are not prescribe during pregnancy,because of their side effect.From the survey of Chittagong medical college & hospital under Chittagong district, we found that, the pregnancy safe drugs are used in gestational diabetes, following standard guidelines.

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