Critical Care Obstetrics part 74 docx

Course d uring p regnancy The expected increase in CrCl during pregnancy, in the presence of diabetic nephropathy, is seen in only about a third of these women; in another third the re

use effective contraceptive measures while waiting to attempt pregnancy until a time when the diabetes and hypertension have been optimally controlled

Prepregnancy e valuation

Women with diabetes should, ideally, be evaluated for the pres-ence or abspres-ence of nephropathy before pregnancy A 24 - hour urine collection for protein excretion and creatinine clearance (CrCl) is recommended A renal biopsy is no longer considered

to be absolutely necessary for diagnosis

Many diabetic women are currently prescribed angiotensin -converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in an effort to prevent or delay the onset of diabetic nephropathy It has been suggested that using these com-pounds in the preconception period, until the pregnancy is diag-nosed, might decrease complications during pregnancy [26,27] However, more recent studies show that these compounds are not safe at any time during pregnancy and should be stopped before conception [28] Therefore, prepregnancy counseling must include the discontinuation of ACE inhibitors and ARBs before conception Counseling should also include the discon-tinuation of statin and fi brate medications before pregnancy Omega - 3 fatty acids may be continued or started during preg-nancy because of potential benefi ts, particularly with diabetes [29]

Further evaluation should include an ophthalmologic exam and an ECG, as well as additional cardiovascular testing including

an echocardiogram and/or stress test if clinically appropriate All women with type 1 diabetes should have an evaluation of their thyroid function [30] including a TSH level and a thyroid per-oxidase antibody titer along with the pertinent routine laboratory studies Further dietary counseling should include the additional changes that are required when signifi cant renal impairment is present

It should be emphasized that excellent glycemic control before pregnancy may not only prevent or minimize the risk

of congenital anomalies but also result in more stable renal function and lower complication rates later in the pregnancy as well [31]

Course d uring p regnancy

The expected increase in CrCl during pregnancy, in the presence

of diabetic nephropathy, is seen in only about a third of these women; in another third the renal function remains stable In the remainder, a decrease occurs which may refl ect the natural pro-gression of diabetic nephropathy and/or a pregnancy effect from glomerular hyperfi ltration, heavy proteinuria, along with wors-ening hypertension and pre - eclampsia [32 – 35]

Microalbuminuria and b lood p ressure l evels

The presence of microalbuminuria before or in early pregnancy

is associated with a 35 – 60% risk for the development of pre eclampsia, much higher than the 6 – 14% risk observed in diabetic

3 Active proliferative retinopathy should, ideally, be treated

before pregnancy If it develops in early gestation (fi rst trimester),

and there is no response to treatment, pregnancy termination

might have to be offered as an alternative

4 Vaginal delivery may be allowed for those patients with

back-ground or successfully treated proliferative retinopathy The

optimal route of delivery for those patients with active

prolifera-tive retinopathy has not been determined, since in non - pregnant

patients vitreous hemorrhages may occur even during periods of

inactivity Vitreous hemorrhages have been observed during both

cesarean sections and vaginal deliveries, but there is concern that

they may occur more readily during the active expulsion phase

of vaginal birth In patients with active proliferative retinopathy,

it is recommended that the mode of delivery be determined on

an individual basis and in consultation with both the obstetrician

and ophthalmologist

Nephropathy

Until fairly recently, women with diabetic nephropathy were

strongly discouraged from attempting pregnancy, and

therapeu-tic abortion was frequently recommended if pregnancy occurred

These recommendations are not supported by more recent

reports, which show signifi cantly improved perinatal outcome

when good metabolic and blood pressure control is achieved

along with current “ state of the art ” obstetric and neonatal care

Better outcomes are consistently obtained in centers offering a

multidisciplinary team approach

Perinatal complications may include congenital anomalies,

fetal growth restriction, fetal death, stillbirth, and preterm

deliv-ery with its associated neonatal morbidity from prematurity

Maternal complications include worsening of renal function

during or after pregnancy, anemia, superimposed pre - eclampsia

or eclampsia, and worsening of other diabetic complications

fre-quently coexisting with nephropathy, mainly retinopathy (see

previous section) These women should also be aware that they

may face future signifi cant morbidity (e.g dialysis, renal

trans-plantation, etc.) and even shortened life spans due to

macro-vascular disease

Diabetic nephropathy usually occurs in uncontrolled type 1

diabetes after 5 – 15 years ’ duration or longer, but it may also be

seen with shorter duration of diabetes as well as in patients with

type 2 diabetes In the United Kingdom Prospective Diabetes

Study (UKPDS) [25] , 17% of newly diagnosed type 2 diabetics

had pre - existing microalbuminuria, 3.8% had macroalbuminuria

and 37% were hypertensive, most likely because many type 2

diabetics have had the disease for several years before the

diagnosis

It should be widely recognized that all reproductive - age women

with diabetes could become pregnant They should be thoroughly

informed about the risks of pregnancy when the diabetes is poorly

controlled and the additional risks of hypertension and overt

diabetic nephropathy These women should be strongly urged to

asleep all those hours) and rest periods lasting 1 – 2 h each during the day (e.g late moring and mid - to late afternoon) will be greatly benefi cial for those with the more advanced nephropathy These women should be made aware that a readjustment of their lifestyle and even their work schedule would likely be recom-mended later in the pregnancy

Hypertension should be appropriately treated There is evi-dence that blood pressure levels (e.g ≤ 130/80 mmHg), lower than the ≤ 140/90 mmHg currently recommended, might provide additional benefi ts including a reduction in premature deliveries [57] Antihypertensive agents that are considered safer during pregnancy, even during organogenesis, include α - methyldopa, clonidine and the β - adrenergic antagonists with low lipid solubil-ity [58 – 61] The non - dehydropyridine calcium channel blockers (e.g diltiazem) are reportedly benefi cial for glomerular function [62,63] Calcium channel blockers during the fi rst trimester were associated with the possibility of limb defects in one study [64] but not found to be teratogenic in a larger prospective study [65]

Frequent visits for close monitoring and liberal hospitaliza-tions are recommended for worsening hypertension, deteriorat-ing renal function, or fetal compromise Periodic ultrasound examinations are useful for dating (fi rst trimester), detection of congenital anomalies (later in second trimester), and assessment

of fetal growth (monthly in third trimester) Intrauterine growth restriction, rather than macrosomia, is more likely in patients with vascular compromise even if the diabetes is not optimally controlled Fetal surveillance should be instituted as soon as there

is willingness to intervene for fetal distress The mother should

be carefully informed of the situation and her wishes taken into consideration A consultation with a neonatologist is strongly recommended to make sure the mother is aware of the prematu-rity risks

Outpatient therapy is acceptable as long as the diabetes and hypertension are well controlled and the renal function is at an acceptable level (determined at least every month in stable patients and more often if unstable); otherwise hospitalization, even prolonged, is strongly advised

Delivery before term may be indicated due to maternal deterio-ration or fetal distress For elective delivery before term, fetal lung maturation should be documented The route of delivery should

be considered on an individual basis Many of these women (68 – 74%) will require cesarean section delivery secondary to prema-turity, malpresentation, and fetal distress Obviously, these decisions should be made in conjunction with the obstetrician/ perinatologist and neonatal consultant

Neonatal survival has steadily improved during the last 20 – 25 years However, perinatal mortality is still reported to be 5 – 7% mainly due to congenital anomalies or severe fetal growth restric-tion Respiratory distress syndrome is reported in 24 – 25% of cases The improved outcome is most likely multifactorial and includes better control of diabetes and hypertension, improved fetal surveillance, as well as improved neonatal care Predictors

of poor outcome are outlined in Table 51.2

women without microalbuminuria before conception [36 – 39]

Blood pressure levels alone in early pregnancy have been found

to have a low sensitivity and specifi city as sole predictors of

hyper-tensive complications in the third trimester, while urinary

micro-albumin excretion was a better predictor of pre - eclampsia ( [36]

The subset of women with both microalbuminuria and chronic

hypertension is reported to have the highest rate of superimposed

pre - eclampsia [40] The highest pregnancy complication rate is

seen in women with a serum creatinine level of ≥ 2.0 mg/dL or a

CrCl < 50 mL/min before or in early pregnancy [31 – 32,41 – 42]

Given the high rate of maternal and fetal complications in women

with this advanced degree of diabetic nephropathy some experts

recommend discouraging pregnancy

Anemia

Anemia due to erythropoietin defi ciency is a common

complica-tion of diabetic nephropathy and may further compromise

fetal oxygenation Erythropoietin has been used during

pregnancy to treat anemia in diabetic nephropathy [43 – 45]

Recently, concerns have been raised about the long - term use

of this medication However, the short - term, judicious use of

erythropoietin, during pregnancy is unlikely to be a cause of

serious long - term morbidity and may be very benefi cial for the

developing fetus

Asymptomatic b acteriuria and p yelonephritis

Screening for and treating asymptomatic bacteriuria seems

justi-fi ed in pregnant women with diabetic nephropathy because it

occurs more frequently in these women Pyelonephritis is a

par-ticularly serious, but preventable, consequence of untreated

bac-teriuria [46,47]

Cigarette s moking

Cigarette smoking should be strongly discouraged in all

pregnant women and in diabetic women in particular Smoking

impairs fetal oxygenation and, as in the case of retinopathy,

it is an independent risk factor for worsening nephropathy

[48 – 50]

Worsening r enal f unction

It is unusual for diabetic nephropathy to progress to end - stage

renal disease during the course of pregnancy [31 – 33,41 – 43,51,52]

Nevertheless, pregnancy may have a deleterious effect and

accel-erate deterioration in those with more impaired renal function

(Cr ≥ 1.2 mg/dL) in early pregnancy [32 – 35,41 – 43,51,52] Overall,

parity alone does not appear to be associated with more rapid

deterioration of renal function according to data from long - term

follow - up of diabetic women with similar degrees of nephropathy

who do not have pregnancies [4,53 – 56]

Management

Strict diabetic control (HbA 1 C < 7%) should be achieved before

conception and maintained at all times throughout pregnancy

Adequate rest at night (e.g ≥ 8 hours, but it is not necessary to be

pressant agents Azathioprine and cyclosporine cross the placenta but do not appear to be teratogenic or cause fetal growth restric-tion [75] There is less experience with the newer immunosup-pressants although tacrolimus has been reported to be associated with fetal/neonatal hyperkalemia [70,76,77]

Diabetic k etoacidosis

Diabetic ketoacidosis (DKA) is an acute and potentially life threatening emergency with very serious consequences for both mother and fetus Until recently, perinatal mortality, after an episode of maternal DKA, was reported to be as high as 90% In the last 15 – 20 years however, it has been reduced to 10 – 35%, [78 – 82] Maternal mortality was reported to be 4 – 15% [83] , con-siderably higher than in the non - pregnant general diabetic popu-lation [84] , but no maternal deaths have been reported in the most recent publications [78 – 82] The frequency of DKA during pregnancy is 1.7 – 3% [78 – 82] and will likely decrease because of the widespread use of self - glucose monitoring

The occurrence of DKA has, traditionally, been considered to

be solely a complication of type 1 diabetes However, the line differentiating type 1 from type 2 diabetes is becoming increas-ingly blurred and DKA is now reported in children, adolescents and adults with the apparent phenotype of type 2 diabetes [85,86] Consequently, an amendment to the current classifi cation of dia-betes has been recently proposed [87,88] DKA during pregnancy has been reported in gestational diabetes as well [89 – 91] , which may represent new cases of ketosis - prone type 2 diabetes present-ing as DKA durpresent-ing pregnancy [92]

There are no data about the long - term outcome of fetuses surviving maternal DKA There is, however, information about the long - term intellectual development of fetuses exposed to

ketosis in utero Ketosis alone is unlikely to have serious long

term consequences except when there is a concomitant elevation

of plasma β - hydroxybutyrate and/or free fatty acids The off-spring of those women had lower behavioral and intellectual development testing [93]

Pathophysiology

DKA occurs when there is an absolute or relative lack of insulin with excessive production of counter - regulatory hormones including glucagon, catecholamines, cortisol and growth hormone This combination leads to increased lipolysis in insu-lin - sensitive tissues including adipose tissue, skeletal muscle and liver resulting in a massive release of free fatty acids (FFAs) In the liver, FFAs undergo β - oxidation with unrestrained ketoacid ( β- hydroxybutyrate and acetoacetate) production, as well as gluconeogenesis which precipitates DKA These conditions also favor proteolysis leading to elevated plasma aminoacids Aminoacids serve as precursors for gluconeogenesis, which results in exacerbation of the hyperglycemia Several glucose transporters (GLUT) are involved as well Both GLUT 2 and GLUT 4 are reduced in insulin defi ciency GLUT 2 transports

Pregnancy in w omen on d ialysis and a fter

r enal t ransplantation

Dialysis

The number of cases of hemodialysis and, less commonly,

con-tinuous ambulatory peritoneal dialysis during pregnancy, is

increasing This information comes primarily from observational

studies of women with all varieties of kidney diseases, including

diabetes mellitus Most reported cases were women on the verge

of requiring dialysis when they conceived (usually unplanned

pregnancies) or women who experienced a rapid decline in renal

function while pregnant [66] Although it might be tempting to

recommend termination of pregnancy under these

circum-stances, it rarely results in substantial improvement in renal

func-tion [67] Interestingly, no increase risk of maternal death has

been reported although severe hypertension, preterm delivery

and oligohydramnios result in a perinatal mortality of 22 – 40%

[68] The judicious management of anemia (erythropoietin and/

or transfusions) and of preterm labor may help to improve

out-comes [69]

Renal t ransplantation

As a result of an overall increased number of renal

transplanta-tions coupled with a strong desire for motherhood, more

preg-nant patients with renal transplants will be seen in the future

About one - fourth of all patients on chronic dialysis or after renal

transplantation have diabetes Current recommendations

empha-size the importance of waiting a minimum of 2 years before

attempting pregnancy Stable graft function including a serum

creatinine < 1.5 mg/dL, proteinuria < 500 mg/day and optimal

blood pressure and glucose control are also prudent requirements

[70] Data reported from pregnancies in women with kidney

transplants secondary to conditions other than diabetes reveal an

improved survival when serum creatinine levels are < 1.5 mg/dL,

98% vs 75% [71] The course during pregnancy is dependent on

baseline glomerular function at the time of conception, control

of hypertension and prompt diagnosis and treatment of urinary

tract infections [72] The outcome of pregnancy in women with

combined pancreas/kidney transplants is similar to those with

kidney transplant alone [73]

There appears to be a low rate of graft dysfunction during

pregnancy; however, hypertension, pre - eclampsia and preterm

delivery are frequent complications [74] A surprising low rate of

complications has been reported with the use of

Table 51.2 Diabetic nephropathy: predictors of poor outcome

Proteinuria of ≥ 3g in the fi rst trimester

Serum creatinine ≥ 1.2 mg/dL

Chronic hypertension, pre - eclampsia, eclampsia

Anemia (hematocrit < 25%)

Poor compliance

ture, however, may not exclude infection Symptoms and signs

of shock will ensue if aggressive treatment is not rapidly instituted

Laboratory d iagnosis

DKA is defi ned as an arterial pH of ≤ 7.30, a serum bicarbonate

of ≤ 15 mmol/L, ketosis (serum acetone present at 1 : 2 dilution), and hyperglycemia of ≥ 300 mg/dL In pregnancy, however, DKA may occur with relatively low blood sugar levels, and it is very important not to dismiss the diagnosis because the blood sugar

is “ too low ” There are reports of profound DKA in diabetic pregnant women with blood sugars of less than 200 mg/dL This relative “ euglycemia ” may lead to misdiagnosis and inappropriate therapy [78,83,90,96,97] (Table 51.3 )

Leukocytosis is almost always present and it does not indicate infection A left shift in the differential is more suggestive of an active infection

Calculating the anion gap [Na − (Cl + HCO 3 ) = 8 – 12] is useful

In DKA it usually is ≥ 15 although it may also be elevated in lactic acidosis, chronic renal insuffi ciency and rhabdomyolysis, or after ingestion of acid substances such as salicylates, ethylene glycol, methanol, formaldehyde, sulfur, toluene and paraldehyde The serum osmolality [2(Na + K) + serum glucose/18] is another useful calculation because the mental status correlates better with this than with any other metabolic derangement A value of 320 mOsm/L or higher is signifi cant with coma occurring with values of ≥ 340 mOsm/L

It is very important to determine the corrected serum sodium (Na), which is very helpful to estimate water defi cit:

measured Na+ ×plasma glucose−

Hyperglycemia dilutes plasma Na by 1.6 mEq/L for every

100 mg/dL of increased glucose and therefore the measured plasma Na should be lower than normal in the presence of sig-nifi cant hyperglycemia A plasma Na that is normal or high at presentation is indicative of massive water defi cit

In pure metabolic acidosis the arterial PCO 2 level should be approximately equal to the last 2 numbers of the arterial pH A lower than predicted PCO 2 value is indicative of respiratory alka-losis and sepsis should be suspected; if higher, respiratory acidosis should be suspected When hypoxemia is also present, pneumo-nia or low - pressure pulmonary edema is most often the cause

Differential d iagnosis

It is the same as for the non - pregnant patient including alcohol and/or drug overdose, encephalopathy of any cause,

hyperosmo-glucose in and out of liver cells and GLUT 4 regulates hyperosmo-glucose

uptake by muscle cells and adipopcytes [94] Excess ketones cause

acidosis and hyperglycemia leading to osmotic diuresis with

resultant volume depletion, dehydration and electrolyte loss

Decreased cardiac output, hypotension and shock may occur If

there is inadequate tissue perfusion, lactic acid will accumulate

resulting in worsening acidosis In an effort to compensate for

acidosis, hydrogen ions enter into cells causing exit of

intracel-lular potassium The serum (extracelintracel-lular) potassium levels will

be elevated initially but total body (intracellular) potassium

depletion may be severe With insulin therapy, the potassium

quickly re - enters the cells resulting in low serum potassium

Serum potassium levels therefore, must be monitored closely and

replaced accordingly

Pregnant, diabetic women may develop DKA more rapidly

than their non - pregnant counterparts due to accelerated lipolysis,

ketosis and protein catabolism associated with pregnancy In

addition, buffering capacity is diminished because of higher

minute alveolar ventilation (progesterone effect), which in turn

results in a compensatory elevated renal bicarbonate excretion

Further potential contributing factors include the increased levels

of hormones that cause insulin resistance during pregnancy, such

as human placental lactogen Persistent nausea and vomiting in

early pregnancy is another potential contributing factor [81]

Precipitating f actors

The common precipitating factors seen outside of pregnancy are

also reported during pregnancy including infection, insulin

omis-sion, insulin pump failure, non - compliance, alcohol and drug use

and medications including corticosteroids and adrenergic

ago-nists which are frequently used in pregnancy Failure to recognize

new - onset diabetes presenting as DKA has been reported to be

the main cause of fetal demise in several recent publications

[80,92,95] Given the increasing reports of ketosis - prone type 2

diabetes, more cases of DKA during pregnancy should be expected

[87,88,92]

Clinical p resentation

In general, DKA develops over a period of 3 – 7 days but it may

develop more precipitously when alcohol ingestion is a

contribut-ing factor The usual initial symptoms of uncontrolled diabetes

are present, including polyuria, polydipsia, blurred vision,

anorexia, nausea, vomiting, abdominal pain, and unintentional

weight loss The abdominal symptoms are caused by elevated

ketones With severe hypokalemia, gastroparesis and even ileus

may occur or be greatly worsened if pre - existing Without

treat-ment, mental changes will develop, ranging from drowsiness

to deep coma Other signs include deep, rapid respirations

(Kussmaul) with a fruity odor (caused by ketones), and signs of

intravascular volume depletion (dry mucous membranes, poor

skin turgor and warm dry skin) Sinus tachycardia and orthostatic

hypotension are other signs of inadequate intravascular volume

The body temperature is usually normal or below normal If fever

is present, an infection should be suspected A normal

Table 51.3 Diagnosis of diabetic ketoacidosis in pregnancy

Serum pH < 7.30 Serum bicarbonate < 15 Serum ketones > 1:2 dilution Any glucose level (can be < 200 mg/dL and even < 150 mg/dL

DKA [98,99] Hyperchloremia almost always develops in the course of DKA treatment and the use of lactated Ringer ’ s instead

of saline has been proposed as prevention However, in uncon-trolled diabetes, lactate infusions might not be well tolerated When the serum glucose decreases to less than or equal to

250 mg/dL dextrose solutions should be administered (D5 0.9% saline or D5 0.45% saline) Since many pregnant women with DKA may have initial glucose levels well below 250 mg/dL, dextrose - containing solutions may be started from the outset

Insulin

Insulin should be administered as soon as fl uid replacement has been started because fl uids alone will not reverse DKA Treatment should be administered by continuous intravenous infusion using only regular insulin Many experts initiate therapy with a primary bolus of intravenous regular insulin utilizing 0.1 units/

kg ideal body weight The general insulin requirements are also 0.1 units per kilogram of body weight per hour but this rate must

be adjusted as often as necessary to maintain a steady glucose diminution The rate of glucose fall should be greater than 10% every 1 – 2 hours, generally 60 mg/dL per hour There is no benefi t

of a more rapid normalization of the serum glucose If, however, desired glucose control is not achieved, the insulin infusion should be readjusted accordingly

Potassium

The potassium defi cit is usually greater than or equal to 3 – 5 mmol/

kg Potassium will start re - entering the cells quickly after the initiation of insulin and a fall in serum levels should be antici-pated No potassium is given during the fi rst 2 – 4 hours except when the initial level is already critically low The rate of admin-istration has to be readjusted according to the serum levels and urinary output Extreme caution is recommended if there is oli-guria or anuria General guidelines are: (i) 40 mEq/h when the serum K level is below 3; (ii) 30 mEq/h if between 3 and 4; (iii) 20 mEq/h if between 4 and 5 and (iv) none if the level is over 5 mEq/L Administering potassium phosphate, instead of only potassium chloride, is advocated but not universally recommended

Bicarbonate

There is almost universal agreement that bicarbonate should be administered when there is severe lactic acidosis in addition to DKA, and also in the presence of life - threatening hyperkalemia with electrocardiographic changes Otherwise, bicarbonate administration is not recommended unless the arterial pH

is below 7.10 However, if there is hypotension many experts advice bicarbonate administration when the pH is 7.20 or less

in an effort to increase the left ventricular ejection fraction and vascular responsiveness Under the above conditions the benefi ts are thought to outweigh the risks of the paradoxical lowering of intracerebral pH by CO 2 diffusion, impaired oxygen-ation from a shift in the oxygen dissocioxygen-ation curve, hyperosmolal-ity, hypernatremia, hypokalemia, late alkalosis and cerebral

lar state, hypoglycemia, uremic coma, trauma, infection,

psycho-sis, syncope and seizures

Treatment

All patients with DKA must be managed in an intensive care

setting and the fetus continuously monitored if at a viable

gesta-tional age (Table 51.4 ) A fl ow sheet detailing all aspects of

man-agement is extremely important and should include the following:

dates/times, serial glucose measurements, serum ketones,

electro-lytes, arterial blood gases, anion gap, insulin administration, and

intake and output (I & O)

Fluid and e lectrolytes

Restoring the extracellular volume with adequate fl uids and

elec-trolytes is the fi rst priority of therapy One of the most common

mistakes made in the treatment of DKA is not giving adequate

fl uids The average defi cit is 5 – 7 L (about 100 mL/kg of body

weight) but can be more severe At least 75% of the fl uid defi cit

must be replaced during the initial 24 hours A rate of 500 –

1000 mL/h for the initial 4 hours and 250 – 500 mL/h for the

fol-lowing 4 hours is recommended The replacement must take into

account the urine output as well as insensible losses Isotonic

fl uids (0.9% normal saline) are generally regarded as the optimal

initial replacement (fi rst 1 – L) If the reported Na level is

“ normal ” or high (here is when the corrected serum Na and

osmolality are very helpful to guide treatment) the fl uid defi cit is

massive and the patient very hyperosmolar Under these severe

hyperosmolar conditions using hypotonic fl uids (0.45% saline)

from the outset might be considered Concerns about the

devel-opment of cerebral edema following rapid fl uid replacement in

the treatment of DKA are important but it appears that cerebral

edema may be more the result of reduced blood volume and

elevated carbon dioxide leading to cerebral vasoconstriction,

ischemia and hypoxia related to the severity and duration of the

Table 51.4 Management of diabetic ketoacidosis during pregnancy

Must be in the intensive care unit!

Fetal monitoring (if viable)

Detailed fl ow chart (vital signs, I & O, electrolytes, glucose, insulin used and serum

ketones)

Fluids: NS 500 – 1000 mL/h x 3 h, ½ NS thereafter

Change to D 5 when glucose ≤ 250 mg/dL

Start with D 5 if initial glucose ≤ 250 mg/dL

Insulin: 0.10 units/kg IV push

0.10 units/kg/h (5 – 10 units/h) IV drip

Readjust if glucose not decreasing by ≥ 60 mg/h

Potassium: None for the fi rst 2 – 4 h

None if serum K > 5 mEq/L

20 mEq/h if serum K 4 – 5, 30 mEq/h if 3 – 4 and 40 mEq/h if < 3

Partial replacement may be given as potassium phosphate

Bicarbonate: None if pH > 7.10

But if hypotensive, replace when pH ≤ 7.20

age, had higher glucose, BUN and osmolality levels, required more insulin and had a prolonged duration of recovery

Coronary a rtery d isease

There is little information regarding pregnancy and ischemic heart disease in diabetic women Two recent papers have reported

on the incidence, mortality and risk factors for pregnancy - related acute myocardial infarction in the United States During the 10 year period from 1991 to 2000 [103] , 151 women had an acute myocardial infarction for an incidence of 1 in 35 700 deliveries; 4% were women with diabetes mellitus but not identifi ed as ges-tational or pre - gesges-tational diabetes The maternal mortality rate was 7.1% but fatalities occurred only in women with an acute myocardial infarction taking place before or at the time of deliv-ery The relative risk of the various factors identifi ed by multivari-ate analysis using logistic regression were:

1 age, particularly 40 years or older: odds ratio (OR) 4.5 and

confi dence interval (CI) 2.0 – 9.8

2 diabetes mellitus: OR 4.3 (CI 2.3 – 7.9)

3 chronic hypertension: OR 24.5 (CI 14.8 – 40.3

4 severe pre - eclampsia: OR 6.9 (CI 3.7 – 13.1) and

5 eclampsia: OR 15.3 (CI 5.3 – 44.1)

In this report, hypertensive disorders greatly increased the risk

of acute myocardial infarction and were a stronger risk factor than diabetes mellitus The incidence of myocardial infarction during pregnancy, reporting data from the years 2000 to 2002 [104] , was 6.2 cases per 100 000 deliveries and a mortality rate of 5.1% Single independent variables associated with increased risk were, again, age over 40 years OR 30.2 (CI 17.2 – 43.2), hyperten-sion OR 21.7 (CI 6.8 – 69.1), thrombophilia OR 25.6 (CI 9.1 – 71.2), smoking OR 8.4 (CI 5.4 – 12.9), need for blood transfusion

OR 5.1 (CI 2.0 – 12.7), and diabetes mellitus OR 3.6 (CI 1.5 – 8.3)

The maternal mortality was much higher (73%), in the few cases reported before 1980 either because treatment was less effective at that time or because of a tendency toward reporting fatal cases The prognosis is better if the myocardial infarction occurs before pregnancy or early in the fi rst trimester than when

it takes place later in the pregnancy or during labor The few cases reported after angioplasty or coronary artery revascularization before conception tolerated pregnancy better and had less neo-natal morbidity from prematurity [105,106]

Women with coronary artery disease tend to be older and have longstanding diabetes A detailed history, physical examination, ECG, echocardiogram, a stress test and, if indicated, a coronary angiogram should be performed before conception in any woman contemplating pregnancy if coronary artery disease is suspected Every effort should be made to treat coronary insuffi ciency before pregnancy Because of the possibility of maternal mortality, preg-nancy is usually discouraged in this group of patients However,

if pregnancy occurs before treatment and termination is not an option, the treatment should be the same as in non - pregnant

dysfunction [98,99] Nevertheless, if bicarbonate replacement is

deemed necessary the use of dilute therapy (i.e putting the

bicar-bonate in a liter of fl uid) is preferable to direct concentrated

administration

Other DKA c omplications

If hypotension persists after adequate volume replacement, sepsis

should be suspected Another possibility could be a silent

myo-cardial infarction, which would be unusual in a childbearing - age

woman but possible in long - standing diabetes with nephropathy

and hypertension Pulmonary edema has been reported in

preg-nant women receiving large amounts of fl uids, ß - adrenergic

ago-nists for premature labor and steroids for lung maturation These

agents have been reported to cause DKA even in gestational

dia-betes [100] Cerebral edema has been reported more frequently

in children and young adults but may be seen at any age This

condition should be suspected when neurologic defi cits reappear

after initial improvement or if there is no improvement despite

adequate biochemical normalization [98,99] Other reported

complications include pancreatitis, hyperlipidemia,

hypocalce-mia, renal failure and vascular thrombosis

It is extremely important that the process of switching from

intravenous to subcutaneous insulin, once DKA resolves and the

patient is ready to resume oral intake, be done properly because

worsening of or even a relapse back into DKA may occur

Intravenous insulin disappears from the plasma in a few minutes

This must be anticipated and subcutaneous insulin injected 1 – 2

hours before stopping intravenous insulin so that the patient is

not left without adequate insulin coverage In addition,

gastroin-testinal dysfunction is common while the CO 2 level is 20 mEq/L

or less, even in the absence of other gastrointestinal conditions

such as gastroparesis or gastritis Therefore, feeding the patient

prematurely may lead to nausea and vomiting

Other c onsiderations

The reports of the autopsies performed after fetal demise have

not shown an obvious pathology and therefore a metabolic

derangement is thought to be the most probable cause of fetal

death Contributing factors include:

1 reduced uterine blood fl ow (from maternal hypovolemia

and excess catecholamines) and indeed transient abnormal

blood fl ow has been reported by Doppler ultrasonography

[101]

2 decreased myocardial contractility from hyperglycemia (shown

in experimental animals) and

3 acidosis since ketoacids cross the placenta freely

Examples of fetal stress that subsided after the maternal DKA was

successfully treated have been published [80,102] These reports

form the basis for recommending rapid and aggressive treatment

of maternal DKA, in an effort to correct the maternal condition,

before emergently intervening for non - reassuring fetal heart rate

tracing

A review of published papers suggests that the women with

DKA who had a fetal demise were at a more advanced gestational

pregnancy in a variety of ways: (i) prevent adjustment to the hemodynamic demands of pregnancy; (ii) make it diffi cult, or impossible, to achieve the tight diabetes control usually recom-mended during pregnancy due to hypoglycemia unawareness and slow gastric emptying; (iii) maternal and fetal malnutrition; and (iv) increased fetal loss, intrauterine growth restriction and preterm labor [110,111]

The therapeutic possibilities are limited for this condition in general, and particularly during pregnancy Antiemetics are seldom of value Metoclopramide may provide symptomatic relief in some patients Intravenous erythromycin (not as effec-tive when given orally) has a motilin - like effect and has been reported to be useful in non - pregnant patients [112] Erythromycin

is safe for the fetus We have used this form of therapy in several pregnant women after all other measures failed, with temporary improvement for days to weeks Parenteral nutrition may become necessary despite its potential risks when used long term It should be initiated before the mother becomes severely malnour-ished and when it becomes obvious that all other available mea-sures have proven ineffective

References

1 Axer - Siegel R , Hod M , Fink - Cohen S , et al Diabetic retinopathy

during pregnancy Ophthalmology 1996 ; 103 ( 11 ): 1815 – 1819

2 Temple RC , Aldridge VA , Sampson MJ , et al Impact of pregnancy

on the progression of diabetic retinopathy in Type 1 diabetes Diabet Med 2001 ; 18 ( 7 ): 573 – 577

3 Lovestam - Adrian M , Agardh CD , Aberg A , Agardh E Pre - eclampsia

is a potent risk factor for deterioration of retinopathy during preg-nancy in Type 1 diabetic patients Diabet Med 1997 ; 14 ( 12 ):

1059 – 1065

4 Diabetes Control and Complications Trial Research Group Effect

of pregnancy on microvascular complications in the Diabetes Control and Complications Trial Diabet Care 2000 ; 23 :

1084 – 1091

5 Nathan DM , Davis M , Cleary P , Lachin J Letter: Response to “ Do all women require intensive retinal surveillance during pregnancy? ”

Diabet Care 2001 ; 24 ( 4 ): 795 – 796

6 Moloney JB , Drury MI The effect of pregnancy on the natural course of diabetic retinopathy Am J Ophthalmol 1986 ; 93 :

745 – 756

7 Serup L The infl uence of pregnancy on diabetic retinopathy Acta Endocrinol 1986 ; 277 (Suppl): 122 – 124

8 Phelps RL , Sakol P , Metzger BE , et al Changes in diabetic retinopa-thy during pregnancy: correlation with regulation of hyperglycemia

Arch Ophthalmol 1986 ; 104 : 1806 – 1810

9 Klein BEK , Moss SE , Klein R Effect of pregnancy on progression of

diabetic retinopathy Diabet Care 1990 ; 13 : 34 – 40

10 Lauszus F , Klebe JB , Bek T Diabetic retinopathy in pregnancy

during tight metabolic control Acta Obstet Gynecol Scand 2000 ;

79 ( 5 ): 367 – 370

11 Larsen M , Colmorn LB , Bonnelycke M , et al Retinal artery and vein

diameters during pregnancy in diabetic women Invest Ophthalmol Vis Sci 2005 ; 42 ( 2 ): 709 – 713

patients with coronary insuffi ciency Diabetes should be

con-trolled but with care to avoid hypoglycemia in order to prevent

catecholamine release and tachycardia, which will increase

myo-cardial demands [105] The route of delivery should be

individu-alized and in consultation with the obstetrician/perinatologist

Shortening the duration of the second stage of labor, to decrease

the Valsalva maneuver, has been suggested [107] The route of

delivery in the reported cases has been 60% cesarean section and

40% vaginal deliveries Continuous cardiac monitoring is

rou-tinely advised but the placement of central line catheters is not

universally endorsed and should be individualized Continuous

epidural anesthesia is recommended for patients in labor to avoid

pain - related stress and tachycardia, which also increases

myocar-dial demands and the risk of an acute cardiac event

Diabetic n europathy

The distal peripheral neuropathy commonly seen in many

dia-betic patients is seldom of any consequence during pregnancy

Several studies have concluded that pregnancy does not adversely

affect neuropathy [108 – 110] , and even improvement of nerve

conduction has been observed towards the third trimester This

phenomenon was attributed to tight glucose control achieved

during pregnancy [110] It has been concluded that pregnancy is

not a signifi cant risk factor for neuropathy and improved

glyce-mic control may actually ameliorate abnormalities with nerve

conduction

Diabetic autonomic neuropathy, however, may pose serious

diffi culties for pregnant women It may be asymptomatic in the

early stages and found only by specifi c examination Diagnosing

autonomic neuropathy for the fi rst time during pregnancy may

not be easy [111] because pregnancy affects the heart rate response

during respiration, as well as the role of the autonomic nervous

system in the cardiovascular adaptation to pregnancy Symptoms

may include loss of sweating in the feet, urinary bladder

dysfunc-tion (and higher risk of urinary tract infecdysfunc-tions), abnormal

car-diovascular refl exes (e.g loss of beat to beat variability, postural

hypotension etc.), and in the more advanced states, sweat

distur-bances of the upper body, gastroparesis, diarrhea, and bladder

atony

Pregnancy may exacerbate gastroparesis and postural

hypoten-sion Vomiting usually starts early in gestation and may not

subside until after delivery The women with asymptomatic

auto-nomic neuropathy before pregnancy have a better prognosis for

postpartum resolution of symptoms and a more benign course

during pregnancy Vomiting interferes with diabetic control and

impairs the nutritional status of the mother (weight loss, ketone

production, etc.) and the fetus (growth restriction) Autonomic

neuropathy may block the early “ alarm ” symptoms of the

cate-cholamine phase of hypoglycemia, thus making these women

vulnerable to neuroglycopenia; this is particularly true when tight

control of the diabetes is attempted, such as is commonly the case

during pregnancy Therefore, autonomic neuropathy may affect

30 Surks MI , Ortiz E , Daniels GH , et al Subclinical thyroid diseases: scientifi c review and guidelines for diagnosis and management

JAMA 2004 ; 291 : 228 – 238

31 Jovanovic R , Jovanovic L Obstetric management when normoglycemia is maintained in diabetic pregnant women with vascular compromise Am J Obstet Gynecol 1984 ; 149 :

617 – 623

32 Mackie ADR , Doddridge MC , Gamsu HR , et al Outcome of preg-nancy in patients with insulin - dependent diabetes mellitus and

nephropathy with moderate renal impairment Diabet Med 1996 ; 13 :

90

33 Dunne FP , Chowdhury TA , Hartland A , et al Pregnancy outcome

in women with insulin - dependent diabetes mellitus complicated by

nephropathy Q J Med 1999 ; 92 : 451

34 Carr D , Binney G , Brown Z , et al Relationship between hemody-namics, renal function, and pregnancy outcome in class F diabetes

Am J Obstet Gynecol 2002 ; 187 (suppl): 152

35 Biesenbach G , Grafi nger P , Stoger H , et al How pregnancy infl uences renal function in nephropathic type 1 diabetic women depends on their pre - conception creatinine clearance J Nephrol

1999 ; 12 : 41

36 Ekbom P , Damm P , Norgaard K , et al Urinary albumin excretion and 24 - hour blood pressure as predictors of preeclampsia in type 1

diabetes Diabetologia 2000 ; 43 : 927

37 Schroder W , Heyl W , Hill - Grasshof B , et al Clinical value of detect-ing microalbuminuria as a risk factor for pregnancy - induced

hyper-tension in insulin - treated diabetic pregnancies Eur J Obstet Gynecol Reprod Biol 2000 ; 94 : 155

38 Ekbom P , Damm P , Feldt - Rasmussen O , et al Pregnancy outcome

in type 1 diabetic women with microalbuminuria Diabet Care 2001 ;

24 : 1739

39 Lauszus FF , Rasmussen OW , Lousen T , et al Ambulatory blood pressure as predictor of preeclampsia in diabetic pregnancies with respect to urinary albumin excretion rate and glycemic regulation

Acta Obstet Gynecol Scand 2001 ; 80 : 1096

40 Combs CA , Rosenn B , Kiztmiller JL , et al Early - pregnancy

protein-uria in diabetes related to preeclampsia Obstet Gynecol 1993 ; 82 :

802

41 Kimmerle R , Zas RP , Cupisti S , et al Pregnancies in women with diabetic nephropathy: long - term outcome for mothers and child

Diabetologia 1995 ; 38 : 227

42 Miodovnik M , Rosenn BM , Khoury JC , et al Does pregnancy increase the risk for development and progression of diabetic

nephropathy? Am J Obstet Gynecol 1996 ; 174 : 1180

43 McGregor E , Stewart G , Junor BJ , et al Successful use of

recombi-nant human erythropoietin in pregnancy Nephrol Dial Transplant

1991 ; 6 : 292

44 Yankowitz J , Piraino B , Laifer A , et al Use of erythropoietin in

pregnancies complicated by severe anemia of renal failure Obstet Gynecol 1992 ; 80 : 485

45 Braga J , Marques R , Branco A , et al Maternal and perinatal

implica-tions of the use of human recombinant erythropoietin Acta Obstet Gynecol Scand 1996 ; 75 : 449

46 Geerlings SE , Stolk RP , Camps MJL , et al Risk factors for

asymp-tomatic urinary tract infection in women with diabetes Diabet Care

2000 ; 23 : 1737

47 Geerlings SE , Stolk RP , Camps MJL , et al Consequences of

asymp-tomatic bacteriuria in women with diabetes mellitus Arch Intern Med 2001 ; 161 : 1421

12 Loukovaara S , Immonen IJ , Yandie TG , et al Vasoactive mediators

and retinopathy during type 1 diabetic pregnancy Acta Ophthalmol

Scand 2005 ; 83 ( 1 ): 57 – 62

13 Lauszus FF , Klebe JG , Bek T , Flyvbjerg A Increased serum IGF - I

during pregnancy is associated with progression of diabetic

reti-nopathy Diabetes 2003 ; 52 ( 3 ): 852 – 856

14 Loukovaraa S , Immonen IJ , Koistinen R , et al The insulin - like

growth factor system and Type 1 diabetic retinopathy during

preg-nancy J Diabet Complications 2005 ; 19 ( 5 ): 297 – 304

15 Kitzmiller J , Main E , Ward B , et al Insulin lispro and the

develop-ment of proliferative diabetic retinopathy during pregnancy Diabet

Care 1999 ; 22 : 874

16 Loukovaara S , Immonen I , Teramo KA , Kaaja R Progression of

retinopathy during pregnancy in type1 diabetic women treated with

insulin lispro Diabet Care 2003 ; 26 ( 4 ): 1193 – 1198

17 Garg SK , Frias JP , Anil S , et al Insulin lispro therapy in pregnancies

complicated by type 1 diabetes: glycemic control and maternal and

fetal outcomes Endocr Pract 2003 ; 9 ( 3 ): 187 – 193

18 Pettitt DJ , Ospina P , Kolaczynski JW , et al Comparison of an

insulin analog, insulin aspart, and regular human insulin with no

insulin in gestational diabetes mellitus Diabet Care 2003 ; 26 :

183 – 186

19 Mathiesen ER , Kinsley B , Amiel SA , et al Maternal glycemic control

and hypoglycemia in Type 1 diabetic pregnancy: a randomized trial

of insulin aspart versus human insulin in 322 pregnant women

Diabet Care 2007 ; 30 ( 4 ): 771 – 776

20 Hofmann T , Horstmann G , Stammberger I Evaluation of the

repro-ductive toxicity and embryotoxicity of insulin glargine in rats and

rabbits Int J Toxicol 2002 ; 21 : 181 – 189

21 Price N , Bartlett C , Gillmer M Use of insulin glargine during

preg-nancy: a case - control pilot study Br J Obstet Gynaecol 2007 ; 114 ( 4 ):

453 – 457

22 Gluckman PD The endocrine regulation of fetal growth in the late

gestation: the role of insulin - like growth factors J Clin Endocrinol

Metab 1995 ; 80 : 1047 – 1050

23 Mein BEK , Moss SE , Klein R Effect of pregnancy on progression of

diabetic retinopathy Diabet Care 1990 ; 13 : 34

24 Early Treatment Diabetic Retinopathy Study Research Group

Grading diabetic retinopathy from stereoscopic color fundus

pho-tographs: an extension of the modifi ed Airlie House classifi cation

ETDRS report number 10 Ophthalmology 1991 ; 98 : 786

25 UK Prospective Diabetes Study Group (UKPDS) X Urinary

albumin excretion over 3 years in diet treated type 2 (non insulin

dependent) patients, and association with hypertension,

hypergly-cemia and hypertriglyceridemia Diabetologia 1993 ; 36 : 1021

26 Hod M , van Dijk DJ , Karp M , et al Diabetic nephropathy

and pregnancy: the effect of ACE inhibitors prior to pregnancy

on maternal outcome Nephrol Dial Transplant 1995 ; 10 :

2328 – 2333

27 Bar JB , Schoenfeld A , Orvieto R , et al Pregnancy outcome in patients

with insulin dependent diabetes mellitus and diabetic nephropathy

treated with ACE inhibitors before pregnancy J Pediatr Endocrinol

Metab 1999 ; 12 : 659

28 Cooper WO , Hernandez - Diaz S , Arbogast PG , et al Major

congeni-tal malformations after fi rst - trimester exposure to ACE inhibitors

N Engl J Med 2006 ; 354 : 2443 – 2451

29 Norris JM , Yin X , Lamb MM , et al Omega - 3 polyunsaturated fatty

acid intake and islet autoimmunity in children at increased risk for

type1 diabetes JAMA 2007 ; 298 ( 12 ): 1420 – 1428

70 Hou S Pregnancy in renal transplant recipients Adv Ren Replace Ther 2003 ; 10 : 40 – 47

71 Davidson JM Pregnancy in renal allograft recipients: prognosis and

management Bailliere ’ s Clin Obstet Gynecol 1994 ; 8 : 501 – 525

72 Armenti VT , Ahlswede KM , Ahlswede BA , et al National Transplantation Pregnancy Registry: outcomes of 154 pregnancies

in cyclosporine - treated female kidney transplant recipients

Transplantation 1994 ; 57 : 502 – 508

73 McGrory CH , Groshek MA , Sollinger HW , et al Pregnancy

out-comes in female pancreas - kidney transplants Transplant Proc 1999 ;

31 : 652 – 656

74 First MR , Combs CA , Weiskittel P , et al Lack of effect of pregnancy

on renal allograft survival or function Transplantation 1995 ; 59 :

472 – 476

75 Oz B , Hackman R , Einarson T , et al Pregnancy outcome after

cyclo-sporine therapy during pregnancy: a meta - analysis Transplantation

2001 ; 71 : 1051 – 1060

76 Kainz A , Harabicz I , Cowlrick IS , et al Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus

Transplantation 2000 ; 70 : 1718 – 1725

77 Pergola PE , Kancharia A , Riley DJ Kidney transplantation during the fi rst trimester of pregnancy: immunosuppression with

mycophe-nolate mofetil, tacrolimus and prednisone Transplantation 2001 ; 71 :

994 – 999

78 Cullen MT , Reece EA , Homko CJ , et al The changing presentations

of diabetic ketoacidosis during pregnancy Am J Perinatol 1996 ; 13 :

449 – 451

79 Chauhan SP , Perry KG Jr , McLaughlin BN , et al Diabetic

ketoaci-dosis complicating pregnancy J Perinatol 1996 ; 16 : 173 – 175

80 Montoro MN , Myers VP , Mestman JH , et al Outcome of pregnancy

in diabetic ketoacidosis Am J Perinatol 1993 ; 10 : 17 – 20

81 Rodgers BD , Rodgers DE Clinical variables associated with diabetic

ketoacidosis during pregnancy J Reprod Med 1991 ; 36 : 797 – 800

82 Kilvert JA , Nicholson HO , Wright AD Ketoacidosis in diabetic

pregnancy Diabet Med 1993 ; 10 : 278 – 281

83 Gabbe SG , Mestman JH , Hibbard LT Maternal mortality in diabetes

mellitus: an 18 - year survey Obstet Gynecol 1976 ; 48 : 549 – 551

84 Wetterhal SF , Olson DR , de Stafano F , et al Trends in diabetes and

diabetic complications Diabet Care 1992 ; 15 : 960 – 967

85 American Diabetes Association Type 2 diabetes in children and

adolescents Pediatrics 2000 ; 105 : 671 – 680

86 Umpierrez GE , Smiley D , Kitabchi AE Narrative review: ketosis -prone type 2 diabetes mellitus Ann Intern Med 2006 ; 144 :

350 – 357

87 Balasubramanyan A , Garza G , Rodriguez L , et al Accuracy and predictive value of classifi cation schemes for ketosis - prone diabetes

Diabet Care 2006 ; 29 : 2575 – 2579

88 Umpierrez GE Ketosis - preone type 2 diabetes Time to revise the

classifi cation of diabetes Diabet Care 2006 ; 29 : 2755 – 2757

89 Maislos M , Harman - Bohem I , Weizman S Diabetic ketoacidosis: rare complication of gestational diabetes Diabet Care 1992 ; 15 :

968 – 970

90 Clark JDA , McConnell A , Hartog M Normoglycemic ketoacidosis

in a woman with gestational diabetes Diabet Med 1991 ; 8 :

388 – 389

91 Pitteloud N , Binz K , Caufi eld A , et al Ketoacidosis during

gesta-tional diabetes Case report Diabet Care 1998 ; 21 : 1031 – 1032

92 Schneider MB , Umpierrez GE , Ramsey RD , et al Pregnancy

com-plicated by diabetic ketoacidosis Diabet Care 2003 ; 26 : 958 – 959

48 Muhlhauser I , Bender R , Bott U , et al Cigarette smoking and

pro-gression of retinopathy and nephropathy in type 1 diabetes Diabet

Med 1996 ; 13 : 536

49 Baggio B , Budakovic A , Dalla Vestra M , et al Effect of cigarette

smoking on glomerular structure and function in type 2 diabetic

patients J Am Soc Nephrol 2002 ; 13 : 2730

50 Chuahiran T , Wesson DE Cigarette smoking predicts faster

pro-gression of type 2 established diabetic nephropathy despite ACE

inhibition Am J Kidney Dis 2002 ; 39 : 376

51 Purdy LP , Hantsch CE , Molitsch ME , et al Effect of pregnancy on

renal function in patients with moderate - to - severe diabetic renal

insuffi ciency Diabet Care 1996 ; 19 : 1067

52 Gordon M , Landon MB , Samuels P , et al Perinatal outcome and

long - term follow - up associated with modern management of

dia-betic nephropathy Obstet Gynecol 1996 ; 87 : 401

53 Rossing K , Jacobsen P , Hommel E , et al Pregnancy and the

progres-sion of diabetic nephropathy Diabetologia 2002 ; 45 : 36 – 41

54 Chatuvedi N , Stephenson JM , Fuller JH , et al The relationship

between pregnancy and long - term maternal complications in the

EURODIAB IDDM complications study Diabet Med 1995 ; 12 : 494

55 Hemachandra A , Ellis D , Lloyd CE , et al The infl uence of pregnancy

on IDDM complications Diabet Care 1995 ; 18 : 950

56 Kaaja R , Sjoberg L , Hellstedt T , et al Long - term effects of pregnancy

on diabetic complications Diabet Med 1996 ; 13 : 165

57 Nielsen LR , Muller C , Damm P , Mathiesen ER Reduced prevalence

of early preterm delivery in women with Type 1 diabetes and

micro-albuminuria – possible effect of early antihypertensive treatment

during pregnancy Diabet Med 2006 ; 23 ( 4 ): 426 – 431

58 Conway , DL , Langer O Selecting antihypertensive therapy in the

pregnant woman with diabetes mellitus J Matern Fetal Med 2000 ;

9 : 66

59 Magee LA Treating hypertension in women of childbearing age and

during pregnancy Drug Saf 2001 ; 24 : 457

60 Rosenthal T , Oparil S The effect of antihypertensive drugs on the

fetus J Human Hypertens 2002 ; 16 : 293

61 Sibai BM Diagnosis and management of gestational hypertension

and preeclampsia Obstet Gynecol 2003 ; 102 : 181

62 Griffi n KA , Picken M , Bakris GL , et al Comparative effects of

selec-tive T - and L - type calcium channel blockers in the remnant kidney

model Hypertension 2001 ; 37 : 1268

63 Hayashi K , Ozawa Y , Fujiwara K , et al Role of actions of calcium

antagonists on efferent arterioles with special references to

glomeru-lar hypertension Am J Nephrol 2003 ; 23 : 229

64 Danielsson BR , Reiland S , Rundqvist E , et al Digital defects induced

by vasodilating agents: relationships to reduction in uteroplacental

blood fl ow Teratology 1989 ; 40 : 351

65 Magee LA , Conover B , Schick B , et al Exposure to calcium channel

blockers in human pregnancy: a prospective, controlled, multicentre

cohort study Teratology 1994 ; 49 : 372

66 Okundaye I , Abrinko P , Hou S Registry of pregnancy in dialysis

patients Am J Kidney Dis 1998 ; 31 : 766

67 Jones DC , Hayslett JP Outcome of pregnancy in women with

mod-erate or severe renal insuffi ciency N Engl J Med 1996 ; 335 :

226 – 232

68 Chao AS , Huang JY , Lien R , et al Pregnancy in women who undergo

long - term dialysis Am J Obstet Gynecol 2002 ; 187 : 152 – 156

69 Hou S Pregnancy in women on dialysis In: Nissenson AR , Fine RN ,

eds Dialysis Therapy , 3rd edn Philadelphia : Hanley and Belfus ,

2002 : 519 – 522

103 Ladner HE , Danielsen B , Gilbert WM Acute myocardial infarction

in pregnancy and the puerperium: a population - based study Obstet Gynecol 2005 ; 105 ( 3 ): 480 – 484

104 James AH , Jamison MG , Biswas MS , et al Acute myocardial infarc-tion in pregnancy: a United States populainfarc-tion - based study

Circulation 2006 ; 113 ( 12 ): 1564 – 1571

105 Hankins GD , Wendel GD Jr , Leveno KJ , et al Myocardial infarction

during pregnancy: a review Obstet Gynecol 1985 ; 65 : 139 – 146

106 Roth A , Elkayam U Acute myocardial infarction associated with

pregnancy Ann Intern Med 1996 ; 125 : 751 – 762

107 Sheikh AU , Harper MA Myocardial infarction during pregnancy:

management and outcome of two pregnancies Am J Obstet Gynecol

1993 ; 169 : 179 – 184

108 Chaturvedi N , Stephenson JM , Fuller JH , et al The relationship between pregnancy and long - term maternal complications in the EURODIAB IDDM complications study Diabet Med 1995 ; 12 :

494 – 499

109 Airaksinen KEJ , Salmela PI , Markku J , et al Effect of pregnancy on autonomic nervous function and heart rate in diabetic and

nondia-betic women Diabet Care 1987 ; 10 : 748 – 751

110 Airaksinen KEJ , Anttila LM , Linnaluoto MK , et al Autonomic infl

u-ence on pregnancy outcome in IDDM Diabet Care 1990 ; 13 : 756

111 Hagay Z , Weissman A Management of diabetic pregnancy

compli-cated by coronary artery disease and neuropathy Obstet Gynecol Clin North Am 1996 ; 23 : 205 – 220

112 Richards RD , Davenport K , McCallum RW The treatment of idio-pathic and diabetic gastroparesis with acute intravenous and chronic

oral erythromycin Am J Gastroenterol 1993 ; 88 : 203 – 207

93 Rizzo T , Metzger BE , Burns WJ , et al Correlation between

antepar-tum maternal metabolism and intelligence of the offspring N Engl

J Med 1991 ; 325 : 911 – 916

94 Fleckman AM Diabetic ketoacidosis Endocrinol Metab Clin North

Am 1993 ; 22 : 181 – 207

95 Sills IN , Rapaport R New onset IDDM presenting with diabetic

ketoacidosis in a pregnant adolescent Diabet Care 1994 ; 17 :

904 – 905

96 Franke B , Carr D , Hatem MH A case of euglycemic diabetic

keto-acidosis in pregnancy Diabet Med 2001 ; 18 : 858 – 859

97 Oliver R , Jagadeesan P , Howard RJ , et al Euglycemic diabetic

keto-acidosis in pregnancy: an unusual presentation J Obstet Gynaecol

2007 ; 27 : 308

98 Glaser N , Barnett P , Mc Caslin I , et al Risk factors for cerebral

edema in children with diabetic ketoacidosis N Engl J Med 2001 ;

344 : 264 – 269

99 Dunger DB , Edge JA Predicting cerebral edema during diabetic

ketoacidosis N Engl J Med 2001 ; 344 : 302 – 303

100 Bedalov A , Balasubramanyan A Glucocorticoid - induced

ketoacido-sis in gestational diabetes Sequela of acute treatment of preterm

labor Diabet Care 1997 ; 20 : 922 – 924

101 Takahashi Y , Kawabata I , Shinohara A , et al Transient fetal

blood fl ow redistribution induced by maternal ketoacidosis

diagnosed by Doppler ultrasonography Prenat Diagn 2000 ; 20 :

524 – 525

102 O ’ Shaughnessy MJ , Beingesser KR , Khieu WU Diabetic ketoacidosis

in pregnancy with a recent normal screening test West J Med 1999 ;

170 : 115 – 118