RIOG003003_0092

92 VOL. 3 NO. 3 2010 REVIEWS IN OBSTETRICS & GYNECOLOGY

MANAGEMENT REVIEW

Type 1 Diabetes Mellitus andPregnancyRoberto Vargas, John T. Repke, MD, FACOG, Serdar H. Ural, MD, FACOG

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Penn State University Collegeof Medicine, Hershey, PA

Diabetes complicates up to 10% of all pregnancies in the United States. Of these, 0.2% to 0.5% are patients with type 1 diabetes mellitus (T1DM).Pregnancies affected by T1DM are at increased risk for preterm delivery,preeclampsia, macrosomia, shoulder dystocia, intrauterine fetal demise, fetal growth restriction, cardiac and renal malformations, in addition to rareneural conditions such as sacral agenesis. Intensive glycemic control and pre-conception planning have been shown to decrease the rate of fetal demise andmalformations seen in pregnancies complicated by T1DM. Recent advances in insulin formulations and delivery methods have increased the number ofoptions available to the obstetric team. Insulin regimens should be tailored toeach individual patient to maximize compliance and ensure proper glycemiccontrol. Intensive preconception counseling with frequent follow-up visits emphasizing tight glucose control is recommended for adequate management.[Rev Obstet Gynecol. 2010;3(3):92-100 doi: 10.3909/riog0114]

2010 MedReviews, LLC

Key words: Insulin Nephropathy Type 1 diabetes mellitus Pregnancy Diabetic ketoacidosis

Type 1 diabetes mellitus (T1DM), previously known as juvenile onset dia-betes or insulin-dependent diabetes mellitus (IDDM), accounts for 5% to10% of diagnosed diabetes in the United States.1 This subclass of diabetesmellitus develops as a result of an autoimmune response directed against insulin-producing cells, located in the pancreas. Due to the destruction of these cells,patients with T1DM require insulin replacement to achieve euglycemia. Onset ofthis disease generally occurs before age 30, and thus can affect women duringtheir reproductive years. Between 0.2% and 0.5% of all pregnancies in the UnitedStates are complicated by T1DM each year.2,3

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Type 1 Diabetes Mellitus and Pregnancy

VOL. 3 NO. 3 2010 REVIEWS IN OBSTETRICS & GYNECOLOGY 93

Before the implementation of in-sulin therapy, infertility was the mostcommon consequence of diabetesmellitus on reproductive-age women,and when pregnancy did occur, fetaland neonatal mortality was as high as60%. Aggressive maternal-fetal man-agement, advances in insulin therapy,and improvements in neonatal inten-sive care units have decreased thisfigure to 2% to 5%.3 The realizationthat improved perinatal outcomes aredirectly correlated with improved

glycemic control and inversely corre-lated with existing end-organ damageled to the development of the Whiteclassification system of diabetes dur-ing pregnancy (Table 1).4

PathophysiologyT1DM is caused by an immune-mediated destruction of insulin-producing cells, located in the pan-creatic islets of Langerhans. Although

the exact cause of this disease stilleludes scientists, it is known that ageneral inflammatory state, termedinsulitis, precedes overt diabetes.During this state of inflammation,macrophages, B lymphocytes, CD4,and CD8 T lymphocytes can be seento infiltrate the islets of Langerhans.A complex cycle of antigen presenta-tion and propagation leads to aneventual accumulation of CD8 lym-phocytes, and gradual destruction ofinsulin-producing cells.5 This decline

in -cell mass eventually leads to aninsulin-deficient state, causing hyper-glycemia in the affected patient.

Pregnancy itself is usually regardedas a diabetogenic state in which post-prandial glucose levels are elevatedand insulin sensitivity is decreased.4

Classically, the decreased response toinsulin activity observed in preg-nancy has been attributed to increasesin hormones such as cortisol, proges-

terone, estrogen, prolactin, andhuman placental lactogen.6 Most re-cently, new molecules such as leptin,tumor necrosis factor- (TNF-), andresistin have been implicated in thismatter. Kirwan and colleagues7

showed that TNF- is the strongestindependent predictor of insulinsensitivity during the late gestationalperiod. In vitro studies showed thatTNF- disrupted insulin signaling andinhibited glucose uptake.7 This studyattributed the rise of TNF- to in-creased placental production with ad-vancing gestational age (Table 2).

Fluctuations in insulin sensitivityduring pregnancy, mostly due tochanging hormone levels, complicateinsulin replacement in gravid Type 1patients with diabetes. In 1984, Weissand Hofmann8 presented data show-ing a 12% decrease in insulin require-ments between 10 and 17 weeks ges-tation. Following the 17th week ofgestation, the total insulin require-ments increase by more than 50%.8

Although these data presented impor-tant fluctuations in insulin require-ments and physiologic changes dur-ing pregnancy, the limited study sizeand different insulin regimens used in

The realization that improved perinatal outcomes are directly correlated withimproved glycemic control and inversely correlated with existing end-organdamage led to the development of the White classification system of diabetesduring pregnancy.

Table 1Modified White Classification System

Class Onset (age) Duration Insulin Criteria

A1 Any Any No Gestational diabetes

A2 Any Any Yes Gestational diabetes

B 20 10 Yes Benign retinal and renal findings

C 10-19 10-19 Yes Age of onset 10-19 years or duration 10-19 years

D 10 20 Yes Age of onset 10 or duration 20 years

F Any Any Yes Nephropathy ( 500 mg/day protein)

R Any Any Yes Proliferative retinopathy

RF Any Any Yes Retinopathy and nephropathy

T Any Any Yes Renal transplant patient

H Any Any Yes Cardiovascular disease

Data from White P.4

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the study limit the statistical signifi-cance. A recent prospective study in-volving 65 T1DM patients furthercharacterized insulin requirementsthroughout pregnancy. Using assaysand glycemic control parameters notpreviously available, Garca-Pattersonand colleagues9 were able to followtotal insulin requirements, insulin re-quirements based on weight, whilecontrolling for glycosylated hemoglo-bin levels (HbA1C), and mean bloodglucose levels. As previously sug-gested by Weiss and Hofmann, 2peaks in insulin requirements, one atweek 9 and the other at week 37, wereobserved.8 After the initial peak ataround 9 weeks, a slow decrease ininsulin requirements was noted. Theaverage nadir point was documentedto be at 16 weeks, with a subsequentrise until 37 weeks gestation.9

Of note, a recent Danish prospec-tive study by Nielsen and colleagues10

showed an increase in C-peptide dur-ing pregnancy in diabetic patients.

This study consisted of 90 gravidT1DM patients with a median dura-tion of diabetes of 17 years (1-35

years). Even in patients with unde-tectable C-peptide prior to pregnancy,a rise in serum levels was noted. Amedian change in C-peptide levels of50% was reported.10 These data pro-vide yet another factor that couldbe contributing to the variability ofinsulin requirements throughout theprogression of pregnancy.

ComplicationsHypoglycemiaHypoglycemia, particularly nocturnal,is a common occurrence with classicinsulin replacement therapies.3 In-creasing insulin requirements, along-side tight glycemic control, increase

the propensity for episodes of insulinoverdose. Counter-regulatory hor-mones, such as cortisol, glucagon,and epinephrine, which protectagainst hypoglycemia, are blunted inpregnancy. The warning signs of hy-poglycemia, such as tachycardia, di-aphoresis, weakness, and pallor, occurin response to these hormones. In ad-dition to the blunted response seenduring pregnancy, patients withT1DM have a reduced glucagon andcortisol response inherent to the dis-ease. The combination of these phe-nomena can mask hypoglycemia.11

Patients and family should be coun-seled on the signs and symptoms ofhypoglycemia and instructed to givethe patient a glass of milk or juicewhen concerned about low bloodsugar.

Diabetic KetoacidosisInsulin deficiency creates a metabolicstate that is interpreted as starvationby the body. In response to the de-creased intracellular glucose concen-trations, the body is forced to tap into

energy stores by processing fattyacids. Fatty acid metabolism leads toketone generation, which the bodycan then use directly as energy in thecase of the brain and heart, or shuttleinto adenosine-5-triphosphate pro-duction. The subsequent accumula-tion of ketones in the blood decreasesplasma pH.12

Hyperglycemia further worsens theinsulin-deficient state by promotingdehydration. The increased concen-tration of glucose increases theplasma osmolarity, in turn, having adiuretic effect. The polyuria caused bythis osmotic diuresis prevents bicar-bonate from being reabsorbed by the

Type 1 Diabetes Mellitus and Pregnancy continued


Insulin deficiency creates a metabolic state that is interpreted as starvationby the body. In response to the decreased intracellular glucose concentra-tions, the body is forced to tap into energy stores by processing fatty acids.

Table 2Molecular Mediators of Insulin Resistance

Enzyme Molecular Action

Progesterone Peripheral glucose uptakeEstrogen Peripheral glucose uptakeCortisol Gluconeogenesis

Insulin sensitivityProlactin Glucose

Mammary glandular tissue GnRH response

Human placental lactogen Lipolysis FFA Mammary glandular tissue Insulin sensitivity

Insulinase Insulin degradationTNF- Insulin receptor activityFFA, free fatty acid; GnRH, gonadotropin-releasing hormone; TNF-, tumor necrosis factor-.Data from Gabbe SG et al.6

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kidney tubules, further concentratingthe ketones and glucose circulatingthroughout the body. The combina-tion of this acidotic state and severedehydration in the context of insulindeficiency is termed diabetic ketoaci-dosis (DKA).12

Overall, DKA is less common thanhypoglycemic episodes during preg-nancy, yet it poses an increased riskto the fetus.3 DKA currently affects1% to 3% of pregnancies with preges-tational diabetes.13 Due to decreasedinsulin sensitivity and overall cata-bolic state seen in pregnancy, DKAmay develop faster than in nonpreg-nant states. The decreased levels ofplasma bicarbonate present in preg-nancy as a physiologic response toincreased minute ventilation furtherdecrease the bodys buffering capac-ity. Infections, such as upper respira-tory and urinary tract infections,along with defective insulin pumps,antenatal corticosteroids, and -mimetic tocolytics, can precipitate

episodes of DKA. Although maternaldeath due to DKA is rare, fetal demisehas been reported in up to 35% ofcases.13 In general, correction of thematernal metabolic derangement will

result in correction of fetal acidosisand may allow for continuation ofgestation, or, if at term, deliver undermore optimal conditions than if im-mediate delivery in the midst of ma-ternal DKA were undertaken.

RetinopathyDiabetic retinopathy is the numberone cause of new-onset blindnessamong Americans between the ages of20 and 74 years. Although only 60%of patients with type 2 diabetes de-velop retinopathy, nearly all T1DMpatients of disease duration greaterthan 20 years will have some retinaldamage. The chronic hyperglycemicstate observed in these insulin-deficientpatients increases the amount of glu-cose that permeates into sensitiveendothelial cells that line capillariesand blood vessels. In the retina, cellsthat support the vascular supply,termed pericytes, are particularly sus-ceptible to chronic hyperglycemia.Continuous damage to endothelial

tissue leads to vascular sclerosis andedema, and ultimately vascular com-promise. In response to damage, is-chemic retinal tissue secretes proan-giogenic growth factors, such as

vascular endothelial growth factor(VEGF) and platelet derived growthfactor (PDGF) in an attempt to restoreblood flow. It is this neovasculariza-tion in response to ischemia that leadsto proliferative diabetic retinopathy.The combination of neovascularizationaround structures such as the foveaand ischemia throughout the retinaleads to blindness, retinal detachment,and intraocular hemorrhages.14

Long-standing concern regardingthe increased rate of progression ofdiabetic retinopathy during earlypregnancy, especially when establish-ing rapid glycemic control with in-sulin, has been of recent debate. Astudy published by the National EyeInstitute15 concluded that the in-creased risk of progression cannot beexplained solely by rapid normaliza-tion of glucose. The authors arguedthat the poor glycemic control, re-quiring rapid normalization, predis-poses patients to the retinalchanges.15 Even with the initial pro-gression of disease that is observedwith normalization, tight control ofplasma glucose levels lowers theoverall long-term progression whencompared with more liberal manage-ment.13 The implications of new in-sulin analogs and their effects on pro-gression of retinopathy are of furtherconcern due to their increased insulingrowth factor (IGF) activity. Initialstudies on insulin lispro have shownno increase in the progression ofretinopathy compared with patientsreceiving regular insulin.16 Laser ther-apy during pregnancy for treatmentof proliferative retinopathy is an ap-propriate option for management.There is a debate over whether to allowa vaginal delivery in cases of subopti-mally treated proliferative retinopathy.There are insufficient data on thistopic; therefore, it is advisable to treatpatients in an individualized mannerin collaboration with input fromendocrinology and ophthalmology.

Treating DKA in Pregnancy

Obtain arterial blood gas, blood glucose, electrolytes, and ketones every hour

IV insulin: 0.2-0.4 U/kg loading dose, then 2-10 U/h

Fluid replacement: Goal 4-6 L over 24 h; replace 1 L in first hour, then 250 mL/h of NS

Start 5% dextrose/NS when blood glucose falls below 250 mg/dL

Potassium replacement: If reduced or normal at presentation, replace at 15-20 mEq/h

If pH 7.10, administer 1 ampule bicarbonate in 1 L of 12NS, normal saline.

Although maternal death due to DKA is rare, fetal demise has been reportedin up to 35% of cases.

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NephropathyDiabetic nephropathy can be describedas a combination of structural changesin the interstitial and glomerular com-partments of the kidney, which can ul-timately lead to end-stage renal disease.These changes can occur in parallel orindividually, and progress in varyingrates. Thickening of the glomerular andtubular basement membranes andhyalinization of the arteriolar supplyhave all been shown to occur in dia-betic patients and hinder renal func-tion. Expansion of the mesangium dueto accumulation of extracellular matrix(ECM) components decreases the sur-face area available for filtration in theglomerular compartment. It is theaccumulation of ECM components likecollagen, laminin, and fibronectin thatcan be ultimately held responsible forthe development of clinical diabeticnephropathy.17

The increase in renal load inherentto pregnancy, combined with height-ened risk of preeclampsia in diabeticpregnancies, further increases thepropensity for renal damage. TheAmerican Congress of Obstetriciansand Gynecologists (ACOG) PracticeBulletin cautions practitioners regard-ing progression of nephropathy toend-stage renal disease in patientswith creatinine levels greater than 1.5mg/dL or overt proteinuria ( 3 gprotein/day). Renoprotective medica-tions commonly used in diabetic pa-tients are contraindicated in preg-nancy due to their teratogenic nature.Alternative medications such asmethyl-dopa are used for their anti-hypertensive and renoprotectiveproperties. A recent study showedthat early and aggressive antihyper-tensive therapy with methyl-dopa inpatients with preexisting renal diseaseimproved fetal outcome.18

PreeclampsiaPreeclampsia is characterized by ges-tational hypertension (blood pressure

140/90 mm Hg) and proteinuria (uri-nary protein 0.3 g/24 h) with onsetafter 20 weeks gestation. Although theprecise etiology of this disease is un-known, various theories including vas-cular damage, immunologic phenom-ena, and dietary deficiencies are amongthe leading suspects.6

Pregestational diabetes mellitus, asseen with T1DM patients, is a well-known risk factor for preeclampsia.19

The risk of developing preeclampsiain gravid T1DM patients is between12% to 15%, compared with 5% to7% in the general population.3,19 Inpatients with preexisting nephropathythe risk rises to as much as 50%.13

Preterm LaborT1DM patients have an increased riskof preterm delivery. A recent cohortstudy20 demonstrated that preterm de-livery rates were as high as 24% inT1DM patients. This value agrees withthose previously reported, whichranged between 26.2% and 31.1%.19,21

The indicated preterm delivery rate inthe cohort study was 15%, comparedwith values of 16.5% and 21.9% in the2 older studies. Spontaneous pretermdeliveries were also elevated at 9%.20

Previous studies have been limiteddue to the lack of controlled variablessuch as diabetes complications, pre-conception glycemic control, glycemiccontrol throughout the pregnancy,and new fetal-monitoring modalities.By following these parameters, thephysicians behind the recently pub-lished cohort study were able toconclude that HbA1C at delivery wassignificantly associated with sponta-neous preterm delivery. The progres-sion of nephropathy and developmentof preeclampsia, alongside HbA1Clevels, were all significantly associ-ated with preterm delivery. Interest-ingly, these authors did not notemacrosomia and polyhydramnios tobe significantly correlated with spon-taneous preterm delivery.20

Fetal OutcomeThe rate of fetal malformations (7.7%vs 7.3%) and spontaneous abortions(4.3% vs 2.2%) approaches that of thegeneral population with good gly-cemic control.22 In a study by Hansonand colleagues,22 a direct relationshipbetween HbA1C and the rate of fetalmalformation was noted. Patients whomaintained HbA1C levels between 5%and 6% had a normal pregnancy,whereas those with levels 10.1%showed an incidence of neonatal mal-formation between 20% and 25%.22

The prevalence of macrosomia in in-fants of diabetic mothers has remainedconstant throughout the years, evenwith tighter glucose control and ad-vances in insulin therapy.13 The risk ofshoulder dystocia during vaginal de-livery doubles when fetal weight is 4000 g.23

ManagementPreconceptionSuccessful management of pregnancyin a T1DM patient begins before con-ception. Research indicates that theimplementation of preconceptioncounseling, emphasizing strict gly-cemic control before and throughoutpregnancy, reduces the rate of perina-tal mortality and malformations.24

The 2008 bulletin from the National



Blood Glucose and HbA1C

% mg/dL

6.0 126

6.5 140

7.0 154

7.5 169

8.0 183

8.5 197

9.0 212

10.0 240

HbA1C, glycosylated hemoglobin levels

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Institute for Health and Clinical Ex-cellence recommends that preconcep-tion counseling be offered to allpatients with diabetes. Physicians areadvised to guide patients on achievingpersonalized glycemic control goals,increasing the frequency of glucosemonitoring, reducing their HbA1Clevels, and recommend avoiding preg-nancy if said level is 10%.25 Othersources suggest deferring pregnancyuntil HbA1C levels are 8%, as thismargin is associated with better out-comes.22 The latest ACOG PracticeBulletin also suggests a thoroughevaluation aimed at uncovering anyunderlying vascular damage. Thisincludes retinal examination by anophthalmologist, 24-hour urine pro-tein and creatinine clearance, andelectrocardiography.23

Dietary GuidelinesDietary recommendations by ACOGemphasize the need for carbohydratecounting and bedtime snacks to pre-vent nocturnal hypoglycemia. Theseguidelines allow for only a 300kcal/day increase from basal calorieconsumption, with a target of 30 to35 kcal/kg/day in females with nor-mal body weight. In patients weigh-ing 120% of their ideal bodyweight, the caloric requirementsshould be restricted to 24 kcal/kg/day.The majority of the diet should becomposed of complex, high-fiberfoods.23 Patients should aim toachieve pre-meal plasma glucose lev-els of 100 mg/dL, followed by 1-hour postprandial levels 140 mg/dL,and 2-hour levels 120 mg/dL.HbA1C levels should remain below6% and overnight values should becontrolled following the same guide-lines, with values no lower than 60 mg/dL.3,23 HbA1C values can beobtained every month, in contrast tothe standard 3-month period, due toincreased red blood cell productionand turnover during pregnancy.26

Glycemic ControlInsulin management is usually tai-lored to the individual patient. Mostadvocate the use of a regular orquick-acting insulin regimen to covermealtime glucose changes, and anintermediate or long-acting insulinbolus twice a day.8,26,27 A randomized,controlled trial published in the

British Medical Journal demonstratedthat the 4-times daily regimen im-proved maternal glycemic control andreduced neonatal complications, com-pared with the twice-daily regimen.In addition, the rates of maternalcomplications during the pregnancywere the same between both dosingregimens.28 The twice-daily regimenallows for increased frequency ofhyperglycemia and nocturnal hypo-glycemic events. Continuous infusionmethods using insulin pumps donot significantly improve outcome,and are suggested only for pregnan-cies complicated with difficultglycemic control and high Whiteclassification.29

Recent developments in alternativeinsulin formulations have increasedthe options patients and physicianshave at their disposal. Although regu-lar human insulin still serves as thebenchmark for mealtime boluses, therapid-onset insulin analogs lispro andaspart have become drugs of choice.Most clinical retrospective trials showno difference in the perinatal out-comes between regimens usinghuman insulin or insulin lispro. In-stead these studies showed that betterpostprandial glucose control wasachieved using the rapid-onset for-mulation.30 Insulin aspart showedsimilar results in a recent study when

used in combination with isophaneinsulin (NPH) as the intermediate-acting insulin. This study demon-strated a tendency toward betterpostprandial glycemic control and asimilar maternal profile when com-pared with human insulin.31

Long-acting insulin formulationshave also been developed in recent

years. Insulin glargine and insulindetemir have come onto the marketas long-acting, peakless formula-tions. Initial studies comparingonce-daily glargine against a twice-daily NPH demonstrated no differ-ence in glycemic control and nochanges in maternal/fetal out-come.32-34 A recent prospective studyconsisting of 56 pregestational dia-betes patients showed improved ma-ternal and perinatal outcomes whencompared with patients receivingNPH.35 In this study, all patients re-ceived insulin lispro as their prandialbolus insulin.

There have been recent concernsover the safety of insulin glargineduring pregnancy due to possible mi-togenic properties in the unbornfetus. Insulin glargine has beenshown to have between 6- and 18-fold greater IGF-receptor bindingaffinity in osteosarcoma cell lines.36

Interestingly, a recent retrospectivestudy involving 102 pregnancies ofT1DM mothers, all of whom used in-sulin glargine throughout their preg-nancy, showed no increase in congen-ital malformations or perinatalcomplications.37 Transplacental per-fusion studies have shown that, ifadministered at therapeutic levels,insulin glargine does not cross theplacenta.38

Insulin management is usually tailored to the individual patient. Mostadvocate the use of a regular or quick-acting insulin regimen to covermealtime glucose changes, and an intermediate or long-acting insulin bolustwice a day.

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Insulin detemir, although also along-acting, peakless formulation, re-quires twice-daily dosing due to a de-creased duration of action.30 Studies todetermine the efficacy of insulin deter-mir compared with NPH are ongoing.Even with data supporting their safetyand efficacy, neither insulin glarginenor insulin detemir is currently indi-cated for use during pregnancy.30

Titration of plasma glucose levelsduring labor can be achieved using

intravenous (IV) infusions of regularinsulin and 5% dextrose. If labor isplanned, ACOG guidelines indicatethat the morning dose of insulinshould be withheld, and IV dosingshould not be initiated until bloodglucose reaches 110 mg/mL. At thatpoint, regular insulin should be ad-ministered at a 1.25 U/hour rate tokeep plasma glucose levels below 110mg/dL. If levels fall to 70 mg/dL orbelow, a 5% dextrose solution should

be started at a rate of 100-150mL/hour. Blood glucose levels shouldbe measured at bedside every hour.23,27

After delivery, insulin sensitivityincreases greatly due to the rapid de-cline of hormonal influences.27 Pa-tients quickly return to their pre-gravid insulin requirements, andinsulin replacement may be restartedat 50% of the gravid dosage as soonas oral nutrient intake resumes(Table 3).23,25,27



Initiate intensive glucose management with a goal of A1C 6.1%. Dietary and diabetic counsel-ing should be offered. Patients with A1C 10% should be counseled against pregnancy.

Comprehensive ophthalmologic examination should be performed.

Baseline serum creatinine and urine albumin/creatinine ratio should be obtained. Counsel patientregarding risk of ESRD if serum creatinine 1.5 mg/dL. Refer to nephrologist if adequate.

Thyroid function tests should also be performed.

Suggest daily multivitamin with at least 400 g of folic acid.

Adequate glycemic control should be maintained. Diabetic counseling should be readily availableto help manage rapidly changing insulin requirements. Consider insulin pump if proper glucosemanagement is not attainable.

Repeat ophthalmologic assessment at 16-18 weeks if baseline retinal examination was abnormal. If normal at baseline, repeat at 28 weeks.

Fetal anatomy scan with 4-chamber cardiac imaging should be performed at 18-20 weeks.

Fetal ultrasound to assess growth and amniotic fluid levels should be performed every 4 weeksafter 28 of weeks gestation.

Biweekly fetal monitoring (NST) can be started at 32 weeks of gestation, or earlier if warranted.

Daily fetal movement counts should be encouraged starting at 28 weeks.

Cesarean delivery should be suggested if fetal size is estimated to be 4500 g.

Fetal lung maturity should be assessed via L/S ratio and phosphatydilglycerol if delivery isplanned before 39 weeks.

Fetal and maternal well-being should be considered when deciding timing and method of delivery.

During labor intravenous access should be established and maintained with normal saline.

Blood glucose should be titrated to a level of approximately 100 mg/dL with 5% IV dextroseand/or IV regular insulin.

Bedside blood glucose should be checked every hour.

Insulin may be reduced to 50% of predelivery requirements after adequate oral intake.

Insulin replacement should be tailored to achieve proper glycemic control and reduce hypoglycemic events.

Breastfeeding is encouraged, but patient should be counseled about increased risk of hypo-glycemia with breastfeeding.

ESRD, end-stage renal disease; IV, intravenous; L/S, lecithin/sphingomyelin; NST, non-stress test.

Postpartum

Labor and Delivery

Gestation

Preconception

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ConclusionsT1DM affects a small percentage ofpregnancies each year, but posesgreat risk to the pregnant mother anddeveloping fetus. Intensive counsel-ing before conception and throughoutpregnancy seems to decrease theprobability of complications and fetalmalformations. Individualized ap-proaches to glycemic control and fre-quent follow-up visits increase the

complexity of management, particu-larly in the noncompliant patient.

Recent advances in the manage-ment of T1DM have started to crossinto the field of obstetrics. Althoughsome novel insulin formulations lackUS Food and Drug Administrationapproval for use in pregnancy, theiruse is widely accepted. Further re-search is needed to address the safetyand efficacy of new insulin, as their

ease-of-use should increase com-pliance and ultimately improveglycemic control.

References1. Centers for Disease Control. National diabetes fact

sheet: general information and national estimateson diabetes in the United States, 2007. Atlanta, GA:Centers for Disease Control and Prevention, Department of Health and Human Services; 2008.

2. Gibbs RS, Danforth DN. Danforths Obstetricsand Gynecology. 10th ed. Philadelphia: WoltersKluwer Lippincott Williams & Wilkins; 2008.

3. Garner P. Type I diabetes mellitus and preg-nancy. Lancet. 1995;346:157-161.

4. White P. Pregnancy complicating diabetes. Am JMed. 1949;7:609-616.

5. Atkinson MA, Eisenbarth GS. Type 1 diabetes:new perspectives on disease pathogenesis andtreatment. Lancet. 2001;358:221-229.

6. Gabbe SG, Niebyl JR, Simpson JL. Obstetrics:Normal and Problem Pregnancies. 5th ed.Philadelphia, PA: Churchill Livingstone/Elsevier;2007.

7. Kirwan JP, Hauguel-De Mouzon S, Lepercq J, et al. TNF-alpha is a predictor of insulin resis-tance in human pregnancy. Diabetes. 2002;51:2207-2213.

8. Weiss PA, Hofmann H. Intensified conventionalinsulin therapy for the pregnant diabetic patient.Obstet Gynecol. 1984;64:629-637.

9. Garca-Patterson A, Gich I, Amini SB, et al. Insulinrequirements throughout pregnancy in womenwith type 1 diabetes mellitus: three changes of di-rection. Diabetologia. 2010;53:446-451.

10. Nielsen LR, Rehfeld JF, Pedersen-Bjergaard U, et al. Pregnancy-induced rise in serum C-peptideconcentrations in women with type 1 diabetes.Diabetes Care. 2009;32:1052-1057.

Main Points Before insulin therapy, infertility was the most common consequence of type 1 diabetes mellitus (T1DM) on reproductive-age

women. When pregnancy did occur, fetal and neonatal mortality was as high as 60%. Aggressive maternal-fetal management, ad-vances in insulin therapy, and improvements in neonatal intensive care units have decreased this figure to 2% to 5%.

T1DM patients are at increased risk for complications such as hypoglycemia, diabetic ketoacidosis, retinopathy, nephropathy,preeclampsia, and preterm labor.

Successful management of pregnancy in T1DM patients begins before conception with the implementation of preconception coun-seling that emphasizes the need for strict glycemic control before and throughout pregnancy. Physicians should guide patients onachieving personalized glycemic control goals, increasing the frequency of glucose monitoring, reducing their glycosylated he-moglobin levels levels, and recommend the avoidance of pregnancy if levels are 10%.

Dietary recommendations from the American College of Obstetrics and Gynecology emphasize the need for carbohydrate count-ing and bedtime snacks to prevent nocturnal hypoglycemia. Guidelines allow for only a 300 kcal/day increase from basal calorieconsumption, with a target of 30 to 35 kcal/kg/day in women with normal body weight and 24 kcal/kg/day for women weighing 120% of ideal body weight.

Recent advances in the management of T1DM have begun to cross into the obstetrics domain. Although novel insulin formulationslack US Food and Drug Administration approval for use in pregnancy, their use is widely accepted. Additional research is neededto address the safety and efficacy of new insulin, as their ease-of-use should increase compliance and improve glycemic control.

Table 3Insulin Replacement

Mealtime Bolus

Insulin Source Onset Duration (h) Peak (h)

Novolin/Humulin R Human 30 min 5-8 2-5

Lispro Synthetic 15 min 4-5 0.5-1.5

Aspart Synthetic 15 min 3-5 1-3

Intermediate/Long-Acting:

NPH Human 1-2 h 18-24 6-12

Glargine Synthetic 1 h 24 None

Detemir Synthetic 1-2 h 24 (12) None

NPH, isophane insulin.Data from Gabbe SG et al6 and Torlone E et al.30

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11. Rosenn BM, Miodovnik M, Khoury JC, SiddiqiTA. Counterregulatory hormonal responses tohypoglycemia during pregnancy. Obstet Gynecol.1996;87:568-574.

12. Cecil RL, Goldman L, Ausiello DA. Cecil Medi-cine. 23rd ed. Philadelphia: Saunders Elsevier;2008.

13. Reece EA, Coustan DR, Gabbe SG. Diabetes inWomen: Adolescence, Pregnancy, and Menopause.3rd ed. Philadelphia: Lippincott Williams &Wilkins; 2004.

14. Kronenberg H, Williams RH. Williams Textbookof Endocrinology. 11th ed. Philadelphia: Saun-ders/Elsevier; 2008.

15. Chew EY, Mills JL, Metzger BE, et al. Metaboliccontrol and progression of retinopathy. The Dia-betes in Early Pregnancy Study. National Insti-tute of Child Health and Human DevelopmentDiabetes in Early Pregnancy Study. DiabetesCare. 1995;18:631-637.

16. Loukovaara S, Immonen I, Teramo KA, Kaaja R.Progression of retinopathy during pregnancy intype 1 diabetic women treated with insulinlispro. Diabetes Care. 2003;26:1193-1198.

17. Brenner BM, Rector FC. Brenner & Rectors TheKidney. 8th ed. Philadelphia: Saunders Elsevier;2008.

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