Dicker et al, Pregnancy planning in diabetics and insulin therapy 161

J. Perinat. Med.15 (1987) 161

Preconceptional diabetes control in insulin-dependent diabetes mellituspatients with continuous subcutaneous insulin infusion therapy

Dov Dicker, Dov Feldberg, Moshe Karp1, Arie Yeshaya, Nurith Samuel, andJack A. Goldman

Department of Obstetrics and Gynecology, Golda Meir Medical Center, and1PThe Institute of Pediatric and Adolescent Endocrinology, Division of JuvenileDiabetes, Beilinson Medical Center, Tel-Aviv University Medical School, Pe-tah-Tikva, Israel

1 Introduction

Programs for maintaining glucose levels strictlywithin normal ranges have improved the out-come of pregnancies complicated by diabetesmellitus [4,10,11]. The diabetic pregnancy con-tinues to present a significant risk for congenitalmalformations and neonatal morbidity [3, 14,15, 20, 21]. It seems that further improvementin the outcome of these pregnancies may beobtained if normal glucose levels are accom-plished before conception, to reduce the inci-dence of congenital malformations [5, 15, 22]and throughout the pregnancy to lower theincidence of macrosomia [3, 23]. This may beachieved with conventional two-dose or mul-tiple insulin injections. Recently, continuoussubcutaneous insulin infusion devices have beenintroduced to improve diabetic control in boththe nonpregnant and pregnant diabetic patient[8, 18, 24]. The value of these insulin pumpsmust be critically assessed. Furthermore colla-borative efforts of the diabetology team (dia-betologist, dietitian, obstetrician, psychologist,social worker and nurse), as well as the patient,through self blood glucose monitoring (SBGM)is mandatory.The purpose of this study was to critically com-pare and assess glucose control and the out-

come of diabetic pregnancies, with preconcep-tional phase counseling, by means of continu-ous subcutaneous insulin infusion therapy tothose receiving insulin injections.

2 Material and methods

Between the years 1981-1985 eighty-three ju-venile onset insulin dependent diabetes mellitus(IDDM) pregnant women were treated at theHigh-Risk Obstetrical Outpatient Clinic of theGolda Meir Medical Center in association withthe Institute of Pediatric and Adolescent Endo-crinology, Division of Juvenile Diabetes, Beilin-son Medical Center in Israel. Fifty-two patientscontemplating pregnancy attended the precon-ceptional clinic and were consulted by a dia-betology team (obstetrician, diabetologist, die-titian, psychologist, social worker and nurse).Two patients were advised against pregnancy,because of severe malignant retinopathy. Theywere permitted to conceive following laser ther-apy. Thirty-one patients who attended the clinicat different stages of pregnancy were deletedfrom the study. All patients completed theirpregnancies and had delivered by the time ofthis report. In order to obtain optimal diabetescontrol before conception and to maintain nor-

1987 by Walter de Gruyter & Co. Berlin · New York

162 Dicker et al, Pregnancy planning in diabetics and insulin therapy

mal glucose levels throughout pregnancy theinsulin need based on body weight was calcu-lated (0.6 U/kg/24h = pregestational; 0.7 U/kg/24h = first trimester; 0.8 U/kg/24h = se-cond trimester; 0.9 U/kg/24h = third trimester;1.0 U/kg/24h = term). The total amount of in-sulin required was divided into insulin amountsthat provided the basal needs and the bolusneeds. Continuous subcutaneous insulin infu-sion pumps (CSIIP), Auto Syringe AS-G6, Me-dix 209/100 Insulin Pump, and recently theNordisk Infuser were used in 18 women. Thirty-four women received three to four injections aday of intermediate (NPH) and short-acting(regular) insulin. All patients were advised toadhere closely to their strict, prescribed diet,(American Diabetes Association diets1800-2200 Kcal/day), divided into three mealsand two to three snacks. All patients performedself blood glucose monitoring 6 — 8 times a dayusing glucose meters and charted the bloodglucose levels. Hemoglobin Ai was measured

twice monthly by cation exchange column chro-matography using microcolumn fast hemoglo-bin test system (Isolab, Akron, OHIO, USA).The normal range in our laboratory is 6.0 — 7.5percent.After the glycosylated hemoglobin levels in thepatients were below 8.5%, which was the cutoffline for increased risk of malformations in MIL-LER'S report [14], they were encouraged to con-ceive. In order to facilitate the very early diag-nosis of pregnancy, patients were asked tomeasure basal body temperature through eachmenstrual cycle. The beta subunits of HCG wasdetermined after a month had elapsed since thelast menstrual period; if the test was negativeit was repeated at weekly intervals while amen-orrhea persisted.Antepartum surveillance included: monthly ul-trasound imaging for fetal growth or anomaliesafter 8 weeks' gestation [16], daily fetal move-ments count after 20 — 22 weeks' gestation [19],

Table I. Diabetes control in 52 IDDM pregnancies with preconceptional therapy.

Period CSIIP(n = 18)

MeanHb Ai(%)

Mean bloodglucose(mg%)

Mean dailyinsulindose (U)

Initial visitAt conception1st trim.2nd trim.3rd trim.

Initial visitAt conception1st trim.2nd trim.3rd trim.

Initial visitAt conception1st trim.2nd trim.3rd trim.

10.777.437.467.367.21

179114124112109

3939445062

++++±

±+±±+

±±±+±

0.490.340.340.340.33

11.27.27.87.06.9

33345

IIT Normal(n = 34)

10.527.567.687.397.31

175117128113110

4242485976

++±±±

±±±+±

±±±±+

0.480.340.350.340.33

11.27.38.07.16.9

33446

(n =

6.766.636.386.436.48

9695919498

pregnant P**20)

±+±±±

±±±++

_————

0.3*0.290.290.290.29

5.90*5.905.605.906.10

N.SN.SN.SN.SN.S

N.SN.SN.SN.SN.S

N.SN.SN.S

< 0.05< 0.001

* Normal non pregnant** Statistical analysis by Students' t testAbbreviations used: CSIIP — Continuous Subcutaneous Insulin Infusion Pump

IIT — Intensified Insulin TherapyNS - Not SignificantTrim — Trimester

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Dicker et al, Pregnancy planning in diabetics and insulin therapy 163

and weekly fetal biophysical profile after 28weeks' gestation [13]. Fetal lung maturity wasevaluated by means of lung profile [12] andamniotic fluid microviscosity [1]. Timing androute of delivery were individualized accordingto maternal and fetal conditions.

3 Results

Table I presents diabetes control and insulinrequirements in the 52 IDDM pregnant womentreated prior to conception with CSIIP or withintensified insulin therapy.

In both groups mean blood glucose levels andmean HbAi were elevated at the initial clinicvisit prior to pregnancy, but normal HbAi aswell as physiologic blood glucose levels wereachieved at conception and by the first trimesterand maintained throughout the pregnancy.Nevertheless, in spite of the almost similardegree of improved diabetic control in bothgroups significantly lower mean daily insulindoses were required during the second(50 ± 4 U; p < 0.05) and third trimesters(62 ± 5 U; P < 0.001) of pregnancy by patients

using infusion pumps in comparison to patientsreceiving intensified insulin therapy. Maternalinformation concerning the 52 gestations withpreconceptional therapy is presented in tableII. Patients using CSIIP were older, of higherparity and had a longer duration of diabetes aswell as more frequent secondary complications.According to White's classification [25] 66.6%of pump users were classified in groups D — Rwhereas only 26.5% of the patients receivinginsulin injections were in the same White'sgroups. The frequencies of pre-eclampsia andcesarean deliveries among pump users werehigher than in patients managed with insulininjections.

In two patients treated with intensified insulinregimen hypoglycemia occured overnight in the3rd trimester. In one woman on the pump, tem-porary hypoglycemia occured in the first tri-mester shortly after the pump's installation.Neonatal data are presented in table III. Meangestational age, mean birth weights, Apgarscores and neonatal complications were notsignificantly different in both groups. No mal-formations were detected in offspring of bothgroups.

Table II. Maternal information on 52 IDDM gestants.

Variable

Mean maternal age (yr)Mean duration of diabetesWhite's classificationABCDFRParityMean duration of pregnancy (wks)Mean weight gain (kg)Pre-eclampsia (%)Cesarean section (%)

CSIIP(n = 18)

26.1 ± 7.116.4 ± 6.6

—157142.3

38.3 ± 0.513.4 + 3.822.244.4

IIT(n = 34)

22.1 ± 3.212.6 ± 5.4

—8

178

—11.9

39.1 + 0.514.2 + 4.18.8

23.5

Abbreviations used: CSIIP — Continuous Subcutaneous Insulin Infusion PumpIIT — Intensified Insulin Therapy

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164 Dicker et al, Pregnancy planning in diabetics and insulin therapy

Table ΙΠ. Neonatal data on 52 infants of IDDM mothers with preconceptional therapy.

Variable

Mean gestational age (wk)Mean birth weight (gm)Mean 1 minute ApgarMean 5 minutes ApgarHypoglycemia [< 30 mg per 100 ml] (%)Hypocalcemia [< 8 mg per 100 ml] (%)Hyper bilirubinemia [> 15 mg per 100 ml] (%)Respiratory distress syndrome (%)

CSIIP(n = 18)

38.3 +3284.5 +

8.1 ±9.0 +

11.15.6

11.15.6

0.5233.2

0.70.8

IIT(n = 34)

39.1 ±3346.1 +

8.4 +9.2 +

11.88.8

11.85.8

0.5237.6

0.70.8

p*

NSNSNSNSNSNSNSNS

* Statistical analysis by Students' t test.Abbreviations used: CSIIP — Continuous Subcutaneous Insulin Infusion Pump

IIT — Intensified Insulin TherapyNS - Not Significant

4 Comment

The emerging evidence that congenital malfor-mations in pregnancy complicated by diabetesmay be linked to disturbances in maternal glu-cose metabolism during the period of embryog-enesis [2, 9, 15, 20] provides a case for theinstitution of strict diabetic control prior toconception. Clinical evidence to support thatposition already has been documented [5, 14,22]. The need is underscored by the fact thatorganogenesis is completed by the 6th or 7thweek of gestation in most of the structures inwhich diabetes related birth defects tend tooccur [15], which is before the patient mayknow that she is pregnant and has not yet cometo medical supervision. Normal glucose levelscan be achieved in pregnant diabetic patientsprior to conception and maintained throughoutpregnancy either by conventional two-dose ormultiple insulin injections [4, 6] as well as withthe use of the newer insulin infusion pumps [8,17,18]. Optimal therapy necessitates individual-ization. Beyond the 28th week, when anti-insu-lin factors attain peak intensity, most pregnantwomen in our Center obtain additional multiple(regular) insulin injections. In fact, the precisedoses are adjusted to achieve good metaboliccontrol. Moreover, we recommend CSIIP inselected, well motivated patients with severediabetes contemplating pregnancy.

Our findings reflect the fact that successful glu-cose control can be obtained in pregnant dia-betic patients prior to and throughout preg-nancy, with the use of CSIIP as well as withintensified insulin therapy. The cost/benefit ra-tio is, in favor of IIT because it is cheaper toprovide. It is necessary to note that patientswith intensified insulin therapy required signifi-cantly higher doses of insulin during the secondand third trimester of pregnancy in comparisonto pump users. Indeed, excessive insulin dosesbecomes a concern since the consequences ofexcessive insulin may compromise both themother and the fetus with hypoglycemia andby suppressing the levels of alternate fetal fuels,such as plasma beta hydroxybutyrate [7]. Infact, patients on intensified insulin therapy inthis study had occasional overnight hypoglyce-mia, while pump users achieved normal glucoselevels without overt insulin administration.Insulin pumps were advantageous during inter-current illness, as adjustment to rapid changesin insulin requirements could be made easilyand effectively, even in the home environment.Patients accepted the pump system well; mainlythe smaller, compact devices were more accept-able. No serious complications resulted fromthe continuous subcutaneous infusion systemduring this study. One pump underwent amechanical "run away", and insulin administra-

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Dicker et al, Pregnancy planning in diabetics and insulin therapy 165

tion was discontinued temporarily. The patientwas given I. V. glucose 10% and extra snacksuntil normal glucose levels were achieved whennormal insulin/diet schedule was resumed.In spite of the successful CSIIP therapy in thisseries it can not be recommended for everydiabetic patient prior to and during gestation,and it should remain an investigational tool.Specific selective criteria for well motivatedpatients need to be established. Although pumpusers in this group had a higher rate of pre-eclampsia which contributed in part to thehigher cesarean section rates, we consider thatmore of these patients had more severe diabetes(66% - White's class D-R).

Our data emphasize the improved metaboliccontrol achieved by either technique in thisseries. We feel that establishment of tight meta-bolic control before conception and duringpregnancy contributed to better control of dia-betes, particularly at the crucial time of concep-tion. The reduction of congenital malformationrates due to preconceptional diabetic controlmust further be studied and proven.We must conclude on the basis of this study,that in spite of the advantageous use of CSIIPin selected cases, the disadvantages of thesedevices, as well as good results achieved withIIT, favor the use of the latter in the treatmentof the pregnant diabetic.

Summary

Preconceptional diabetes management is an importantprerequisite for pregnancy planning and its value hasbeen well-documented. Glucose control and the outcomeof pregnancy, managed in the preconceptional period,with continuous subcutaneous insulin infusion therapyto those receiving insulin injections are compared.Fifty-two juvenile onset insulin dependent diabeticwomen contemplating pregnancy were regularly con-sulted by a diabetology team starting at least two monthsbefore conception. Glucose control was achieved bycontinuous subcutaneous insulin infusion pumps(CSIIP) in 18 patients, and 34 women received intensive

insulin therapy (IIT). In both groups, normal glucoselevels and normal HbAi were achieved at conception,maintained during the period of organogenesis andthroughout pregnancy.In view of the fact that perinatal results, such as theoccurrence of malformations, mean gestational age,mean birth weight and neonatal complications were notsignificantly different in both groups, we believe thatboth methods are equally effective. Consequently, theless costly and yet effective IIT may be the method ofchoice, while the more expensive pump should be usedmainly in selected cases.

Keywords: Diabetes mellitus, diabetic pregnancy, insulin infusion pump, preconceptional diabetes control, preg-nancy planning in diabetics.

Zusammenfassung

Diabeteseinstellung vor der Konzeption bei insulinabhängi-gen Patientinnen mit kontinuierlicher subkutaner Insulin-infusionDie Bedeutung der Diabeteseinstellung vor einer geplan-ten Schwangerschaft ist bekannt und nachgewiesen. Be-reits vor der Konzeption erhielten die Frauen entwedereine kontinuierliche subkutane Insulininfusionstherapieoder Insulininjektionen in üblicher Weise. Wir habendiese beiden Kollektive hinsichtlich ihrer Blutzuckerspie-gel und der Schwangerschaftsverläufe miteinander ver-glichen.50 Frauen mit insulinabhängigem juvenilen Diabetes,die eine Schwangerschaft planten, wurden mindestens 2Monate vor Konzeption von Diabetologen beraten. Bei18 Patientinnen wurde der Glukosespiegel mit subkuta-nen Insulininfusionen über eine Pumpe eingestellt, 34

Patientinnen erhielten Insulingaben in üblicher Form,wurden aber strenger eingestellt. In beiden Gruppenwurde eine Normoglykämie und ein normaler Hb Ai-Wert bei Konzeption erreicht, die auch in der Phase derOrganogenese und über die gesamte Schwangerschaftaufrechterhalten werden konnten.Im Hinblick auf verschiedene perinatale Parameter wieHäufigkeit von Mißbildungen, durchschnittliches Gesta-tionsalter und Geburtsgewicht sowie neonatale Kompli-kationen gab es zwischen beiden Gruppen keine signifi-kanten Unterschiede, so daß wir glauben, daß beideMethoden gleich effektiv sind. Die weniger kosteninten-sive und dennoch effektive strenge Einstellung mit Insu-lininjektionen sollte die Methode der Wahl sein, wäh-rend die teure Insulinpumpe hauptsächlich ausgewähltenFällen vorbehalten sein soll.

Schlüsselwörter: Diabeteseinstellung vor Konzeption, Diabetes mellitus, Diabetes und Schwangerschaft, Insulin-infusionspumpe, Schwangerschaftsplanung bei Diabetes.

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166 Dicker et al, Pregnancy planning in diabetics and insulin therapy

Resume

Contröle du diabete avant la conception chez les patientesinsulino-dependantes par perfusion continue d'Insulinesous-cutaneeL'equilibre du diabete avant la conception est une neces-site importante pour la plannification de la grossesse etsa valeur est bien documentee. On compare le contröleglycemique et le devenir de la grossesse chez des patientesprises en charge a la periode pre-conceptionnelle ä aidede perfusion continue d'Insuline sous-cutanee a ceux depatientes traitees par injections d'Insuline.Cinquante deux femmes atteintes d'un diabete insulino-dependant a debut juvenile, souhaitant une grossesseont etc suivies regulierement par une equipe diabetologi-que en debutant au moins deux mois avant la concep-tion. Chez 18 patientes, le contröle glycemique etaitrealise ä aide de pompes ä perfusion continue d'Insuline

sous-cutanee (CSIIP), chez 34 de contröle etait realisepar une augmentation de l'insulinotherapie (ITT). Dansles deux groupes, ä la conception une glycemie normaleet une HbAi normale etaient obtenues et maintenuespendant toute la periode d'organogenese et tout au longde la grossesse.Nous pensons que les 2 methodes sont equivalentes dansla mesure ou les resultats perinataux, comme le tauxde malformations, Page gestationnel moyen, le poid denaissance moyen et les complications neonatales ne sontpas differents de fagon significative dans les deux grou-pes.Par consequent, la methode de choix est ITT qui estla plus economique et neanmoins aussi efflcace, alorsque les pompes, beaucoup plus couteuses, devraient etrereservees principalement a des cas selectionnes.

Mots-cles: Contröle pre-conceptionnel du diabete, diabete sucre, grossesse chez la diabetique, plannification desgrossesses chez la diabetique, pompe a perfusion d'Insuline.

References

[1] BARKAI G, S MASHIACH, D LANZER, Z KAYAM, MBRISK, B GOLDMAN: Determination of fetal lungmaturity from amniotic fluid microviscosity in highrisk pregnancy. Obstet Gynecol 59 (1982) 615

[2] COCKROFT DL, M FREINKEL, LS PHILLIPS, GESHAMBAUGH: Metabolic factors affecting organo-genesis in diabetic pregnancy. Clin Res 23 (1981)577 A

[3] ENZI G, EM INELMEN, F CARETTA, F VILLANI, VZANARDO, F DEBIASI: Development of adiposetissue in newborns of gestational-diabetic and insul-in-dependent diabetic mothers. Diabetes 29 (1980)100

[4] FREINKEL N, BE METZGER, JM POTTER: Pregnancyin diabetes. In: ELLENBERG M, H RIFKIN (eds):Diabetes Mellitus Theory and Practice,pp 689 —714. Medical Examination Publishing,New York 1983

[5] FUHRMANN K, H REIHER, K SEMMLER, F FISHER,M FISHER, E GLOCKNER: Prevention of congenitalmalformations in infants of insulin dependent dia-betic mothers. Diabetes Care 6 (1983) 219

[6] GABBE SG: Medical complications of pregnancymanagement of diabetes in pregnancy, six decadesof experience. In: PITKIN RM, FJ ZLATNIK (eds):Year Book of Obstetrics and Gynecology, Part I,pp 37-49. Year Book, Chicago 1980

[7] GIRARD JR: Metabolic fuels of the fetus. Isr J MedSei 11 (1975) 591

[8] HERTZ RH, KC KING, SC KALHAN: Managementof third trimester diabetic pregnancies with the useof continuous subcutaneous insulin infusion ther-apy: A pilot study. Am J Obstet Gynecol 149 (1984)256

[9] HORTON WE JR, TW SADLER: Effects of maternaldiabetes on early embryogenesis: alterations in mor-phogenesis produced by the ketone body, beta-hydroxybutyrate. Diabetes 32 (1983) 610

[10] JOVANOVIC L, M DRUZIN, CM PETERSON: Effect ofeuglycemia on the outcome of pregnancy in insulin-dependent diabetic women as compared with nor-mal control subjects. Am J Med 71 (1981) 921

[11] KITZMILLER JL, JP CLOHERTY, MD YOUNGER, ATABATABII, SB ROTCHILD, I SOSENKO, MF EPSTEIN,S SINGH, RK NEFF: Diabetic pregnancy and perin-atal morbidity. Am J Obstet 131 (1978) 560

[12] KULOVTCH MV, L GLUCK: The lung profile II. Com-plicated pregnancy. Am J Obstet Gynecol 135(1979) 64

[13] MANNING FA, LC PLATT, L SIPOS: Antepartumfetal evaluation: Development of a fetal biophysicalprofile. Am J Obstet Gynecol 136 (1980) 787

[14] MILLER E, JW HARE, JP CLOHERTY, PJ DUNN, REGLEASON, JS SOELDNER, JL KITZMILLER: Elevatedmaternal HbAlc in early pregnancy and major con-genital anomalies in infants of diabetic mothers. NEngl J Med 304 (1981) 1331

[15] MILLS JL, L BAKER, AS GOLDMAN: Malformationsin infants of diabetic mothers occur before theseventh gestational week. Implications for treat-ment. Diabetes 28 (1979) 292

[16] PEDERSEN JF, L MOLSTED-PEDERSEN: Early fetalgrowth delay detected by ultrasound marks in-creased risk of congenital malformations in diabeticpregnancy. Br Med J 283 (1981) 2691

[17] POTTER JM, JPD RECKLESS, DR CULLEN: Subcu-taneous continuous insulin infusion and control ofblood glucose concentrations in diabetics in thirdtrimester of pregnancy. Br Med J 1 (1980) 1099

J. Perinat. Med. 15 (1987)

Dicker et al, Pregnancy planning in diabetics and insulin therapy 167

[18] RUDOLF MCJ, DR COUSTAN, RS SHERWIN, SE BA- [23] SUSA JB, C NEAVE, P SEHGAL, DB SINGER, WPTES, P FELIG, M GENEL, WV TAMBORLANE: Efficacy ZELLER, R SCHWARTZ: Chronic hyperinsulinemia inof the insulin pump in the home treatment of preg- the fetal Rhesus monkey: effects of physiologicnant diabetics. Diabetes 30 (1981) 891 hyperinsulinemia on fetal growth and composition.

[19] SADOVSKY E, H JAFFE, WZ POLISHUK: Fetal move- Diabetes 33 (1984) 656ment monitoring in normal and pathological preg- [24] TAMBORLANE WV, RS SHERWIN, M GENEL, P FELIG:nancies. Int J Gynecol Obstet 12 (1974) 75 Reduction to normal of plasma glucose in juvenile

[20] SOLER NG, CH WALSH, JM MALINS: Congenital diabetes by subcutaneous administration of insulinmalformations in infants of diabetic mothers. Q J with a Portable infusion pump. N Engl J Med 300Med 178 (1976) 303 (1979) 573

[21] SOLER NG, SM SOLER, JM MALINS: Neonatal mor- ^ ^HITE P: Classificationjof obstetric diabetes. Am Jbidity among infants of diabetic mothers. Diabetes Obstet °?η6(Χ)1 13° <1978> 228

Care 1 (1978) 340 Received February 14, 1986. Revised July 17, 1986.[22] STEEL JM, ED JOHNSTONE, AF SMITH, UP DUN- Accepted August 25, 1986.

CAN: Five years experience of a "prepregnancy" Jack A. Goldman, M. D.clinic for insulin dependent diabetics. Br Med J 285 Professor and Chief(1982) 353 Department of Obstetrics and Gynecology

Golda Meir Medical Center (Hasharon Hospital)Petah-Tikva, Israel 49 372

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