Continuous Subcutaneous Insulin Infusion

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“dawn phenomenon” (particularly evident in late pregnancy). [13] of nausea and/or hyperemesis gravidarum. [11] Finally, an increased flexibility in life style (time ...
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, 3, 000-000

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Continuous Subcutaneous Insulin Infusion (CSII) in Diabetic Pregnancy: A Review Angela Napoli*, Camilla Festa, Marzia Dongiovanni, Luca Mattei and Antonietta Colatrella Dept. of Clinical Sciences, 2nd Faculty of Medicine, Sapienza University, Rome, Italy Received: November 11, 2008; Accepted: January 21, 2009; Revised: February 2, 2009

Abstract: In 2008, ADA provided new standards of care and recommendations including therapeutic actions favourably affecting health outcomes of patients with diabetes. In this context, Continuous Subcutaneous Insulin Infusion (CSII) becomes a great flexible therapeutic alternative, because of glucose sensors’ availability, theoretical support and improved therapeutic decisions. However, there are no conclusive studies on the benefits of CSII in pregnancy. In particular, ’80’ randomized and controlled trials describe the pregnancy outcomes of few type 1 and type 2 diabetic patients. A recent Cochrane review, including 61 pregnancies concluded that there is no sufficient evidence to support any sort of insulin administration in diabetic pregnancy. Similar conclusions were reported by another review and a meta-analysis of 6 randomized and controlled trials on 213 subjects. No better results were obtained by recent retrospective studies. Doubts exist about CSII timing (before/and or after conception). Poor results are due to the inadequate patients selection, education, and abilities. Multi -centre studies are needed to verify the real utility of insulin pump during pregnancy, considering risks, costs and benefits including quality of life, in order to outline recommendations for an appropriate use. This review article also discussed some recent patents related to the field.

Keywords: CSII, pregnancy. INTRODUCTION In 2008, ADA provided new standards of care and recommendations including therapeutic actions favourably affecting health outcomes of patients with diabetes. Regarding preconception care, HbA1C levels must be as close to normal as possible since conception and throughout all pregnancy, because they are the basis of a favorable outcome for both mother and child [1-3]. However, despite recent progress in the treatment and the ‘89 S.Vincent’s Declaration (proposing to make the risks of a diabetic pregnancy similar to those of a non-diabetic pregnancy, in 5 years) [4], this ambitious target has not yet been achieved [5-8]. ADVANTAGES In this context, Continuous Subcutaneous Insulin Infusion (CSII) becomes a great therapeutic alternative, because glucose sensors’ availability, theoretically support and improve therapeutic decisions [9-10]. It is noteworthy that multiple daily subcutaneous insulin injections ‘MDI schedules’, use different types of insulin (short acting insulin before each meal plus one or more injections of long acting insulins/day) in contrast with CSII. With insulin pump, bolus (simple, double or square waved) can be adapted to the type and duration of meal allowing the control of post-prandial hyperglycaemia secondary to the delayed gastric emptying that is physiological in *Address correspondence to this author at the Dept. of clinical sciences, 2nd faculty of medicine, Sapienza University, Rome, Italy; Tel: +390633775335; Fax: +39-0633775740; E-mail: [email protected] 1872-2148/09 $100.00+.00

pregnancy and further enhanced by diabetic gastropathy, if present. Moreover, it can be injected to correct unexpected hyperglycaemic episodes [11]. On the other side, the basal continuous subcutaneous insulin infusion mimics the physiologic pancreatic insulin secretion. Because of these characteristics, manifold benefits can be reached such as the improvement of metabolic control in terms of: about 0.5% decrease in glycated haemoglobin, reduction of glycaemic variability, and hypoglycaemia (particularly common in the first trimester of pregnancy) [12], partly due to minor variability of insulin absorption when insertion of the infusion set is correctly changed every two or three days. Another advantage is the proper management of the so called “dawn phenomenon” (particularly evident in late pregnancy) [13] of nausea and/or hyperemesis gravidarum. [11] Finally, an increased flexibility in life style (time and type of meals, physical activity etc.) and frequent contacts with the medical team improve the compliance of patients [14]. DISADVANTAGES The costs of insulin pumps and infusion sets are high. Rare pumps malfunctioning or misusing, the infections of placement sites and the exclusive use of rapid insulin associated with greater disposition to ketoacidosis during pregnancy, make ketoacidotic complications easier [14]. RECOMMENDATIONS •

The National Institute for Clinical Excellence recommends the use of insulin pumps, under the guidance of specialized team (doctors, experts in CSII, nurses and dieticians 'specialized' in the treatment of diabetes), in pregnancy planning or during pregnancy of type 1

© 2009 Bentham Science Publishers Ltd.

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diabetic patients, when MDI therapy cannot reduce HbA1c values less than 7.5% or < 6.5%, in the presence of microalbuminuria [15]. •

A Position Statement of American Diabetes Association [16] promotes the use of insulin pumps during pregnancy in the patients who want to improve metabolic control or who wish greater flexibility in meals and activities, see Table 1.

Table 1. Available Recommendations for Insulin Pump in Pregnancy Recommendations Planning of pregnancy or pregnancy in patients with unsatisfying glycaemic control (HBA1c > 7.5% or > 6.5% with microalbuminuria), if follow-up is intensive under specialized team control (CSII expert doctor, diabetes specialist nurse and dietician) Patients asking higher life style’s and diet flexibility;

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National Inst. Clinical Excellence, 2003/2008 [12]

ADA, 2004 [13]

patients with unsatisfying control

Insulin pumps would make the management of morning sickness, hyperemesis gravidarum, glycaemic excursions, hypos, the dawn phenomenon, and postpartum insulin requirement fluctuations easier. Such as Lee et al. inverted an insulin pump, which can efficiently regulate blood glucose concentration [17]. Randomized and controlled trials about CSII in gestation describe the pregnancy outcomes of few, type 1 and type 2 diabetic patients [18-21]. A recent Cochrane review, including 61 pregnancies [22], concludes that there is no sufficient evidence to support any sort of insulin administration, in diabetic pregnancy. Similar conclusions were reported by another review and a meta-analysis [23] of 6 randomized and controlled trials on 213 subjects see Table 2. All these studies showed indistinguishable improvements of glycaemic control between groups (MDI vs CSII) throughout pregnancy, with no different insulinic needs and/or maternalfetal outcomes (length of gestation, mode of delivery, birthweight, perinatal hypoglycaemia and mortality). The higher number of hypos (CSII 22.3% vs MDI 19.2%, Odd Ratio 1.34, p = 0.46) of ketoacidosis (7.1% vs 0.0% episodes, Odd Ratio 3.26, p = 0.23) described in CSII, did not reach the level of significance as well as the progression of retinopathy, (CSII 23.5% vs MDI 11.0%, OR 2.16, p = 0.29). Only one study reported a case of insulin pump disconnection. Equally, recent retrospective studies on type 1 diabetic pregnancies did not report any significant benefit in terms of maternal and fetal outcomes (fetal growth velocity, fetal size, birthweight, maternal glycaemic control) as compared to conventional insulin therapy [24-26], see Table 2. A recent study on 116 type1 diabetic pregnancies also did not show better outcomes as well [27]. It was remarkable to see how analogous results described in pregnancies under CSII, were reported in women with more severe diabetes than that of women under MDI [28]. Another study showed

Napoli et al.

more ketoacidosis episode (CSII 13% ns MDI 1.6%, p=0.04) due to the use of insulin pump, [25] even though the authors concluded that total risk is really low. Recently, a small, nonrandomized study in UK suggests that the use of insulin pump offers no benefit in terms of normalizing fetal growth velocity, fetal size, birthweight or improving maternal glycaemic control as compared to conventional insulin therapy [29]. One [30] of the few studies in type 2 diabetic pregnancy or GDM, requiring more than 100 U/die of insulin, showed the efficacy of insulin pumps in terms of metabolic control and perinatal outcomes. For example, Steil et al. disclosed a method to control and monitor insulin delivery and to optimize the delivery of insulin to achieve a desired blood glucose [31], and recently, Uchino et al. patented a method to optimize insulin infusion rate of a continuous subcutaneous insulin infusion therapy [32]. CSII TIMINGS Ideally insulin pump should be used conception allowing women to achieve both a sufficient 'technical' knowledge and new thinking that would result in a gradual optimization of metabolic control. Positioning the pump in the first trimester of pregnancy, requires even more intensive checks, because of the possible worsening of metabolic control that at this stage could lead to an increased risk of spontaneous abortions or malformations. A negative analysis of costs at start is widely rewarded by the expected reduction of chronic complications and fetal anomalies in following pregnancies [33]. However, Gabbe and colleagues, in a retrospective casecontrol study on type1 diabetic women (24 starting insulin pump during pregnancy, 12 before pregnancy and 24 under MDI), conclude that starting CSII during gestation does not lead to a deteriorating of metabolic control, besides, women are really pleased about the great flexibility of this approach, easing contacts with medical opinion as well, they fruitfully prolong it after delivery [33]. CURRENT & FUTURE DEVELOPMENTS Thanks to our experience of over 25 years in subcutaneous and intraperitoneal continuous insulin infusion inside and outside pregnancy, we think that an imperative condition for success with CSII is patients’ education, motivation, psychological stability and acceptance of illness, in addition to physicians expertise in CSII, possibly supported by a multidisciplinary team. Moreover, patients must be down-to-earth, informed about ‘pro and cons’ of insulin pumps, and acquire the technical skills to handle this new therapy; this phase must verify the patient’s ability and availability to intensively selfmonitor capillary glycaemia, possibly supported by using sensors [11,13]. Finally, patients need to become familiar with carbohydrates’ counting can possibly be supported by partners sharing the training.

CSII in Diabetic Pregnancy

Table 2.

Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2009, Vol. 3, No. 2

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Studies Comparing CSII and MDI in Pregnancy

No. of patients Author (year)

Country

Type of study CSII

MDI

Type of DM

Maternal and fetal Outcomes CSII vs MDI

Coustan (1986)

USA

randomized controlled trial

11

11

IDDM

No difference

Laatikainen (1987)

Finland

randomized controlled trial

13

18

DM type 1

No difference

Botta (1986)

Italy

randomized controlled trial

5

5

DM type 1

No difference

Burkart (1988)

Germany

randomized controlled trial

48

41

DM type 1

No difference

Carta (1993)

Italy

randomized controlled trial

14

15

DM type 1 and 2

No difference

Lapolla (2003)

Italy

Observational retrospective

25

68

DM type 1

No difference

Hieronimus (2005)

France

33

23

DM type 1

No difference

Observational Retrospective

Chen (2007)

USA

Observational

30

60

DM type 1

 rate of maternal DKA + neonatal hypos in CSII

29

29

DM type 1

No difference

Retrospective

Gimenez (2007)

Spain

Observational Retrospective

Kernaghan (2008)

UK

Observational prospective non- randomized

18

24

DM type 1 and 2

No difference

Cypryk (2008)

Poland

Descriptive, Retrospective, Observational

30

86

DM type 1

No difference

CSII use is absolutely contraindicated in patients with severe behavior disorders, inadequate glycaemic selfmonitoring, and non-acceptance of disease.

REFERENCES

These criteria, particularly strict in pregnancy, are not always properly valued in clinical practice.

[2]

CALL TO ACTIONS

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The poor results in term of pregnancy outcomes, obtained through CSII in diabetic pregnancies are likely due to lesser number of women observed in available studies

[4]

Multi -centre studies are needed to verify the real benefits of continuous subcutaneous insulin infusion in diabetic pregnancy, adjusted throughout gestation by intensive capillary glucose monitoring, possibly together with continuous glucose monitoring systems [9-10]. The results in term of pregnancy outcomes, quality of life, risks and costs would outline recommendations for an appropriate use.

[1]

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[9]

CONFLICT OF INTEREST The authors do not have any conflict of interest. [10]

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