Authors: Jothydev Kesavadev  ( Chairman & Managing Director, Jothydev\'s Diabetes Research Center, Trivandrum & Kochi. )

Control of blood glucose during pregnancy is difficult because of wide variations, ongoing hormonal changes and mood swings. The need for multiple injections, pain at the injection site, regular monitoring and skillful handling of the syringes/pen further makes insulin therapy inconvenient. Insulin pump is gaining popularity in pregnancy because it mimics the insulin delivery of a healthy human pancreas. Multiple guidelines have also recommended the use of insulin pump in pregnancy to maintain the glycaemic control. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal and the newer devices can shut down insulin delivery before the occurrence of hypoglycaemia. Pump insulin of choice is rapid acting analogue insulin. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinic experience.
Keywords: Insulin pump, Pregnancy, Gestational Diabetes mellitus, Type 1 diabetes, Type 2 diabetes, Continuous Subcutaneous Insulin Infusion.

Introduction
There has been a considerable increase in the number of women in the childbearing age being affected with diabetes. In pregnancy, the metabolic physiology differs from non-pregnant women, characterized by fasting hypoglycaemia due to insulin-independent glucose uptake by the placenta, postprandial hyperglycaemia, and carbohydrate intolerance mainly attributed to placental hormones. Insulin resistance also keeps on increasing exponentially during the second trimester and early third trimester.¹ The international scientific organizations have raised the importance of glycaemic control as close to normal as is safely possible, during pre-pregnancy, pregnancy and post-pregnancy periods. This helps reduce the risk of foetal malformations, perinatal and maternal complications.² Insulin is the preferred agent for management of gestational diabetes, not adequately controlled with diet, exercise, and metformin. Judicious use of multiple basal profiles in insulin pump and measured boluses before every meal including snacks mimic physiological secretion from a normal pancreas. It eliminates the necessity of extra injections and the risk of hypoglycaemia, as with multiple daily insulin (MDI). Diabetes in pregnancy can be gestational diabetes or a known subject with type 1 diabetes, type 2 diabetes or other forms of diabetes. This review underscores the role of insulin pump in pregnancy, their usage, advantages and disadvantages in the light of existing literature and clinical experience.

Challenges with Insulin Therapy for Diabetes in Pregnancy
The goal of insulin therapy during pregnancy is to achieve glucose profiles similar to those of pregnant women without diabetes and normal glucose tolerance. Insulin can be administered by two methods viz. Multiple Daily Injections (MDI) or via Insulin pump/continuous subcutaneous insulin infusion (CSII).³ Moreover, control of blood glucose during pregnancy is difficult because of wide variations in insulin requirement, occurring due to ongoing hormonal changes.⁴ As pregnancy progresses, increasing foetal demand lowers maternal fasting and between-meal blood glucose, thereby increasing the risk of symptomatic hypoglycaemia. Hence combinations and timing of insulin injections are quite different from those that are effective in the nonpregnant state. Further, with rising insulin resistance, the insulin regimens need a continuous modification from the first to third trimester. The need for multiple injections, apprehension and fear of injections, mood swings and skillful handling of the  yringes/pen also makes insulin therapy inconvenient.⁵

Insulin Pump Therapy in Pregnancy:
Mimicking Physiology of Healthy Pancreas Insulin pump is a small computerized, external, battery powered device that delivers insulin into the sub-cutaneous tissue 24 hours a day using a preset programme. The pump can release small doses of insulin continuously (basal), or a bolus dose close to mealtime to control the spike in blood glucose after a meal.⁶ Historically, the first insulin pump was introduced in the early 60s by a Los Angeles doctor, Arnold Kadish. In the early 80s, this pump gained recognition as a replacement to regular insulin delivery for type 1 diabetes patients. During the initial years, results using insulin pump were often unsatisfactory. In the beginning of the 90s, more user friendly models with features like bolus calculators and compatibility with personal computers were launched which gave greater control on insulin intake and could monitor blood glucoses more efficiently. Real-time insulin pumps were introduced in 2006 by Medtronic MiniMed (Northridge, CA), which had a glucose sensor along with the pump.⁷ MiniMed 640G is a novel insulin pump belonging to the first generation of artificial pancreas wirelessly communicating with sensor and a tiny glucometer(remote) with an integrated algorithm to suspend the pump at least 30 minutes before the onset of a hypoglycaemia. This is a step ahead of the previous 530G (Veo pump) which suspends insulin delivery soon after the onset of a hypoglycaemia. The future devices are being designed to control, in addition to hypoglycaemia, hyperglycaemia and thus leading on to a fully automated delivery either of insulin alone or in combination with other glucoregulatory hormones such as glucagon. Insulin pump therapy has become increasingly popular for managing diabetes during pregnancy. It has been proven to be better than MDI in reducing HbA1c and hypoglycaemic episodes, thereby, improving metabolic control and foetal-maternal outcomes (Table-1)



Glycaemic Targets and Recommendations for Pump Usage in Pregnancy
American Diabetes Association (ADA) recommends that women with gestational diabetes mellitus (GDM) should maintain capillary blood glucose within the following range: preprandial glucose <95 mg/dl (5.3 mmol/l), 1-h postprandial glucose <140 mg/dl (7.8 mmol/l), and 2-h postprandial glucose <120 mg/dl (6.7 mmol/l).⁸ The American College of Obstetrics and Gynaecology (ACOG) guidelines also recommend the same glycaemia range, the only exception being that both 130 mg/dl and 140 mg/dl 1-h postprandial glucose values are considered acceptable.⁹ Other recommendations suggest maintaining fasting glucose levels of <90-99 mg/dl (5.0-5.5 mmol/l), 1-h postprandial glucose levels of <140 mg/dl (7.8 mmol/l), and 2-h postprandial glucose levels of <120-127 mg/dl (6.7-7.1 mmol/l). Due to increased red blood cell turnover, HbA1c is lower in normal pregnancy than in normal nonpregnant women.¹⁰ Even if it is not possible to achieve the recommended levels of glycaemic control, any improvement can be beneficial given that perinatal complications are linked to increasing serum glucose values.v American Association of Clinical Endocrinologists Consensus Panel on insulin pump management have recommended insulin pump therapy to be safer and effective for maintaining glycaemic control in pregnancies complicated by gestational diabetes mellitus (GDM)/ T2DM requiring large insulin doses. ¹¹ They recommend CSII in women with preexisting type 1 diabetes who are pregnant or considering pregnancy.³ The National Institute for Health and Care Excellence (NICE) guidelines recommends CSII in pregnant women with T1DM when the target HbA1c (normally <6.1%) in the first trimester or preconception cannot be achieved without disabling hypoglycaemia.^4,12 American Association of Diabetes Educators (AADE) recommends use of insulin pump in women doing preconception planning and those who are pregnant.¹³ ADA also recommends the use of pump as safe in pregnancy. International Diabe es Federation (IDF) recommends insulin pump as an additional in the comprehensive care level in T2DM.¹⁴ Kesavadev et al in the Indian consensus guidelines also recommend the use of insulin pump for pregnant women with type 1 diabetes (T1DM), to ensure better glycaemic control and outcome as compared to MDI treatment.¹⁵ In another guideline for insulin pumps in India, for women with type 1 or type 2 diabetes having poor glycaemic control, who contemplate starting a family, use of an insulin pump can help in maintaining near normoglycaemia throughout the pregnancy.¹⁶

Clinical usage of Pumps: Advice and Precaution in Pregnancy
CSII/insulin pump should only be used in patients who are motivated and knowledgeable in self-care, including insulin adjustment. To ensure patient safety, prescribing physicians must have expertise in CSII therapy, and users must be thoroughly educated and periodically reevaluated. Sensor-augmented CSII, including those with a threshold-suspend function, preferably the new predictive hypoglycemia suspend pumps should be considered for patients who are at risk of hypoglycaemia.¹⁷ Usually subjects will require 2-12 weeks to get acclimatized with an insulin pump. Hence, preferably, in known subject with known diabetes, pumps are initiated well ahead of planning a pregnancy. In the GDM candidate, selection and support by a multi-disciplinary team will be pivotal in determining success.

Contraindications to Insulin Pump Therapy in Pregnancy
1. Candidate unsuitable for getting trained for successful use of pump as per guidelines¹⁶
2. Unwilling for glucose monitoring/Continuous Glucose Monitoring
3. Lack of resources to procure insulin pump/accessories
4.  Uncontrolled known type 1 or type 2 diabetes after first trimester
5. Psychological barriers to get acclimatized with devices attached to the body
6. Uncontrolled sugars due to technical errors despite repeated training when pump is first initiated in GDM

Insulin in Insulin Pump
Insulin aspart is the preferred insulin in the pump as it is considered safe in pregnancy with least instances of occlusion.¹⁸ It more closely mimics the endogenous insulin than regular human insulin and the tendency for hypoglycaemia is significantly less (Table-2)

Insulin glulisine, a rapid acting analogue insulin falls under category C in pregnancy.

Infusion Site Selection in Pregnancy
Forum for Injection Technique (FIT), India, recommends abdomen as the preferred infusion site for insulin pump and upper arm/thigh as alternate sites. ¹⁹ During the first trimester, infusion sites are similar to that in non-pregnant. However, it is more comfortable to shift sites away from the abdomen as the pregnancy progresses. Although the sites on the abdomen does not hurt the foetus, but using areas with stretch marks or tight skin that a patient cannot pinch is not recommended. Sites along the sides of abdomen & upper buttocks, which gain adipose tissue are more favoured at the later stages of pregnancy.

Rotation of Infusion Sites
Rotation of the sites every 24-48 hours, unlike every 3 days in the absence of pregnancy, helps in reducing the risk of blockages and therefore prevents high blood glucose levels and also reduces the risk of site infection. Choosing a new infusion site every time allows the skin to recover, ensuring that insulin absorption in any area does not suffer from too intensive use. The 45 degree angle cannula may prove more comfortable with progress of pregnancy as compared to 90 degree cannula. Many women need a deeper insertion angle and use a longer cannula.

Infusion Site During Labour
At the time of labour, a new infusion set should be inserted with the help of a cannula placed at the upper arm or beneath the lower rib, near the back. When the cannula is inserted in the upper arm it can be easily seen and completely out of the way avoiding a potential caesarean section site, the area to be cleansed or covered under drapes.

Precautions to be Followed
The pump should not be disconnected for more than one hour without taking extra insulin. The insulin used for pump therapy has a short action and duration: disconnecting from the pump for more than one hour may result in hyperglycaemia.²⁰ Proper aseptic precautions should be maintained to avoid infection. Hands should be clean when dealing with infusion sets and sites. All parts of the infusion set should be clean and no part of an infusion set should be reused. Further, infusion site should be frequently inspected for any rashes, itching or erythema. In case of any such signs the cannula should be removed and a new cannula should be inserted in a different site.

Clinical Evidence: Efficacy, Outcomes and Safety
Studies have shown that insulin pump therapy can achieve better glucose control as compared to MDI in diabetes patients and can reduce hypoglycaemic episodes up to 84%. In addition, insulin pump therapy improves compliance and can help reduce the risk of many long-term complications, both macro and microvascular. A (2004) meta-analysis of six small randomized trials, failed to demonstrate any difference in the pregnancy outcomes or glycaemic control between CSII and MDI in pregnant women with diabetes.²¹ However, some observational studies have a few isolated suggestions of lower HbA1c, diabetic ketoacidosis, increased weight gain,  and neonatal hypoglycaemia among insulin pump users, but otherwise have not found any differences in maternal and perinatal outcomes.^22-24 Most of these studies had fewer patients, hence these studies were underpowered for the outcomes of interest. However recent studies by Wender-Ozegowska et al, Talaviya et al and Kallas-Koeman et al has successfully demo strated the better glycaemic control and thereby improved pregnancy outcome in women with T1DM on CSII as compared to MDI.^25-27 In a retrospective observational study including pregnant women with T1DM, Talaviya et al (2013) reported CSII to be associated with greater reduction in HbA1c level during each trimester of pregnancy compared to MDI treated patients. Moreover, the rate of abortion, preterm labour, caesarean section and hypoglycaemia in the new born were lesser in CSII treated group.²⁶ Wender-Ozegowska et al (2013) reported decreased insulin requirement along with significant decline in HbA1c levels and hypoglycaemic episodes in CSII treated patient.²⁵ In another large study, Kallas-Koeman et al (2014) found lower mean HbA1c in each trimester in women with type 1 diabetes who used insulin pump. Furthermore, there were no episodes of maternal hypoglycaemia, diabetic ketoacidosis or increased weight gain during pregnancy²⁷ (Table-3)



Safety
Pump therapy is as safe as multiple-injection therapy when recommended procedures are followed. Potential complications peculiar to pump therapy, however, must be explained to users. Undetected interruptions in insulin delivery may result in ketotic episodes more often and more quickly with CSII, which is of particular concern in pregnancy. Infections or inflammation at the needle site may also complicate CSII therapy but can be minimized by careful hygiene and frequent site changes. Hypoglycaemia can occur in pump users as with conventional treatments.

Conclusion
It is quite evident that blood glucose is normally very low in pregnancy in healthy women. To maintain the same pattern in those women with diabetes in pregnancy, the only solution will be to make use of newer generation insulin pumps which almost totally eliminates the risk of hypoglycaemia while helping maintain glucose as close to normal as possible. An important parameter for success of insulin pumps depend on the choice of the right patients based on clinical parameters, psychological factors, education status, family support and economic background. Insulin pumps have shown better response than MDI in GDM. Based on existing evidences, it could be suggested that greater flexibility of CSII leads to better compliance during and after pregnancy and appears to be safe for use in pregnancy.

References
1.American Diabetes Association. Management of diabetes in pregnancy. Sec. 12. In: Standards of medical care in diabetes - 2015. Diabetes Care 2015; 38 (Suppl 1): 77-9.
2.Palatnik A, Mele L, Landon MB, Reddy UM, Ramin SM, Carpenter MW, et al. Timing of treatment initiation for mild gestational diabetes mellitus and perinatal outcomes. Am J Obstet Gynecol 2015; 213: 560.e1-8.
3.Grunberger G, Bailey TS, Cohen AJ, Flood TM, Handelsman Y, Hellman R, et al. Statement by the American association of clinical endocrinologists consensus panel on insulin pump management. Endocr Pract 2010; 16: 746-62.
4.Pickup JC. Management of diabetes mellitus: is the pump mightier than the pen? Nat Rev Endocrinol 2012; 8: 425-33.
5.Kavitha N, De S, Kanagasabai S. Oral hypoglycemic agents in pregnancy: an update. J Obstet Gynaecol India 2013; 63: 82-7.
6.Kesavadev J. Fasting in ramadan with an insulin pump. J Pak Med Assoc 2015; 65 (Suppl 5): S47-50.
7.Alsaleh FM, Smith FJ, Keady S, Taylor KM. Insulin pumps: from inception to the present and toward the future. J Clin Pharm Ther 2010; 35: 127-38.
8.American Diabetes Association. Management of diabetes in pregnancy. Sec. 12. In standards of medical care in diabetes - 2016. Diabetes Care 2016; 39 (Suppl. 1): 94-8.
9.American College of Obstetricians and Gynecologists committee on Practice Bulletins. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001. Gestational diabetes. Obstet Gynecol 2001; 98: 525-38.
10.Metzger BE, Buchanan TA, Coustan DR, de Leiva A, Dunger DB, Hadden DR, et al. Summary and recommendations of the fifth international workshop-conference on gestational diabetes mellitus. Diabetes Care 2007; 30 (Suppl 2): S251-60.
11.Grunberger G, Abelseth JM, Bailey TS, Bode BW, Handelsman Y, Hellman R, et al. Consensus statement by the American association of clinical endocrinologists/ American college of endocrinology insulin pump management task force. Endocr Pract 2014; 20: 463-89.
12.National Institute for Health and Care Excellence Guidelines. Diabetes in pregnancy: management from preconception to the postnatal period. NICE Guideline 3, London 2015: pp 1-65.
13.Chiang JL, Kirkman MS, Laffel LM, Peters AL. Type 1 diabetes through the life span: a position statement of the American diabetes association. Diabetes Care 2014; 37: 2034-54.
14.International Diabetes Federation Guideline Development Group. Global guideline for type 2 diabetes. Diabetes Res Clin Pract 2014; 104: 1-52.
15.Kesavadev J, Jain SM, Muruganathan A, Das AK. Consensus evidence-based guidelines for use of insulin pump therapy in the management of diabetes as per Indian clinical practice. J Assoc Physicians India 2014; 62: 34-41.
16.Kesavadev J, Das AK, Unnikrishnan R, Joshi SR, Ramachandran A, Shamsudeen J, et al. Use of insulin pumps in India: suggested guidelines based on experience and cultural differences. Diabetes Technol Ther 2010; 12: 823-31.
17.Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS, Bailey TS, et al. American association of clinical endocrinologists and American college of endocrinology - clinical practice guidelines for developing a diabetes mellitus comprehensive care plan - 2015. Endocr Pract 2015; 21 (Suppl 1): 1-87.
18.Bode BW. Comparison of pharmacokinetic properties, physicochemical stability, and pump compatibility of 3 rapid-acting insulin analogues-aspart, lispro, and glulisine. Endocr Pract 2011; 17: 271-80.
19.Tandon N, Kalra S, Balhara YPS, Baruah MP, Chadha M, Chandalia HB, et al. Forum for injection technique (FIT), India: the Indian recommendations 2.0, for best practice in insulin injection technique, 2015. Indian J Endocrinol Metab 2015; 19: 317-31.
20.Ketterer C, Mussig K, Gerstenecker AK, Fritsche A. [Insulin pump therapy: indications and risks - Case 7/2010]. Dtsch Med Wochenschr 2010; 135: 1617.
21.Mukhopadhyay A, Farrell T, Fraser RB, Ola B. Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and meta-analysis of randomized, controlled trials. Am J Obstet Gynecol 2007; 197: 447-56.
22.Bruttomesso D, Bonomo M, Costa S, Dal Pos M, Di Cianni G, Pellicano F, et al. Type 1 diabetes control and pregnancy outcomes in women treated with continuous subcutaneous insulin infusion (CSII) or with insulin glargine and multiple daily injections of rapid-acting insulin analogues (glargine-MDI). Diabetes Metab 2011; 37: 426-31.
23.Cyganek K, Hebda-Szydlo A, Katra B, Skupien J, Klupa T, Janas I, et al. Glycemic control and selected pregnancy outcomes in type 1 diabetes women on continuous subcutaneous insulin infusion and multiple daily injections: the significance of pregnancy planning. Diabetes Technol Ther 2010; 12: 41-7.
24.Chen R, Ben-Haroush A, Weismann-Brenner A, Melamed N, Hod M, Yogev Y. Level of glycemic control and pregnancy outcome in type 1 diabetes: a comparison between multiple daily insulin injections and continuous subcutaneous insulin infusions. Am J Obstet Gynecol 2007; 197: 404.e1-5.
25.Wender-Ozegowska E, Zawiejska A, Ozegowska K, Wroblewska-Seniuk K, Iciek R, Mantaj U, et al. Multiple daily injections of insulin versus continuous subcutaneous insulin infusion for pregnant women with type 1 diabetes. Aust N Z J Obstet Gynaecol 2013; 53: 130-5.
26.Talaviya PA, Saboo BD, Joshi SR, Padhiyar JN, Chandarana HK, Shah SJ, et al. Pregnancy outcome and glycemic control in women with type 1 diabetes: a retrospective comparison between CSII and MDI treatment. Diabetes Metab Syndr 2013; 7: 68-71.
27.Kallas-Koeman MM, Kong JM, Klinke JA, Butalia S, Lodha AK, Lim KI, et al. Insulin pump use in pregnancy is associated with lower HbA1c without increasing the rate of severe hypoglycaemia or diabetic ketoacidosis in women with type 1 diabetes. Diabetologia 2014; 57: 681-9.
28.Wollitzer AD, Zisser H, Jovanovic L. Insulin pumps and their use in pregnancy. Diabetes Technol Ther 2010; 12 (Suppl 1): S33-6.
29.Simmons D, Thompson CF, Conroy C, Scott DJ. Use of insulin pumps in pregnancies complicated by type 2 diabetes and gestational diabetes in a multiethnic community. Diabetes Care 2001; 24: 2078-82.