Anda di halaman 1dari 16

Cochrane Database of Systematic Reviews

Different insulin types and regimens for pregnant women with

pre-existing diabetes (Protocol)

O’Neill SM, Kenny LC, Khashan AS, Beirne PV, Smyth RMD, Kearney PM

O’Neill SM, Kenny LC, Khashan AS, Beirne PV, Smyth RMD, Kearney PM.
Different insulin types and regimens for pregnant women with pre-existing diabetes.
Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD011880.
DOI: 10.1002/14651858.CD011880.

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol)
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) i
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Protocol]

Different insulin types and regimens for pregnant women with

pre-existing diabetes

Sinéad M O’Neill1, Louise C Kenny1 , Ali S Khashan1,2 , Paul V Beirne2 , Rebecca MD Smyth3 , Patricia M Kearney2

1 Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork, Cork, Ireland. 2 Department of

Epidemiology and Public Health, University College Cork, Cork, Ireland. 3 School of Nursing, Midwifery and Social Work, The
University of Manchester, Manchester, UK

Contact address: Sinéad M O’Neill, Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork,
5th Floor, Cork University Maternity Hospital, Wilton, Cork, Munster, Ireland.

Editorial group: Cochrane Pregnancy and Childbirth Group.

Publication status and date: New, published in Issue 9, 2015.

Citation: O’Neill SM, Kenny LC, Khashan AS, Beirne PV, Smyth RMD, Kearney PM. Different insulin types and regimens for
pregnant women with pre-existing diabetes. Cochrane Database of Systematic Reviews 2015, Issue 9. Art. No.: CD011880. DOI:

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.


This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of different combinations of insulin types and regimens in pregnant women with pre-existing diabetes for improving
maternal and fetal health and well-being.

BACKGROUND type 1 diabetes was considered a disorder of children and ado-

lescents generally occurring in early life with a sudden onset of
insulin deficiency. Age at onset of diagnosis is no longer a restrict-
ing factor (Atkinson 2014). Type 2 diabetes has been largely at-
Description of the condition tributed to increasing obesity and socioeconomic status (Kothari
2014; Morton 2014). GDM is a carbohydrate intolerance result-
ing in hyperglycaemia (an excess of sugar in the blood) of vari-
able severity with onset or first recognition during pregnancy. It
Diabetes mellitus
does not exclude the possibility that the glucose intolerance may
The term diabetes mellitus (DM) describes a metabolic disorder of antedate pregnancy but has been previously unrecognised. The
multiple aetiology characterised by chronic hyperglycaemia with definition applies irrespective of whether or not insulin is used for
disturbances of carbohydrate, fat and protein metabolism resulting treatment or the condition persists after pregnancy (WHO 1999).
from defects in insulin secretion, insulin action, or both (WHO This review will only include women with pre-existing DM (type
1999). DM can occur during pregnancy in two forms, pre-gesta- 1 or 2).
tional diabetes mellitus and gestational diabetes mellitus (GDM)
(Daflapurkar 2014). Pre-gestational diabetes refers to type 1 or
type 2 diabetes and is diagnosed before conception. Historically, Pathophysiology

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 1
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DM can be defined as abnormal glucose metabolism due to lack • Dietary factors (including low vitamin D consumption,
of or relatively low insulin production. It results in elevation of early exposure to cow’s milk or cow’s milk formula, and exposure
blood glucose levels with effects on all the vital organs. Type 1 DM to cereals before four months of age. None of these factors has
describes a condition in which the pancreas is no longer able to been shown to directly cause type 1 DM).
produce sufficient insulin due to the destruction of the beta cells • Geography. Certain countries, such as Finland and Sweden,
by an autoimmune process. According to the World Health Or- have higher rates of type 1 DM.
ganization (WHO) definition, type 1 DM “includes those cases
attributable to an autoimmune process, as well as those with beta- It is not fully understood why some people develop type 2 DM and
cell destruction and who are prone to ketoacidosis for which nei- others do not. Certain factors increase the risk, however, including
ther an aetiology nor a pathogenesis is known (idiopathic). It does the following (Kim 2002).
not include those forms of beta-cell destruction or failure to which • Weight (the more fatty tissue present, the more resistant
specific causes can be assigned (e.g. cystic fibrosis, mitochondrial cells become to insulin).
defects, etc.)” (WHO 1999). Type 2 DM includes the common • Inactivity (the less active a person is, the greater the risk.
major form of diabetes which results from defects in insulin secre- Physical activity helps control weight, uses up glucose as energy
tion, almost always with a major contribution from insulin resis- and makes cells more sensitive to insulin).
tance (Nolan 2011; WHO 1999). • Family history (risk increases if a parent or sibling has type
2 DM).
• Race (certain races - including blacks, Hispanics, American
Epidemiology Indians and Asian-Americans are at higher risk although it is not
DM is increasing globally and the number of adults with diabetes clear why).
has more than doubled over nearly three decades driven by both • Age (risk increases as you get older, perhaps due to less
population growth and ageing, as well as the increasing levels of exercise, lost muscle mass and weight gain as you age. however,
overweight/obesity (Danaei 2011). In Canada, the percentage of type 2 DM is also increasing dramatically among children,
pregnant women with pre-existing DM rose from 0.7% to 1.5% adolescents and younger adults).
between 1996 and 2010 (Feig 2014). Similar increasing trends of • GDM (if a woman developed gestational diabetes when
DM in pregnant women have been reported in the United States pregnant, her risk of developing prediabetes and type 2 DM later
(Albrecht 2010; Lawrence 2008) and the United Kingdom (Bell increases. If a woman gave birth to a baby weighing more than
2008). Type 2 diabetes accounts for approximately 85% to 90% of nine pounds (four kilograms), the risk of type 2 DM also
all cases of diabetes in European countries and is the driving force increases).
behind increasing diabetes rates (Wass 2011). Furthermore, DM • Polycystic ovary syndrome (a common condition
is the most common pre-existing medical condition complicating characterised by irregular menstrual periods, excess hair growth
pregnancy and the outcome for diabetic pregnancy remains poor and obesity - increases the risk of DM).
despite improvements in care (Kumareswaran 2013). Pre-existing • High blood pressure over 140/90 millimetres of mercury
DM complicates approximately 1.3% of pregnancies, one third (mm Hg) is linked to an increased risk of type 2 DM.
of these are type 1 DM, the remaining two thirds are type 2 DM • Abnormal cholesterol and triglyceride levels (low levels of
(Bell 2008; Feghali 2012). high-density lipoprotein (HDL), or “good,” cholesterol, results
in an increased risk of type 2 DM as does a high level of
Risk factors associated with DM • Gender (higher prevalence of diabetes among men and men
develop diabetes at lower body mass index (BMI) levels than
Although the exact causes of type 1 DM are unknown, factors women).
that may signal an increased risk include the following (Daneman
• Family history (risk increases if a parent or sibling has type
1 DM). Possible complications in pregnant women with DM
• Environmental factors (circumstances such as exposure to a and their offspring
viral illness likely play some role in type 1 DM). Diabetes in pregnancy is associated with risks to the woman
• The presence of damaging immune system cells and the developing fetus (Adam 2014; Ali 2011; Bartz 2012;
(autoantibodies). Sometimes family members of people with Billionnet 2014; Carter 2012; Feig 2014; Fraser 2014; Holman
type 1 DM are tested for the presence of diabetes autoantibodies. 2014; Kapoor 2007; Krane 2014; Morken 2014; Øverland 2014;
The presence of these antibodies is associated with an increased Ryu 2014; Tennant 2014; Yessoufou 2011).
risk of developing type 1 DM, but not everyone who has these • Increased risk of complications of DM including
autoantibodies develops DM. ketoacidosis, hypoglycaemia, retinopathy and nephropathy.

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 2
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• Increased risk of obstetric complications including glucose levels that occurs after eating. This insulin has a peak ac-
pregnancy induced hypertension, thromboembolism, obstructed tion of two to six hours and can last for up to eight hours.
labour, polyhydramnios, maternal infection, caesarean section, 2. Rapid-acting insulin analogues (e.g. Aspart, Lispro): geneti-
pre-eclampsia and preterm labour. cally engineered analogues of human insulin which work like in-
• Increased risk of fetal and neonatal complications including sulin normally produced with a meal. Onset of action is approxi-
miscarriage, stillbirth, congenital malformations, macrosomia, mately 15 minutes, peaking at one hour and lasting three to four
birth injury, perinatal mortality, postnatal adaptation problems hours. They can be injected shortly before, during or immediately
(e.g. hypoglycaemia (reduced levels of blood sugar)), fetal after meals.
distress, respiratory distress syndrome and jaundice. 3. Long-acting insulin analogues (e.g. Detemir, Glargine): genet-
• Long-term outcomes of offspring born to diabetic mothers ically modified analogues with an onset of action at one to three
include an increased risk of obesity, impaired cognitive ability hours, plateau and last for 20 to 24 hours. Generally used once- or
and type 2 diabetes. twice-daily to produce a constant flow of insulin, physiologically
similar to normal endogenous basal insulin secretion.
4. Intermediate-acting (medium-acting) insulins (e.g. isophane/
Management of DM in pregnancy neutral protamine Hagedorn (NPH)): These have an onset of action
The management of pregnant women with type 1 diabetes in- of two to four hours, peak at six to seven hours and last 20 hours.
volves the use of insulin to control blood glucose levels. During Isophane insulin is ideal for twice-daily insulin regimens and can
pregnancy a woman’s insulin requirements may increase by up to be mixed with soluble insulin.
three to four times her pre-pregnancy dose and insulin manage- 5. Mixed insulin (Biphasic insulin): is a combination of
ment is tailored to the individual (McCance 2010). In type 2 dia- medium-acting and rapid-acting or short-acting insulin.
betes, lifestyle changes including a healthy diet and regular exercise 6. Mixed analogue: is a combination of medium-acting insulin
are the first line of treatment, with the use of oral hypoglycaemic and rapid-acting analogue.
agents or insulin to lower blood glucose if necessary. The manage-
ment of diabetes in pregnancy is therefore complex and includes a
combination of preconception care, glycaemic control and moni- Insulin regimens
toring, obtaining target blood glucose levels, monitoring glycated In this review the term “insulin regimen” refers to an overall strat-
haemoglobin (HbA1c) levels, retinal assessment, carefully tailored egy for insulin delivery that typically specifies:
insulin treatment, ketone testing, renal assessment, monitoring fe- a) the frequency of insulin injections (e.g. once, twice daily);
tal growth and well-being and postnatal care (Balaji 2011; Ballas b) the type of insulin administered (e.g. intermediate-, long-act-
2012; NICE 2015). ing); and
c) the timing of insulin injections (e.g. bedtime, before breakfast).
The main insulin regimens are as follows.
Description of the intervention
Insulin is a hormone made naturally in the body by pancreatic Once-daily regimen
beta cells. This hormone controls the level of glucose in the blood.
There are different types of insulin available, which are classified • Long- or intermediate-acting insulin administered at
according to how quickly and for how long they work on various bedtime in people with type 2 diabetes only.
parts of the body. There are also many different methods of ad- • It may be used in addition to oral hypoglycaemic agents.
ministering insulin, referred to as ’regimens’. This review focuses • This regimen is generally used when starting insulin in type
on the efficacy and safety of different insulin types and the various 2 diabetes and when it is necessary for others to administer the
regimens of insulin delivery during pregnancy. The appropriate injections.
insulin type and regimen for each woman will depend on a num-
ber of factors including the type of diabetes, previous control, age,
Twice-daily regimen
dexterity, eyesight and personal and cultural preferences (Greuter
2012). • A biphasic insulin is injected twice a day (before breakfast
and before the evening meal).
• Assumes three meals a day are consumed and peak action
Types of insulin varies according to the amount of soluble insulin in the mixture.
Insulins can be classified into various types according to their du- • Optimal glycaemic control can be difficult to maintain
ration of action (Mooradian 2006; NICE 2015). resulting in hypoglycaemic episodes.
1. Short-acting insulin (e.g. Humulin, Novolin): should be in- • Additional snacks are often required given the overlap
jected 15 to 30 minutes before a meal, to cover the rise in blood between short-acting and long-acting insulin between meals.

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 3
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Basal-bolus regimen How the intervention might work
• Intermediate- or long-acting insulin is administered at Insulin, a hormone made by beta cells of the pancreas works on var-
bedtime to cover overnight insulin requirements and is combined ious parts of the body when it is chemically released into the blood-
with rapid- or short-acting insulin injections to cover mealtimes. stream. This process results in the control of glucose (sugar) levels
in the blood. Normally, after you have eaten, various foods are bro-
This is the most commonly used insulin regimen when intensified ken down into sugars, the main one being glucose, which passes
insulin therapy is used to provide optimal glycaemic control and through the gut wall into the bloodstream. To remain healthy, the
is also known as multiple daily injections (MDI). blood glucose level should be neither too high or too low. For
example, if blood glucose level rises (after eating), then the in-
sulin level should also rise. Insulin works on the cells making them
absorb glucose from the bloodstream, some of which is used for
Continuous subcutaneous insulin infusion, or insulin pump energy, some of which is converted into glycogen or fat (energy
therapy stores). When blood glucose levels fall (between meals), insulin
levels fall and this glycogen or fat is then converted back into glu-
• Continuous subcutaneous insulin infusion (CSII) or insulin
cose which is released into the cells of the bloodstream, Patients
pump therapy is where basal insulin is given via a catheter
with diabetes need to control the level of glucose in their blood
supplied from a syringe reservoir worn under clothing.
and this is usually tailored to their individual needs and dependent
• The woman can activate pre-meal boluses and the pump
on the type of diabetes present. Overall, there is a lack of clear
can be deactivated for up to one hour to facilitate activities such
evidence regarding the benefits and risks of the various insulin
as swimming.
types and regimens, particularly the newer insulin therapies. The
• The pump can be pre-programmed and the insulin
evidence so far suggests that (Anonymous 2015):
absorption is more predictable than multiple daily injections as a
• rapid-acting insulin analogues may improve postprandial
hyperglycaemia and reduce hypoglycaemia (Siebenhofer 2006);
• CSII provides some advantages over multiple daily
• long-acting insulin analogues may reduce nocturnal
injections in type 1 diabetes for children and adults who have
hypoglycaemia and weight gain (Gough 2007) but some studies
recurrent hypoglycaemia, delayed meals or pre-breakfast
found them no better than conventional NPH insulin. (Home
2005; Horvath 2007);
• the newer treatments seem to be safe so far (Siebenhofer
CSII regimens have been covered extensively in two previous 2004);
Cochrane reviews and will not be included in the current review • the rapid-acting insulin analogues (Aspart and Lispro) do
(Farrar 2007; Misso 2010). not seem to adversely affect pregnancy or the health of the fetus
or newborn baby;
• use of isophane insulin (NPH insulin) as the first choice for
long-acting insulin during pregnancy is recommended and
Insulin dosage
insulin Detemir or Glargine in women with diabetes who have
Insulin dosage should be individualised to achieve/maintain a tar- established good blood glucose control before pregnancy (NICE
get blood glucose level and is determined by various factors in- 2015);
cluding body weight, body fat, physical activity, insulin sensitivity, • twice-daily regimens using isophane insulin (NPH insulin)
blood glucose levels, and target blood glucose. Insulin dosage is or long-acting insulin analogues (insulin Glargine) may be more
usually determined based on body weight (insulin unit per kg body suitable for those who require assistance, or have a dislike of
weight). One international unit of insulin (1 IU) is defined as the injecting;
“biological equivalent” of 34.7 µg of pure crystalline insulin (Beals • multiple injection regimens using unmodified or soluble
2013). Daily insulin requirements may be higher during illness, insulin or rapid-acting insulin analogues, are suitable for well-
stress, pregnancy, in obese patients, trauma, during concurrent use motivated individuals with a good understanding of disease
with medications having hyperglycaemic effects, or after surgery, control, or those with active or erratic lifestyles (NICE 2015).
and may be lower with exercise, weight loss, calorie restricted diets,
or during concurrent use of medications having hypoglycaemic The current review interventions may result in a better under-
effects. Total daily doses should not be adjusted by more than 10% standing of the following in pregnant women with pre-existing
increments. Supplemental doses may be prescribed during illness diabetes.
or to correct high preprandial blood glucose. In addition, dosage
adjustments may be required when the brand, type, or species of
insulin is changed (Teuscher 2007). Improved glycaemic control

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 4
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Improvement in glycaemic control levels (i.e. optimum HbA1c To assess the effects of different combinations of insulin types
levels, fasting plasma glucose). and regimens in pregnant women with pre-existing diabetes for
improving maternal and fetal health and well-being.

Reduction of hypoglycaemic or hyperglycaemic

A reduction or absence in the number of hyperglycaemic or hy- METHODS
poglycaemic episodes reported in the trials.

Safety and efficacy

Criteria for considering studies for this review
Measurement of the safety and efficacy of various insulin types
and regimens.

Types of studies
Satisfaction and quality of life reported by women; maternal and We will include randomised controlled trials and cluster-ran-
infant outcomes. domised trials, irrespective of the number of trial arms with re-
ported data that evaluate different insulin types or regimens. We
will exclude quasi-randomised controlled trials and trials using a
cross-over design. We will include studies published in abstract
Why it is important to do this review
form and will attempt to contact authors for further details. Con-
Several Cochrane reviews have evaluated the effects of various in- ference abstracts will be superseded by full publications.
terventions for managing pre-existing diabetes in pregnancy in-
cluding: early pregnancy screening to improve maternal and child
health (Allnutt 2015); monitoring blood glucose during preg-
nancy (Moy 2014); glycaemic control (Middleton 2012); oral anti- Types of participants
diabetic agents for impaired glucose tolerance (Tieu 2010a) and Women with a singleton pregnancy who have pre-existing diabetes
CSII versus MDI of insulin (Farrar 2007). In addition, there are (type 1 or type 2) and randomised to receive different insulin types
other Cochrane reviews which cover various aspects of diabetes or regimens. Trials will be excluded if women are randomised prior
management around conception, pregnancy and birth (e.g. elec- to pregnancy. Women who meet the diagnostic criteria for GDM
tive delivery, exercise, antenatal breast milk expression, precon- will not be included. Diagnostic criteria for DM and GDM will be
ception care, and contraceptive advice (Boulvain 2001; Ceysens based on various definitions as reported by individual trialists ac-
2006; East 2014; Tieu 2010b; Visser 2013). cording to local health authorities and professional organisations.
Our review will assess evidence related to different insulin types Women will be eligible regardless of gestation, age, or parity.
and regimens and contribute to knowledge that can ultimately be
used by pregnant women with pre-existing diabetes and their clin-
icians to minimise the risk of adverse birth outcomes and diabetic
complications for mothers. This review is timely given that cur- Types of interventions
rently pregnant women with diabetes have significantly worse out- We will include randomised controlled trials making any of the
comes than their non-diabetic counterparts. Achieving improved following comparisons.
pregnancy outcomes for women with diabetes needs to be pri-
oritised particularly given that the prevalence of diabetes among
women of childbearing age is increasing. Furthermore, whilst there
have been advances in the different insulin types and regimens Comparisons between different insulin types used within
available which have crossed into the field of obstetrics, further similar insulin regimens
research is needed to address the safety and efficacy of these new For example:
drugs on the market to improve compliance and glycaemic control 1. basal bolus regimen of NPH insulin given at bedtime
especially during pregnancy. combined with Aspart to cover mealtimes versus basal bolus
regimen of Glargine given at bedtime combined with Aspart to
cover mealtimes (i.e. a comparison of the effects of different
insulin types [NPH versus Glargine] when used within a basal
OBJECTIVES bolus regimen).

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 5
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Comparisons between different insulin regimens with hyperbilirubinaemia, necrotising enterocolitis, intracranial
similar insulin types used within the regimens haemorrhage, artificial (tube) feeding).
For example: 4. Preterm birth < 37 weeks.
1. twice-daily insulin regimenversus four times daily insulin 5. Small-for-gestational age at birth.
regimen: 6. Five minute Apgar score < 7.
• twice-daily regimen: morning dosage = one third human 7. Birthweight centile corrected for gestational age, parity,
regular insulin and two thirds human intermediate insulin; ethnicity, maternal weight and fetal sex (Z scores used where
afternoon dosage = equal parts regular and intermediate insulin; available).
• four-times daily regimen: first three dosages of regular 8. Neonatal anthropometry (length, head circumference,
insulin 30 minutes before a meal; final dosage: bedtime, ponderal index).
intermediate insulin. 9. Neonatal adiposity (fat mass, skinfold thickness).
10. Measures of growth and neurodevelopment at childhood
Comparisons between different insulin regimens with
different insulin types used within the regimens
For example:
1. a biphasic insulin injected twice a day (pre-breakfast and 1. Vaginal delivery (spontaneous/ventouse/forceps).
pre-evening meal)versus basal bolus regimen of NPH insulin 2. Postpartum haemorrhage.
given at bedtime combined with Aspart to cover mealtimes. 3. Severe perineal trauma (third and fourth degree tear).
4. Measures of diabetic metabolic control (levels of HbA1c,
daily mean self-monitored blood glucose, post-prandial and
Types of outcome measures fasting, continuous glucose monitoring).
5. Maternal hypoglycaemia and hyperglycaemia episodes
requiring intervention.
Primary outcomes 6. Weight gain in pregnancy.
7. Induction of labour (reasons related to diabetes).
8. Postpartum infection.
Infant 9. Breastfeeding.
1. Macrosomia (birthweight greater than 4000 g, birthweight 10. Retinopathy.
greater than 90% for gestational age after correcting for neonatal 11. Quality of life (psychological impact of management assess
sex and ethnicity). by psychometric testing using a reliable standardised
2. Perinatal death. questionnaire).
12. Use of healthcare resources (rate of antenatal clinic visits and
admission for treatment relating to diabetic control, ultrasound
growth scans, biophysical scans, dopplers, cardiotocographs).
1. Caesarean section (emergency or elective). 13. Woman’s preference/satisfaction with treatment.
2. Pre-eclampsia. 14. Economic evaluation.

Secondary outcomes
Search methods for identification of studies
The following methods section of this protocol is based on a stan-
Infant dard template used by the Cochrane Pregnancy and Childbirth
1. Fetal anomaly divided into major and minor (for those Group.
randomised preconceptually, as an additional outcome for those
randomised during pregnancy).
2. Birth trauma including shoulder dystocia, nerve palsy and Electronic searches
fracture. We will contact the Trials Search Co-ordinator to search the
3. Composite outcome measure of neonatal morbidity Cochrane Pregnancy and Childbirth Group’s Trials Register.
(admission and length of stay in neonatal intensive care unit, The Cochrane Pregnancy and Childbirth Group’s Trials Register
mechanical ventilation, neonatal infection, neonatal is maintained by the Trials Search Co-ordinator and contains trials
hypoglycaemia, insulin sensitivity [cord insulin, c-peptide], identified from:
jaundice requiring therapy, respiratory distress syndrome,

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 6
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1. monthly searches of the Cochrane Central Register of attempt to contact authors of the original reports to provide fur-
Controlled Trials (CENTRAL); ther details.
2. weekly searches of MEDLINE (Ovid);
3. weekly searches of Embase (Ovid);
4. monthly searches of CINAHL (EBSCO); Assessment of risk of bias in included studies
5. handsearches of 30 journals and the proceedings of major Two review authors (SON, RS) will independently assess risk of
conferences; bias for each study using the criteria outlined in the Cochrane
6. weekly current awareness alerts for a further 44 journals Handbook for Systematic Reviews of Interventions (Higgins 2011).
plus monthly BioMed Central email alerts. We will resolve any disagreement by discussion or by involving a
Details of the search strategies for CENTRAL, MEDLINE, Em- third assessor.
base and CINAHL, the list of handsearched journals and confer-
ence proceedings, and the list of journals reviewed via the current
awareness service can be found in the ‘Specialized Register’ section (1) Random sequence generation (checking for possible
within the editorial information about the Cochrane Pregnancy selection bias)
and Childbirth Group.
Trials identified through the searching activities described above We will describe for each included study the method used to gen-
are each assigned to a review topic (or topics). The Trials Search erate the allocation sequence in sufficient detail to allow an assess-
Co-ordinator searches the register for each review using the topic ment of whether it should produce comparable groups.
list rather than keywords. We will assess the method as:
In addition, we will search and the WHO In- • low risk of bias (any truly random process, e.g. random
ternational Clinical Trials Registry Platform (ICTRP) for unpub- number table; computer random number generator);
lished, planned and ongoing trial reports (see: Appendix 1 for • high risk of bias (any non-random process, e.g. odd or even
terms we plan to use). date of birth; hospital or clinic record number); or
• unclear risk of bias.

Searching other resources

(2) Allocation concealment (checking for possible selection
We will examine the reference lists of included studies and any
relevant studies identified. Where studies can be accessed only as
abstracts, we will contact the authors for more details. We will describe for each included study the method used to con-
We will not apply any language or date restrictions. ceal allocation to interventions prior to assignment and will assess
whether intervention allocation could have been foreseen in ad-
vance of, or during recruitment, or changed after assignment.
We will assess the methods as:
Data collection and analysis • low risk of bias (e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes);
• high risk of bias (open random allocation; unsealed or non-
Selection of studies opaque envelopes, alternation; date of birth);
Two review authors (SON, PK) will independently assess for in- • unclear risk of bias.
clusion all the potential studies we identify as a result of the search
strategy. We will resolve any disagreement through discussion or,
if required, we will consult a third person (ASK). (3.1) Blinding of participants and personnel (checking for
We will create a study flow diagram to map out the number of possible performance bias)
records identified, included and excluded. We will describe for each included study the methods used, if
any, to blind study participants and personnel from knowledge of
which intervention a participant received. We will consider that
Data extraction and management studies are at low risk of bias if they were blinded, or if we judge
We will design a form to extract data. For eligible studies, two that the lack of blinding would be unlikely to affect results. We
review authors (SON, RS) will extract the data using the agreed will assess blinding separately for different outcomes or classes of
form. We will resolve discrepancies through discussion or, if re- outcomes.
quired, we will consult a third person (LK). We will enter data into We will assess the methods as:
Review Manager software (RevMan 2014) and check for accuracy. • low, high or unclear risk of bias for participants;
When information regarding any of the above is unclear, we will • low, high or unclear risk of bias for personnel.

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 7
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(3.2) Blinding of outcome assessment (checking for possible We will assess whether each study was free of other problems that
detection bias) could put it at risk of bias:
We will describe for each included study the methods used, if any, • low risk of other bias;
to blind outcome assessors from knowledge of which intervention • high risk of other bias;
a participant received. We will assess blinding separately for dif- • unclear whether there is risk of other bias.
ferent outcomes or classes of outcomes.
We will assess methods used to blind outcome assessment as:
(7) Overall risk of bias
• low, high or unclear risk of bias.
We will make explicit judgements about whether studies are at
high risk of bias, according to the criteria given in the Handbook
(4) Incomplete outcome data (checking for possible attrition (Higgins 2011). With reference to (1) to (6) above, we will assess
bias due to the amount, nature and handling of incomplete the likely magnitude and direction of the bias and whether we
outcome data) consider it is likely to impact on the findings. We will explore the
We will describe for each included study, and for each outcome impact of the level of bias through undertaking sensitivity analyses
or class of outcomes, the completeness of data including attrition - see Sensitivity analysis.
and exclusions from the analysis. We will state whether attrition
and exclusions were reported and the numbers included in the
analysis at each stage (compared with the total randomised par- Assessing the quality of the body of evidence using
ticipants), reasons for attrition or exclusion where reported, and the GRADE approach
whether missing data were balanced across groups or were related We will create ’Summary of findings’ tables for the main compar-
to outcomes. Where sufficient information is reported, or can be isons made in the review by importing data from Review Manager
supplied by the trial authors, we will re-include missing data in 5 (RevMan 2014) into GRADE profiler (GRADEpro 2014). The
the analyses which we undertake. following outcomes will be included in the ’Summary of findings’
We will assess methods as: tables.
• low risk of bias (e.g. no missing outcome data; missing • Macrosomia
outcome data balanced across groups); • Perinatal death
• high risk of bias (e.g. numbers or reasons for missing data • Pre-eclampsia
imbalanced across groups; ‘as treated’ analysis done with • Caesarean section (emergency or elective)
substantial departure of intervention received from that assigned • Fetal anomaly
at randomisation); • Birth trauma including shoulder dystocia, nerve palsy and
• unclear risk of bias. fracture
• Composite outcome measure of neonatal morbidity
(admission and length of stay in neonatal intensive care unit,
(5) Selective reporting (checking for reporting bias)
mechanical ventilation, infection, jaundice requiring therapy,
We will describe for each included study how we investigated the respiratory distress syndrome, necrotising enterocolitis,
possibility of selective outcome reporting bias and what we found. intracranial haemorrhage, artificial (tube) feeding)
We will assess the methods as: • Operative birth (caesarean/ventouse/forceps delivery)
• low risk of bias (where it is clear that all of the study’s pre-
specified outcomes and all expected outcomes of interest to the The quality of the evidence for each outcome will be assessed using
review have been reported); the GRADE approach as described in section 12.2 in theHandbook
• high risk of bias (where not all the study’s pre-specified (Schunemann 2011). We will downgrade the evidence from “high
outcomes have been reported; one or more reported primary quality” by one level for serious (or by two levels for very serious)
outcomes were not pre-specified; outcomes of interest are limitations, depending on our assessments of the risk of bias, in-
reported incompletely and so cannot be used; study fails to directness of evidence, serious inconsistency, imprecision of effect
include results of a key outcome that would have been expected estimates or potential publication bias.
to have been reported);
• unclear risk of bias.
Measures of treatment effect

(6) Other bias (checking for bias due to problems not

covered by (1) to (5) above) Dichotomous data
We will describe for each included study any important concerns For dichotomous data, we will present results as summary risk
we have about other possible sources of bias. ratio with 95% confidence intervals.

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 8
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Continuous data in the overall assessment of treatment effect by using sensitivity
For continuous data, we will use the mean difference if outcomes analyses.
are measured in the same way between trials. We will use the For all outcomes, we will carry out analyses, as far as possible,
standardised mean difference to combine trials that measure the on an intention-to-treat basis, i.e. we will attempt to include all
same outcome, but use different methods. participants randomised to each group in the analyses, and all
participants will be analysed in the group to which they were
allocated, regardless of whether or not they received the allocated
Unit of analysis issues intervention. The denominator for each outcome in each trial
will be the number randomised minus any participants whose
outcomes are known to be missing.
Cluster-randomised trials
We will include cluster-randomised trials in the analyses along
Assessment of heterogeneity
with individually-randomised trials. We will adjust their sample
sizes using the methods described in the Handbook [Section 16.3.4 We will assess statistical heterogeneity in each meta-analysis using
or 16.3.6] using an estimate of the intracluster correlation co-ef- the Tau², I² and Chi² statistics. We will regard heterogeneity as
ficient (ICC) derived from the trial (if possible), from a similar substantial if an I² is greater than 30% and either a Tau² is greater
trial or from a study of a similar population. If we use ICCs from than zero, or there is a low P value (less than 0.10) in the Chi² test
other sources, we will report this and conduct sensitivity analyses for heterogeneity.
to investigate the effect of variation in the ICC. If we identify both
cluster-randomised trials and individually-randomised trials, we
plan to synthesise the relevant information. We will consider it Assessment of reporting biases
reasonable to combine the results from both if there is little het- If there are 10 or more studies in the meta-analysis, we will in-
erogeneity between the study designs and the interaction between vestigate reporting biases (such as publication bias) using funnel
the effect of intervention and the choice of randomisation unit is plots. We will assess funnel plot asymmetry visually. If asymmetry
considered to be unlikely. is suggested by a visual assessment, we will perform exploratory
We will also acknowledge heterogeneity in the randomisation unit analyses to investigate it.
and perform a subgroup analysis to investigate the effects of the
randomisation unit.
Data synthesis
We will carry out statistical analysis using the Review Manager
Multi-armed trials software (RevMan 2014). We will use fixed-effect meta-analysis
We will include multi-armed trials and record all outcome data in for combining data where it is reasonable to assume that studies are
the review as two-arm comparisons. We will include the data for estimating the same underlying treatment effect: i.e. where trials
different arms in independent two-arm comparisons in separate are examining the same intervention, and the trials’ populations
meta-analyses where possible. If we are unable to include the data and methods are judged sufficiently similar. If there is clinical het-
in separate comparisons, we will combine them to create a sin- erogeneity sufficient to expect that the underlying treatment ef-
gle pair-wise comparison (Higgins 2011). If the control group is fects differ between trials, or if substantial statistical heterogeneity
shared by two or more study arms, we will divide the control group is detected, we will use random-effects meta-analysis to produce
between relevant subgroup categories to avoid double counting the an overall summary, if an average treatment effect across trials is
participants. For dichotomous data, we plan to divide the events considered clinically meaningful. The random-effects summary
and the total population, while for continuous data we will assume will be treated as the average of the range of possible treatment
the same mean and standard deviation (SD) divided by the total effects and we will discuss the clinical implications of treatment
population. effects differing between trials. If the average treatment effect is
not clinically meaningful, we will not combine trials.
If we use random-effects analyses, the results will be presented as
Cross-over trials the average treatment effect with 95% confidence intervals, and
We will not include cross-over trials. the estimates of Tau² and I².

Dealing with missing data Subgroup analysis and investigation of heterogeneity

For included studies, we will note levels of attrition. We will explore It is very unlikely that an investigation of heterogeneity will pro-
the impact of including studies with high levels of missing data duce useful findings unless there is a substantial number of studies

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 9
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(at least 10 studies for each characteristic in the meta-analysis) ac- If ICCs from other sources are used, we will conduct sensitivity
cording to section in the Cochrane Handbook for Systematic analyses to investigate the effect of variation in the ICC.
Reviews of Interventions (Higgins 2011). As noted in Section 9.7 of the Cochrane Handbook for Systematic
We plan to carry out the following subgroup analyses: Reviews of Interventions, “many issues suitable for sensitivity anal-
1. by type of diabetes (type 1 versus type 2); ysis are only identified during the review process when the indi-
2. gestational age when women were recruited to the trial (< vidual peculiarities of the studies under investigation are identi-
12 weeks versus > 12 weeks); fied” (Higgins 2011). If it is deemed appropriate during the review
3. maternal age (> 35 years versus < 35 years); process to conduct further sensitivity analyses (in addition to the
4. body mass index (at or before trial entry), overweight (> 25 pre-specified analyses outlined above), then we will explain the
kg/m2 ) versus normal weight (<= 25 kg/m2 ) and obese (> 30 kg/ reasons for conducting these additional analyses in our review and
m2 ) versus normal weight (<= 25 kg/m2 ); the analyses will be clearly labelled as “non-prespecified analyses”.
5. by unit of randomisation (randomised by individual
participant versus randomised by cluster).
Subgroup analyses will be restricted to the review’s primary out-
We will assess subgroup differences by interaction tests available
within RevMan (RevMan 2014). We will report the results of We would like to acknowledge the assistance of the Pregnancy
subgroup analyses quoting the Chi2 statistic and P value, and the and Childbirth Group Editors, Trial Search Co-ordinator and in
interaction test I² value. particular Helen West for her guidance on protocol development.
As part of the pre-publication editorial process, this protocol has
been commented on by three peers (an editor and two referees
Sensitivity analysis who are external to the editorial team) and the Group’s Statistical
We will carry out the following sensitivity analyses for the reviews
primary outcomes as required. We will compare those trials judged This project was supported by the National Institute for Health
as having a low risk of bias for allocation concealment with those Research, via Cochrane Infrastructure and Cochrane Programme
trials judged to have unclear or high risk of bias in order to assess Grant funding to Cochrane Pregnancy and Childbirth. The views
any substantive differences in the overall result. We will also carry and opinions expressed therein are those of the authors and do
out a sensitivity analysis to explore the fixed-effect or random- not necessarily reflect those of the Systematic Reviews Programme,
effects analyses for primary outcomes with statistical heterogeneity. NIHR, NHS or the Department of Health.


Additional references improve maternal and infant health. Cochrane Database

of Systematic Reviews 2015, Issue 4. [DOI: 10.1002/
Adam 2014 14651858.CD011601]
Adam S, Lombaard HA, Van Zyl DG. Are we missing at-
risk babies? Comparison of customised growth charts v. Anonymous 2015
standard population charts in a diabetic population. South Anonymous. Insulin regimens: what is the evidence for
African Journal of Obstetrics and Gynaecology 2014;20(3): new insulin therapies?.
88–90. insulin-regimens [accessed June 2015].
Albrecht 2010
Albrecht SS, Kuklina EV, Bansil P, Jamieson DJ, Whiteman Atkinson 2014
MK, Kourtis AP, et al. Diabetes trends among delivery Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes.
hospitalizations in the US, 1994-2004. Diabetes Care 2010; Lancet 2014;383(9981):69–82.
Balaji 2011
Ali 2011 Balaji V, Seshiah V. Management of diabetes in pregnancy.
Ali S, Dornhorst A. Diabetes in pregnancy: health risks and Journal of the Association of Physicians of India 2011;59
management. Postgraduate Medical Journal 2011;87(1028): (Suppl):33–6.
Allnutt 2015 Ballas 2012
Allnutt KJ, Allan CA, Brown J. Early pregnancy screening Ballas J, Moore TR, Ramos GA. Management of diabetes in
for identification of undiagnosed pre-existing diabetes to pregnancy. Current Diabetes Reports 2012;12(1):33–42.
Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 10
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Bartz 2012 Farrar 2007
Bartz S, Freemark M. Pathogenesis and prevention of type Farrar D, Tuffnell DJ, West J. Continuous subcutaneous
2 diabetes: parental determinants, breastfeeding, and early insulin infusion versus multiple daily injections of insulin
childhood nutrition. Current Diabetes Reports 2012;12(1): for pregnant women with diabetes. Cochrane Database
82–7. of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/
Beals 2013 14651858.CD005542.pub2]
Beals JM, DeFelippis MR, Kovach PM, Jackson JA. Feghali 2012
”Insulin“ in Pharmaceutical Biotechnology. Pharmaceutical Feghali MN, Driggers RW, Miodovnik M, Umans JG.
Biotechnology. Springer New York, 2013:255–75. Diabetes in Pregnancy. First Edition. San Diego: Academic
Bell 2008 Press, 2012.
Bell R, Bailey K, Cresswell T, Hawthorne G, Critchley J,
Feig 2014
Lewis BN. Trends in prevalence and outcomes of pregnancy
Feig DS, Hwee J, Shah BR, Booth GL, Bierman AS,
in women with pre-existing type I and type II diabetes.
Lipscombe LL. Trends in incidence of diabetes in pregnancy
BJOG: an international journal of obstetrics and gynaecology
and serious perinatal outcomes: a large, population-based
study in Ontario, Canada, 1996-2010. Diabetes Care 2014;
Billionnet 2014 37(6):1590–6.
Billionnet C, Weill A, Simeoni U, Ricordeau P, Alla F,
Fraser 2014
Jacqueminet S, et al. The risk of macrosomia linked to
Fraser A, Lawlor DA. Long-term health outcomes in
diabetes in pregnancy: data from the French population In
offspring born to women with diabetes in pregnancy.
2011. Archives of Disease in Childhood 2014;99(Suppl 2):
Current Diabetes Reports 2014;14(5):1–8.
Boulvain 2001 Gough 2007
Boulvain M, Stan CM, Irion O. Elective delivery in diabetic Gough SC. A review of human and analogue insulin trials.
pregnant women. Cochrane Database of Systematic Reviews Diabetes Research and Clinical Practice 2007;77(1):1–15.
2001, Issue 2. [DOI: 10.1002/14651858.CD001997]
GRADEpro 2014 [Computer program]
Carter 2012 McMaster University. GRADEpro. [Computer program on
Carter MF, Xenakis E, Holden A, Dudley D. Neonatal]. Version 2015. McMaster University,
intensive care unit admissions and their associations with 2014.
late preterm birth and maternal risk factors in a population-
Greuter 2012
based study. Journal of Maternal-fetal & Neonatal Medicine
Greuter MJ, van Emmerik NM, Wouters MG, van Tulder
MW. Quality of guidelines on the management of diabetes
Ceysens 2006 in pregnancy: a systematic review. BMC Pregnancy and
Ceysens G, Rouiller D, Boulvain M. Exercise for Childbirth 2012;12:58. [PUBMED: 22741571]
diabetic pregnant women. Cochrane Database of
Systematic Reviews 2006, Issue 3. [DOI: 10.1002/ Higgins 2011
14651858.CD004225.pub2] Higgins JPT, Green S, editors. Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1.0 [updated
Daflapurkar 2014 March 2011]. The Cochrane Collaboration, 2011.
Daflapurkar SB. Diabetes in pregnancy. High Risk Cases Available from
in Obstetrics. First Edition. New Delhi: Jaypee Brothers
Medical Publishers Ltd, 2014. Holman 2014
Danaei 2011 Holman N, Bell R, Murphy H, Maresh M. Women with
Danaei G, Finucane MM, Lin JK, Singh GM, Paciorek pre-gestational diabetes have a higher risk of stillbirth at all
CJ, Cowan MJ, et al. National, regional, and global trends gestations after 32 weeks. Diabetic Medicine 2014;31(9):
in systolic blood pressure since 1980: systematic analysis 1129–32.
of health examination surveys and epidemiological studies Home 2005
with 786 country-years and 5·4 million participants. Lancet Home P, Rosskamp R, Forjanic-Klapproth J, Dressler A. A
2011;377(9765):568–77. randomized multicentre trial of insulin glargine compared
Daneman 2006 with NPH insulin in people with type 1 diabetes. Diabetes/
Daneman D. Type 1 diabetes. Lancet 2006;367(9513): metabolism Research and Reviews 2005;21(6):545–53.
847–58. Horvath 2007
East 2014 Horvath K, Jeitler K, Berghold A, Ebrahim SH, Gratzer
East C, Dolan WJ, Forster DA. Antenatal breast milk TW, Plank J, et al. Long-acting insulin analogues versus
expression by women with diabetes for improving infant NPH insulin (human isophane insulin) for type 2 diabetes
outcomes. Cochrane Database of Systematic Reviews 2014, mellitus. Cochrane Database of Systematic Reviews 2007,
Issue 7. [DOI: 10.1002/14651858.CD010408.pub2] Issue 2. [DOI: 10.1002/14651858.CD005613.pub3]
Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 11
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Kapoor 2007 Morton 2014
Kapoor N, Sankaran S, Hyer S, Shehata H. Diabetes in Morton S, Kirkwood S, Thangaratinam S. Interventions to
pregnancy: a review of current evidence. Current Opinion modify the progression to type 2 diabetes mellitus in women
in Obstetrics and Gynecology 2007;19(6):586–90. with gestational diabetes: a systematic review of literature.
Current Opinion in Obstetrics and Gynecology 2014;26(6):
Kim 2002
Kim C, Newton KM, Knopp RH. A systematic review of
gestational diabetes and the incidence of type 2 diabetes. Moy 2014
Diabetes Care 2002;25(10):1862–8. Moy FM, Ray A, Buckley BS. Techniques of monitoring
blood glucose during pregnancy for women with pre-existing
Kothari 2014 diabetes. Cochrane Database of Systematic Reviews 2014,
Kothari D, Lim BH. Diabetes and pregnancy: time to Issue 4. [DOI: 10.1002/14651858.CD009613.pub2]
rethink the focus on type 2 diabetes. Australian and New
Zealand Journal of Obstetrics and Gynaecology 2014;54(2): NICE 2015
181–3. NICE. Diabetes in pregnancy: management of diabetes
and its complications from preconception to the postnatal
Krane 2014
period. [accessed
Krane NK, Pasala R, Baudy A. Pregnancy and diabetic
June 2015] 2015.
nephropathy. Diabetes and Kidney Disease. New York:
Springer, 2014. Nolan 2011
Nolan CJ, Damm P, Prentki M. Type 2 diabetes across
Kumareswaran 2013 generations: from pathophysiology to prevention and
Kumareswaran K, Elleri D, Allen JM, Caldwell K, Nodale management. Lancet 2011;378(9786):169–81.
M, Wilinska ME, et al. Accuracy of continuous glucose
monitoring during exercise in type 1 diabetes pregnancy. RevMan 2014 [Computer program]
Diabetes Technology & Therapeutics 2013;15(3):223–9. The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). Version 5.2. Copenhagen:
Lawrence 2008 The Nordic Cochrane Centre, The Cochrane Collaboration,
Lawrence JM, Contreras RC, WansuSacks DA. Trends in the 2014.
prevalence of pre-existing diabetes and gestational diabetes
Ryu 2014
mellitus among a racially/ethnically diverse population of
Ryu RJ, Hays KE, Hebert MF. Gestational diabetes mellitus
pregnant women, 1999-2005. Diabetes Care 2008;31(5):
management with oral hypoglycemic agents. Seminars in
Perinatology. Elsevier, 2014; Vol. 38:508–15.
McCance 2010
McCance DR, Holmes VA. Insulin Regimens in Pregnancy: a Schunemann 2011
Practical Manual of Diabetes in Pregnancy. Oxford: Wiley- Schunemann HJ. GRADE: from grading the evidence
Blackwell, 2010. to developing recommendations. A description of the
system and a proposal regarding the transferability
Middleton 2012 of the results of clinical research to clinical practice
Middleton P, Crowther CA, Simmonds L. Different [GRADE:Von der Evidenz zur Empfehlung. Beschreibung
intensities of glycaemic control for pregnant women desSystems und Losungsbeitrag zur Ubertragbarkeit
with pre-existing diabetes. Cochrane Database of vonStudienergebnissen]. Zeitschrift fur Evidenz,
Systematic Reviews 2012, Issue 8. [DOI: 10.1002/ Fortbildungund Qualitat im Gesundheitswesen 2011;103(6):
14651858.CD008540.pub3] 391–400.
Misso 2010 Siebenhofer 2004
Misso ML, Egberts KJ, Page M, O’Connor D, Shaw J. Siebenhofer A, Plank J, Berghold A, Horvath K, Sawicki
Continuous subcutaneous insulin infusion (CSII) versus PT, Beck P. Meta-analysis of short-acting insulin analogues
multiple insulin injections for type 1 diabetes mellitus. in adult patients with type 1 diabetes: continuous
Cochrane Database of Systematic Reviews 2010, Issue 1. subcutaneous insulin infusion versus injection therapy.
[DOI: 10.1002/14651858.CD005103.pub2] Diabetologia 2004;47(11):1895–905.
Mooradian 2006 Siebenhofer 2006
Mooradian AD, Bernbaum M, Albert SG. Narrative review: Siebenhofer A, Plank J, Berghold A, Jeitler K, Horvath
a rational approach to starting insulin therapy. Annals of K, Narath M, et al. Short acting insulin analogues versus
Internal Medicine 2006;145:125–34. regular human insulin in patients with diabetes mellitus.
Cochrane Database of Systematic Reviews 2006, Issue 2.
Morken 2014
[DOI: 10.1002/14651858.CD003287.pub4]
Morken NH, Källen K, Jacobsson B. Predicting risk of
spontaneous preterm delivery in women with a singleton Tennant 2014
pregnancy. Paediatric and Perinatal Epidemiology 2014;28 Tennant PWG, Glinianaia SV, Bilous RW, Rankin J, Bell R.
(1):11–22. Pre-existing diabetes, maternal glycated haemoglobin, and

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 12
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
the risks of fetal and infant death: a population-based study. Wass 2011
Diabetologia 2014;57(2):285–94. Wass JA, Stewart PM. Oxford Textbook of Endocrinology and
Teuscher 2007 Diabetes. Second Edition. New York: Oxford University
Teuscher A. Insulin: A Voice for Choice. Karger Medical and Press, 2011.
Scientific Publishers, 2007. WHO 1999
Tieu 2010a World Health Organization. Definition, Diagnosis and
Tieu J, Coat S, Hague W, Middleton P. Oral anti-diabetic Classification of Diabetes mellitus and its Complications. Part
agents for women with pre-existing diabetes mellitus/ 1: Diagnosis and Classification of Diabetes Mellitus. Geneva:
impaired glucose tolerance or previous gestational diabetes WHO, 1999.
mellitus. Cochrane Database of Systematic Reviews 2010,
Issue 10. [DOI: 10.1002/14651858.CD007724.pub2] Yessoufou 2011
Yessoufou A, Moutairou K. Maternal diabetes in pregnancy:
Tieu 2010b
early and long-term outcomes on the offspring and the
Tieu J, Middleton P, Crowther CA. Preconception care for
concept of “metabolic memory”. Experimental Diabetes
diabetic women for improving maternal and infant health.
Research 2011;2011:218598.
Cochrane Database of Systematic Reviews 2010, Issue 12.
[DOI: 10.1002/14651858.CD007776.pub2] Øverland 2014
Visser 2013 Øverland EA, Vatten LJ, Eskild A. Pregnancy week at
Visser J, Snel M, Van Vliet HAAM. Hormonal versus non- delivery and the risk of shoulder dystocia: a population
hormonal contraceptives in women with diabetes mellitus study of 2,014,956 deliveries. BJOG: an international
type 1 and 2. Cochrane Database of Systematic Reviews 2013, journal of obstetrics and gynaecology 2014;121(1):34–41.
Issue 3. [DOI: 10.1002/14651858.CD003990.pub4] ∗
Indicates the major publication for the study


Appendix 1. Search terms

type 1 diabetes AND pregnancy
type 2 diabetes AND pregnancy
insulin AND diabetes AND pregnancy

All six review authors were involved in the development of this protocol. Sinéad O’Neill co-ordinated and drafted the protocol, and
is the guarantor of the review. Louise Kenny, Rebecca Smyth and Patricia Kearney assisted in conceiving the review and offered a
clinical perspective. Ali Khashan provided statistical advice, as well as general advice on the protocol. Paul Beirne assisted with securing
fellowship funding and provided detailed comments on the protocol. Paul Beirne will not be involved in the full review.

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 13
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
SON: None known.
AK: None known.
LK: None known.
PB: None known.
RS: None known.
PK: None known.


Internal sources
• The Irish Centre for Fetal and Neonatal Translational Research (INFANT), University College Cork (UCC), Ireland.
LK is a Science Foundation Ireland (SFI) Principal Investigator (08/IN/.1/B2083) and the Director of the SFI funded centre
INFANT (12/RC/2272)
• University College Cork (UCC), Ireland.
PB, SON, AK, and LK are employees of UCC and receive support from the University in the form of a salary.

External sources
• Health Research Board (HRB), Ireland.
SON is the recipient of a full Cochrane Fellowship (Grant no: CTF-2014-884) from the HRB, Ireland
• National Institute for Health Research (NIHR), UK.
NIHR Cochrane Programme Grant Project: 13/89/05 - Pregnancy and childbirth systematic reviews to support clinical guidelines

Different insulin types and regimens for pregnant women with pre-existing diabetes (Protocol) 14
Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.