2013

http://informahealthcare.com/jmfISSN: 1476-7058 (print), 1476-4954 (electronic)

J Matern Fetal Neonatal Med, Early Online: 1–5! 2013 Informa UK Ltd. DOI: 10.3109/14767058.2013.794214

REVIEW

Pregnancy in women with type 1 diabetes: Have the goals of St. Vincentdeclaration been met concerning foetal and neonatal complications?

Miriam Colstrup1,2, Elisabeth R. Mathiesen1,2,4, Peter Damm1,4,5, Dorte M. Jensen3, and Lene Ringholm1,2

1Center for Pregnant Women with Diabetes and 2Department of Endocrinology, Rigshospitalet, University of Copenhagen, Denmark, 3Department

of Endocrinology, Odense University Hospital, University of Southern Denmark, Odense, Denmark, 4Faculty of Health Sciences, University of

Copenhagen, Denmark, and 5Department of Obstetrics, Rigshospitalet, Copenhagen, Denmark

Abstract

Objective: In 1989 the St. Vincent declaration set a five-year target for approximating outcomesof pregnancies in women with diabetes to those of the background population.We investigated and quantified the risk of adverse pregnancy outcomes in pregnant womenwith type 1 diabetes (T1DM) to evaluate if the goals of the 1989 St. Vincent Declaration havebeen obtained concerning foetal and neonatal complications.Methods: Twelve population-based studies published within the last 10 years with in total14 099 women with T1DM and 4 035 373 women from the background population wereidentified. The prevalence of four foetal and neonatal complications was compared.Results: In women with T1DM versus the background population, congenital malformationsoccurred in 5.0% (2.2–9.0) (weighted mean and range) versus 2.1% (1.5–2.9), relative risk(RR)¼ 2.4, perinatal mortality in 2.7% (2.0–6.6) versus 0.72% (0.48–0.9), RR¼ 3.7, pretermdelivery in 25.2% (13.0–41.7) versus 6.0% (4.7–7.1), RR¼ 4.2 and delivery of large for gestationalinfants in 54.2% (45.1–62.5) versus 10.0%, RR¼ 4.5. Early pregnancy HbA1c was positivelyassociated with adverse pregnancy outcomes.Conclusion: The risk of adverse pregnancy outcomes was two to five times increased in womenwith T1DM compared with the general population. The goals of the St. Vincent declarationhave not been achieved.

Keywords

Congenital malformations, perinatal mortality,preterm delivery, type 1 diabetes

History

Received 25 February 2013Revised 11 March 2013Accepted 27 March 2013Published online 14 May 2013

Introduction

Over the course of the last century, the outcomes of

pregnancy in women with diabetes were transformed from

usually being fatal for mother and child, to one where

expectations were raised by the St. Vincent Declaration of

1989 [1], which advocated pregnancy outcomes in women

with diabetes approximating that in women without diabetes

within five years [2]. Obtaining and maintaining strict

glycaemic control before and during pregnancy is crucial to

prevent or reduce the risk of adverse pregnancy outcome in

women with type 1 diabetes [3–10]. Specifically, as organo-

genesis takes place in the first trimester of pregnancy,

inadequate pre-conceptional glycaemic control is associated

with an increased risk of congenital malformation [11].

Supplementation with folic acid peri-conceptionally up to 12

gestational weeks might reduce the risk of an adverse

pregnancy outcome including congenital malformations

[12,13]. Given the relatively low incidence of congenital

malformations and perinatal mortality, large studies are

required for accurate risk estimates.

This review explores four complications: congenital mal-

formations, perinatal mortality (including stillbirth), preterm

delivery and delivery of a large for gestational age (LGA) infant

with the aim to investigate and quantify the risk of these

adverse pregnancy outcomes in pregnant women with type 1

diabetes compared with the background population and to

investigate whether the goals of St. Vincent declaration of 1989

have been met concerning foetal and neonatal complications.

Methods

All clinical or register-based population studies with original

data including at least 200 women with type 1 diabetes

published within the last 10 years were identified in the

PubMed database by using Medical Subject Heading terms

and text words: Diabetes mellitus type 1 AND pregnancy –

with complications OR epidemiology. Of the 835 titles

scanned, 41 abstracts were read and 10 relevant articles

found. The identified articles were reviewed and the

reference lists were checked to look for further relevant

articles. An additional two articles were found [5,8]. The

inclusion criteria were studies reporting data on at least two

Address for correspondence: Lene Ringholm, Department of Endocri-nology, Center for Pregnant Women with Diabetes, 2131 Rigshospitalet,University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen,Denmark. E-mail: enel@dadlnet.dk

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of the following adverse outcomes in women with type 1

diabetes: 1) congenital malformations, 2) perinatal mortality,

3) preterm delivery and 4) LGA infants. Studies including

data on both type 1 diabetes and type 2 diabetes with no

distinction between data on the two were excluded from this

study.

The material consists of 12 papers of which seven report

nationwide data: France [3], Scotland [7], the Netherlands [4],

Denmark [5], Sweden [14] and Norway [15,16] where [15] is

a complement to [16]. Five studies report regional data from

Belgium [17], UK [6,8,18] and Ireland [19].

Some studies only include singleton pregnancies [3,14],

other studies singleton, twin and triplet pregnancies [4–8,18],

while four studies did not specify this [15–17,19].

The complications are defined as follows:

Congenital malformations were either defined according to

the EUROCAT system [3,6–8,15,18] or as major malforma-

tions if they were lethal, life-shortening, life-threatening,

requiring major surgery or affecting in a significant way the

quality of life, with some variation between the studies

[4,5,14,19].

EUROCAT [20] is a network that collects data on

congenital malformations from 23 European countries. Its

objective is among others to plan and evaluate the effective-

ness of health services (including primary prevention). Minor

congenital malformations were only included in two studies

[4,5] and were defined as the remainder of the anomalies

present [5] or as either hypospadia, vertebral anomalies or

clubfoot [4]. Stillbirth was defined slightly different between

studies as foetal death [17], after 22 [3], 24 [4–6,18,19] or 28

gestational weeks [14], respectively. Perinatal mortality was

defined as stillbirths or infant death within the first seven

[4–6,14,16,19] or 28 days [3,17,18] of life.

Preterm delivery was defined as delivery before 37 weeks

[3–5,14,16,19]. LGA was defined as birth weight �90th

percentile of the background population adjusted for gesta-

tional age and sex [4,5,7,18]. Two studies had other

definitions and these are marked and described in Table 1

[14,19].

Statistical methods

Data is given as weighted mean and range. Weighted mean

(�X) was calculated using the formula:

ð�XÞ¼ w1 �x1þw2 �x2þ . . .þwn �xnð Þ= w1þw2þ . . . :þwnð Þ,

where w is the number of women in the given study, x is the

risk of complication in percent and n is the number of studies.

Nine studies [4–7,14–17,19] included exact numbers of the

background population, so the weighted mean for the

background population was calculated using only data from

these studies.

The relative risk (RR) was given in some articles, and in

the rest it was calculated using the equation: RR¼ P(women

with diabetes)/P(women from the background population),

where P is the percentage of women with the given

complication. The overall RR for each of the four complica-

tions was calculated using the weighted mean of the women

with type 1 diabetes and women from the background Tab

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2 M. Colstrup et al. J Matern Fetal Neonatal Med, Early Online: 1–5

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population, respectively. Due to lack of precise numbers in

some of the background population, it was not possible to

calculate 95% confidence intervals, so in general range is

presented instead.

Results

The material consists of in total 14 099 pregnant women with

type 1 diabetes [3–8,14–19] and 4 035 373 pregnancies from

relevant background populations [4–7,14–17,19] covering

pregnancies from 1985 to 2008 (Table 1). The prevalence of

congenital malformation in women with type 1 diabetes was

5.0% (2.2–9.0) (weighted mean and range) versus 2.1% (1.5–

2.9) in the background population, RR¼ 2.4 (1.5–6.4).

These numbers are for live born babies with congenital

malformations and do not take into account antenatal

terminations due to congenital malformation. In the six

studies with relevant information [4,5,7,8,15,19], 0.44% (0–

2.2) of pregnancies complicated by type 1 diabetes were

terminated due to antenatally diagnosed congenital

malformation.

The perinatal mortality rate was 2.7% (2.0–6.6) versus

0.72% (0.48–0.9), RR¼ 3.7 (2.8–9.4) and higher in unplanned

than planned pregnancies, 8.1% versus 0.7%, RR¼ 11.6 [3].

In Sweden, the perinatal mortality declined from 3.1% in

1982–1985 to 2.0% in 1991–2003 [14]. However, it was

still significantly higher in women with type 1 diabetes

compared with the background population (2.0% versus

0.48%, RR¼ 4.2) [14].

Perinatal mortality occurred more frequently in women

with first trimester HbA1c48.0% (IFCC 64 mmol/mol)

compared with women with first trimester HbA1c58.0%

(IFCC 64 mmol/mol) (9.2% versus 2.5%, RR¼ 3.7) [3]. Up to

90% of cases with perinatal mortality and congenital malfor-

mations occurred in unplanned pregnancies and in women

who had first trimester HbA1c48.0% (IFCC 64 mmol/mol)

[3]. Even with HbA1c below 8.0% (IFCC 64 mmol/mol), the

risk of perinatal mortality was markedly higher in women

with type 1 diabetes compared with the background popula-

tion (2.5% versus 0.7%, RR¼ 3.6) [3].

Preterm delivery occurred in 25.2% (13.0–41.7) with a RR

of 4.2 (2.2–8.6) compared with the background population

and LGA infants occurred in 54.2% (45.1–62.5) of the cases

with a RR of 4.5 (Table 1). Over time, the rate of LGA infants

in Sweden has increased, both in women with diabetes and in

a control group [14]. In women with type 1 diabetes, the LGA

rate increased from 27.6% in 1991–1997 to 35.0% in 1998–

2003 compared to an increase from 3.4% to 3.8% in the

background population [14].

Two studies included data on pre-conception counselling

[3,5] which was given in 48.5% and 58% of women with type

1 diabetes, respectively. Planning of pregnancy was reported

in one study [4] where 84% of women had planned

pregnancies. Adequate preparation for pregnancy with pre-

conception folic acid supplement and first trimester

HbA1c� 7.0% (IFCC 58 mmol/mol) was reported in 18.8%

[18]. Data on folic acid supplements were given in three

studies [4,15,18]. Adequate pre-conceptional supplement

varied from 9.7% of women [15] to 70% [4]. There was a

higher occurrence of first trimester HbA1c48.0% (IFCC

64 mmol/mol) in women not receiving preconception care

compared with women who did receive pre-conception care

(55.0% versus 4.3%) [3].

Discussion

This review of 12 original population-based studies of

pregnancy outcomes in women with type 1 diabetes shows

that these women have a markedly increased risk of adverse

pregnancy outcomes. The relative risks for congenital mal-

formations, perinatal mortality, preterm delivery and LGA

infants were two- to fivefold that of the background popula-

tion. Therefore, the current outcomes of pregnancies in

women with type 1 diabetes still fail to meet the goals of the

St. Vincent Declaration of 1989, advocating that pregnancy

outcomes in women with diabetes should approximate that in

women without diabetes within five years [2].

A strength of this study is that it includes a total of 14 099

women with type 1 diabetes and 4 035 373 pregnancies in the

background population. The search for studies has been

thorough and includes 12 articles from 9 different countries

published within the last 10 years.

In the included studies, there are some differences as to

how the complications are defined and the CEMACH study

[6] did not define ‘‘serious adverse pregnancy outcomes’’.

Furthermore, no relevant studies outside of Europe were

identified. Original studies from Australia and North America

were excluded because there was no differentiation between

women with type 1 diabetes and type 2 diabetes. No studies

from Asia, South America or Africa corresponded with the

inclusion criteria.

Data collection in the studies included in this review

differed and thus the quality of the data material varied. Some

studies collected data through registries [14–17] and the

remaining studies [3–8,18,19] collected data on the hospital

site. Possible reasons for differential outcomes between the

countries are hard to identify as there are differences between

the countries in the organization of care for women with

diabetes, the knowledge level of the population and the

quality and access to care in pregnancy.

Higher first trimester HbA1c is associated with higher risk

of adverse pregnancy outcomes [5] such as congenital

malformations [4,19], perinatal mortality [19] preterm deliv-

ery [4,19] and LGA [19]. The CEMACH study [6] found that

median HbA1c was higher in women with serious adverse

pregnancy outcomes than women without serious adverse

pregnancy outcomes.

Jensen [21] reported gradually increasing risk of both

perinatal mortality and congenital malformation among type 1

diabetic pregnancies with increasing peri-conceptional HbA1c

levels. Even at HbA1c levels below 6.9% (IFCC 52 mmol/mol)

(corresponding to the meanþ 3 standard deviations for a non-

pregnant population), the risk of perinatal mortality was

significantly higher than in the background population. If a

threshold for HbA1c exists below which the risk of perinatal

mortality equals the risk for non-diabetic women, this might

be lower than 6.9% (IFCC 52 mmol/mol). Similarly, Evers [4]

found that even in pregnancies where women monitor their

blood glucose values very closely throughout the whole

pregnancy with HbA1c within the recommended range, the

DOI: 10.3109/14767058.2013.794214 Adverse pregnancy outcomes in women with type 1 diabetes 3

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risk of complications is still increased in women with type 1

diabetes compared with the background population. Although

HbA1c is used as a measure of blood glucose regulation in

many studies [3–6,18,19], it cannot be used as the only tool to

monitor patients regarding their glycaemic control throughout

pregnancy because plasma glucose measurements can dis-

close wide variations in plasma glucose that might not

otherwise be recognised [22].

Clinical recommendations for peri-conceptional HbA1c in

women with type 1 diabetes are usually an HbA1c below the

meanþ 2–3 standard deviations. However, in pregnant

women without type 1 diabetes HbA1c levels are markedly

lower than this [23]. Women with type 1 diabetes, impaired

hypoglycaemia awareness and severe hypoglycaemia before

pregnancy have a clinically significant risk of severe hypo-

glycaemia in early pregnancy [24]. Thus, it might not be

realistic to aim for lower HbA1c in this subgroup of women

with type 1 diabetes. Individual goals for HbA1c should be

discussed aiming at the lowest possible level.

It is not fully understood why hyperglycaemia may lead to

congenital malformations, but hyperglycaemia may induce

cell damage and apoptosis during organogenesis and thereby

result in congenital malformations [25]. These findings

suggest that short-term variability in blood glucose can

affect the pregnancy outcome and that tight glycaemic control

prior to conception and around the time of conception is

crucial. High third trimester HbA1c (measured at 28 weeks)

together with increasing albuminuria and blood pressure have

also been shown to be clinically significant predictors for

preterm delivery [26]. These observations underline that

treatment of pregnant women with type 1 diabetes should

focus on both glycaemic control and blood pressure/albumin-

uria to prevent preterm delivery [27].

It is a clinically useful observation that the risk of an

adverse pregnancy outcome is halved with each percentage

reduction in HbA1c achieved before pregnancy [11].

Folic acid is an essential nutrient required for DNA

replication [28]. During pregnancy the demand for folic acid

increases as it is needed for growth and development of the

foetus. Folic acid deficiency has been associated with

congenital abnormalities of the foetus [28]. In order to

reduce the risk of congenital malformations all women are

advised to take folic acid supplements from before conception

until 12 gestational weeks [12]. In this study, only three

studies [4,15,18] included data on pre-conceptional supple-

mentation with folic acid, with numbers varying between less

than 10% up to 70% of women taking appropriate folic acid

supplementations in first trimester.

Achieving optimal levels of glycaemic control, pre-

pregnancy counselling and folic acid intake is associated

with improved pregnancy outcomes [13]. Optimally all

women with type 1 diabetes should attend preconception

counselling in order to plan their pregnancy appropriately.

Women without preconception counselling had higher HbA1c

levels [3,4,29] and were at excess risk of pregnancy compli-

cations [3–5,29]. Despite a high percentage of planned

pregnancies in the study by Evers [4], the relative risk of

adverse pregnancy outcomes still remained high in women

with type 1 diabetes compared with the background popula-

tion, suggesting that several factors play a role in reducing

these risks. Development over time including several minor

clinical improvements may play a role for change in the risk

of adverse pregnancy outcomes in women with type 1

diabetes. In Denmark, for example, the rate of stillbirths

among women with type 1 diabetes was 2.0% in 1993–1999

[5], but during the following years, the levels of glycaemic

control improved considerably and in 2000–2009 the rate of

stillbirths declined to 0.7% in the largest Danish centre [30].

Meanwhile the risk for LGA both in women with type 1

diabetes and in the background population increased signifi-

cantly over time in Sweden, possibly partly due to increasing

BMI in women with type 1 diabetes [14].

In summary, women who were adequately prepared for

pregnancy – receiving preconception care, having good

glycaemic control and taking folic acid supplements –

were less likely to experience pregnancy complications

[3–5,15,18,19].

In conclusion, a quarter of a century after the St. Vincent

declaration of 1989, women with type 1 diabetes still have a

two to five times increased risk of adverse pregnancy

outcomes compared with the background population.

Aiming for pre-conception counselling with folic acid

supplement before and in early pregnancy and strict gly-

caemic control during pregnancy is essential to approximate

the targets of St. Vincent’s declaration.

Declaration of interest

The authors report no declarations of interest.

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DOI: 10.3109/14767058.2013.794214 Adverse pregnancy outcomes in women with type 1 diabetes 5

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