Preconception care in women with known pre-diabetes

Optimising diabetes management, including glycaemia and coexisting morbidities, before conception has been shown to improve pregnancy outcomes. It is important for women planning pregnancy to seek healthcare advice and support to be able to do this. This may be provided by a range of specialist services within primary or secondary care. Contraception should be used until these measures have been put in place. High-dose folic acid (5 mg) should be prescribed and taken for three months prior to stopping contraception and throughout the first trimester to reduce the risk of congenital abnormalities. All medications, including antihypertensives, statins, and glucose lowering treatments, should be reviewed and, where required, switched to alternative medication which is more suitable during pregnancy.¹⁴
The range of glucose-lowering medications has expanded markedly in recent years including development of agents such as glucagon-like peptide 1 (GLP-1) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones and sodium glucose cotransporter 2 (SGLT2) inhibitors. The British National Formulary (BNF) indicates all of these agents to be avoided in pregnancy for reasons ranging from lack of information on their effects to toxicity in animal studies. Sulphonylureas are listed to be avoided in pregnancy due to risk of neonatal hypoglycaemia. Glibenclamide was previously used in pregnancy but the adult formulation has been withdrawn (see section 5.5).
Blood glucose levels should be optimised when women with diabetes are planning pregnancy. To facilitate this, opportunistic conversation should be initiated during every annual review with women of childbearing age, including consideration of use of insulin pumps and CGM to optimise individual glucose levels. Body mass index should be reviewed and weight management advice offered if appropriate. Guidance from the Royal College of Obstetrics and Gynaecology recommends provision of advice on weight and lifestyle by primary care services to all women of childbearing age during prepregnancy counselling.¹⁵ Other lifestyle factors should be discussed such as contraception, healthy eating and exercise, stopping smoking and avoiding alcohol and other drugs.

Blood glucose
No evidence was identified which compared planned or achieved blood glucose target ranges in women planning pregnancy.

The St Vincent Declaration in 1989 set a goal that pregnancy outcomes in women with pregestational diabetes should approximate those of the general population. To do this, women must achieve as near normal blood glucose levels during pregnancy as can safely be achieved without dangerous levels of hypoglycaemia. In over three decades since the Declaration, this goal has not been achieved, nor has there been clear articulation of the optimal targets required to support it.¹⁶

A mixed-methods systematic review incorporated 32 studies by narrative synthesis on the impact of T2DM on women’s health and wellbeing during reproductive years.¹⁷ Several studies reported that risks associated with diabetes during pregnancy were understood by pregnant women to different extents, including variable blood glucose levels (80%), congenital malformations (48%) and fetal macrosomia (35%). Awareness of pregnancy risks for women with T2DM was reported as an incentive to attend prepregnancy care. The authors report a number of studies suggesting that while attendance at prepregnancy care was often low, those women who attended had achieved significantly improved glucose levels before pregnancy and in the first two trimesters.

The barriers to attending prepregnancy care included the pregnancy being not ‘fully planned’ (45%), fertility concerns (31%) and negative relationship with healthcare professionals (21%). Based on evidence from qualitative research, women reported that healthcare professionals emphasised medical aspects of diabetes management such as blood glucose levels, diet and exercise. Studies described some consultations with professionals to be like tick-box exercises as they focused on asking questions from a template that failed to include women’s reproductive needs.
From a population perspective, it may be more important to increase the proportion of women with pre-existing diabetes who actively plan for pregnancy than to focus on the ideal blood glucose target alone.

The National Pregnancy in Diabetes (NIPID) audit measures the quality of pregestational diabetes care against National Institute for Health and Care Excellence (NICE) guideline-based criteria and the outcomes of pregestational diabetic pregnancies in England and Wales. In 2021, the NIPID report showed that, between 2014 and 2020, seven out of eight women were not adequately prepared for pregnancy and this figure did not improve during that period.¹⁸

Glycated haemoglobin (haemoglobin A1c)
Studies which provide data on the association between HbA1c and maternal and fetal outcomes are from a range of study designs and are of varying quality. Evidence cited in NICE guideline NG3 on diabetes in pregnancy: management from preconception to the postnatal period includes studies published in the 1980s whose participants are less representative of contemporary Scottish women.¹⁴ Across all studies that were considered, the populations vary significantly and participants have a wide range of HbA1c values at baseline. This variation also includes a spectrum of ethnicities and BMI values which are less generalisable to the current Scottish population.

Evidence which includes a systematic review, prospective and retrospective cohort studies and retrospective surveys consistently suggests that lower periconceptual HbA1c is associated with lower risk of congenital anomalies,^19-21 preterm birth,²² stillbirth,^21,23 Caesarean birth²⁴ and early onset pre-eclampsia²⁴ in women with T1DM or T2DM planning a pregnancy.

However, studies are inconsistent in HbA1c thresholds used. Several suggest that there is no safe threshold level, but a continuous relationship between HbA1c at delivery and frequency of good perinatal outcome.²¹ One systematic review reports a relative risk of 3.2 for risk of congenital anomalies in those with pregestational diabetes compared with those without.²⁰ A cohort study reported risk of major anomalies increasing within different ranges of HbA1c from a relative risk (RR) of 2.35 with HbA1c range 58–79 mmol/mol, RR 3.17 with HbA1c range 80–104 mmol/mol to a RR of 7.75 for those with an HbA1c of >102 mmol/mol.¹⁹

A meta-analysis of 36 studies investigating the effectiveness of prepregnancy care for women with diabetes included 24 observational studies (n=4,927 women) which reported that prepregnancy care likely results in a reduction in HbA1c in the first trimester of pregnancy by an average of 1.27% (95% confidence interval (CI) 1.33 to 1.22, I²=98).²⁵ The authors note that heterogeneity can be explained by the wide time period in which studies were published (1982–2017), during which time many innovations in the management of diabetes have occurred with substantial reduction in the target level of HbA1c.

A retrospective cohort study conducted in France and Italy of 107 pregnancies in women with T1DM treated using insulin pumps demonstrated that lower mean HbA1c in pregnancies that were planned (prepregnancy HbA1c: 53 mmol/mol vs 64 mmol/mol), was associated with a reduced risk of preterm birth (RR 0.44, 95% CI 0.25 to 0.76).²² There was no statistically significant difference in rates of pre-eclampsia, hypertension or delivery by Caesarean section between groups with planned and unplanned pregnancies. Compared with women in the general French population, women with T1DM in the study cohort had twice the rate of congenital anomalies, ten times the large for gestational age (LGA) rate, four times the rate of prematurity and a rate of birth by Caesarean section which was three times higher. The authors concluded that additional metrics of glucose levels beside HbA1c should be considered.
A Scottish population-based study assessed the risk of stillbirth in women with T1DM or T2DM.²³ A higher HbA1c level prepregnancy was associated with a higher risk of stillbirth in both women with T1DM (odds ratio (OR) 1.03) and T2DM (OR 1.02) diabetes. Overall, stillbirth rates were highest in women with T2DM (22.9/1000) compared with T1DM (16.1/1000). The stillbirth rate in the general population in Scotland was 3.8/1000 births in 2021.²⁶

A retrospective survey of 533 women with T1DM conducted in the United States of America (USA) reported that women who planned their pregnancies had significantly lower HbA1c at the time of conception than those who did not (mean 49 mmol/mol vs 61 mmol/mol).²⁴ Those with higher HbA1c had higher rates of Caesarean birth, more weight gain, more hypoglycaemic episodes and earlier pre-eclampsia.

The NICE guideline identified five observational studies which reported associations between prepregnancy HbA1c and risk of congenital malformations or perinatal mortality.¹⁴ There was variation in HbA1c thresholds for optimal pre-pregnancy levels used across the studies (range 45.4 to 63.9 mmol/mol) and none of the studies set specific target values for women to achieve. The threshold values were established by various means, including derivation from regression results of scatter plot data and arbitrary selection or inference by study authors.
In general when all studies were considered, there was inconsistency in the association between perinatal outcomes and prepregnancy HbA1c above and below the single threshold considered in each study. Some studies reported a significantly increased risk above the threshold used, while others showed no relationship. One study showed a reduced risk of congenital malformations (RR 0.30, 95% CI 0.12 to 0.74) and perinatal mortality (RR 0.28, 95% CI 0.11 to 0.68) in women with HbA1c of 64 mmol/mol or less compared with HbA1c >64 mmol/mol.
A further study showed no effect of HbA1c <52 mmol/mol on risk of congenital malformations (RR 0.74, 95% CI 0.38 to 1.44) or perinatal mortality (RR 0.55, 95% CI 0.23 to 1.23) compared with HbA1c of ≥52 mmol/mol. A retrospective cohort study found an increased risk of congenital malformations in women with HbA1c >45 mmol/mol compared with HbA1c of ≤45 mmol/mol (OR 5.22, 95% CI 3.15 to 8.32). The NICE guideline development group noted that data from this study showed a threshold effect where the risk of congenital malformations increased in an approximately linear fashion above an HbA1c of 45 mmol/mol. Specifically, an 11 mmol/mol increase in HbA1c was associated with a 30% increase in risk. This indicates that even if women do not achieve an HbA1c below 45 mmol/mol they could still reduce their risk of having a baby with a congenital malformation. However, the NICE group felt that it was important to align the recommendations with those made in the NICE guideline on type 1 diabetes in adults²⁷ and therefore recommended 48 mmol/mol as the target threshold.
Based on a single study, the NICE guideline development group also noted associative data to suggest that the risk of stillbirth is particularly high for women with an HbA1c >86 mmol/mol and advised that such women should be strongly advised to avoid pregnancy.

Despite study variation, the balance of evidence is that lower HbA1c reduces the risk of pregnancy complications. The use of rtCGM and the advent of closed loop insulin pumps makes these levels more attainable than in the past, however, reducing glucose levels towards normal carries a potential to increase the incidence of hypoglycaemia. The effect of this and the pressures of striving for normal glucose levels on time and mental health should not be ignored. An individualised balance must be sought.
Although a goal of <48 mmol/mol is desirable, there appears to be a linear relationship between HbA1c level and adverse perinatal outcomes suggesting that any reduction in prepregnancy HbA1c while avoiding excessive hypoglycaemia is likely to be beneficial.

Recommendation

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Women with T1DM or T2DM planning a pregnancy should aim for an HbA1c as low as possible without excessive hypoglycaemia.

Good practice

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Women should be offered advice on weight management prior to pregnancy in line with guidance from the Royal College of Obstetricians and Gynaecologists and national programmes (for example, A Healthier Future: type 2 diabetes prevention, early detection and intervention framework). This is likely to be of particular benefit to women with type 2 diabetes or prior GDM when planning pregnancy.

Good practice

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Advise women that HbA1c <48 mmol/mol can minimise risk of perinatal mortality and morbidity but should not be used a strict threshold for access to assisted conception services. An individualised approach should be used.

Good practice

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Other risk factors such as BMI, smoking, hypertension and level of diabetic retinopathy should be taken into account when individualised HbA1c targets are being considered.

Good practice

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Pregnancy should be avoided if HbA1c >86 mmol/mol.

Evidence from population-based studies indicates that only 34–38% of eligible women receive prepregnancy counselling.²⁸ As such, optimising baseline care for women of reproductive age with T2DM becomes more important.

Good practice

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Referral of women with T2DM who are planning a pregnancy to secondary care for optimisation of their diabetes should be considered, including the possibility of the use of CGM if preconception glycaemic targets are not being met. If not already being used, this is an opportunity to further consider medication to lower cardiovascular risk.

Good practice

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Diabetes and obstetric teams should take opportunities to engage with all women with pre-existing diabetes early in pregnancy irrespective of their attendance at prepregnancy counselling clinics. This should be as soon as possible after a positive pregnancy test, ie before the formal ‘booking’ appointment takes place.

Good practice

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All medications should be reviewed prepregnancy for suitability in pregnancy and women should be advised to take 5 mg folic acid for at least 3 months prior to conception and throughout the first trimester.

Preconception care in women with known pre-diabetes

Glycaemic targets when planning a pregnancy