Managing diabetes in women during preconception and pregnancy

More than 35,000 women with either pre-existing or gestational diabetes (GDM) give birth in England and Wales every year^[1]
. Around 90% of these pregnancies are in women with GDM, however, the number of pregnancies in women with type 2 diabetes (T2D) is increasing. These women with T2D tend to be older, more overweight, come from more socially deprived backgrounds, and prevalence is higher in those of Asian (70%) and black origin (90%) compared with 30% of women of white origin^[2]
.

Unless well managed, pregnant women with diabetes face an increased risk of adverse outcomes including miscarriage, pre-eclampsia, surgical delivery and acceleration of pre-existing diabetes complications. Babies born to mothers with diabetes face an increased risk of pre-term delivery, birth trauma, being large for gestational age, higher rates of admission to neonatal units, stillbirth and neonatal death^[2]
. In addition, there are emerging data showing that offspring to mothers with diabetes are at greater risk of childhood obesity and progression to T2D in later life^[3]
.

Rates of adverse outcomes for women with diabetes in pregnancy have improved over recent decades but they remain significantly elevated compared with the background population. For example, the UK National Pregnancy in Diabetes Audit (NPDA) data for 2015^[2]
showed that the stillbirth rate has reduced significantly since the Confidential Enquiry into Maternal and Child Health: Pregnancy in type 1 and type 2 diabetes in 2002–2003^[4]
. However, for women with type 1 diabetes (T1D) and T2D the stillbirth rate is still 10.7 and 10.5 per 1,000 births, respectively, compared with rates in the general population of 4.7 per 1,000 live and stillbirths^[2]
.

When considering other contributory factors to poor outcomes in pregnancies with diabetes, it is known that maternal social deprivation and older age are significant factors^[5]
, along with unplanned pregnancies, smoking, poor peri-natal care, pre-existing diabetes complications (e.g. nephropathy), lack of pre-conceptual folic acid supplementation and lack of baseline retinal examination^[5]
. However, despite knowledge of the potential risks, recent data from the NPDA show that women continue to be poorly prepared for pregnancy, for example, only 16% of women with T1D and 38% of women with T2D have the desired first trimester HbA_1c of <48mmol/mol, which has been shown in association studies to reduce the major risks of adverse pregnancy outcomes.

With an increasing population of individuals with T2D and rising national obesity levels, the number of pregnancies affected by diabetes are likely to rise beyond the current 5%. This will undoubtedly add to the burden on already stretched diabetes and obstetric services. Most women with T2D are likely to be managed solely in primary care and it is important to remember that some of the highest risk women with pre-existing diabetes are those who do not attend for their formal diabetes care. These are women, however, who are still likely to be engaging with their pharmacists, dentists, optometrists and other healthcare professionals. Indeed, Dhavliker and Purohit, highlight that “Pharmacists are uniquely placed to provide such advice through new registration, well women, contraception and medication reviews.”^[6]

It is therefore the role of every healthcare professional to educate all women of childbearing age on healthy lifestyle choices and the importance of early pre-conceptual care, and encourage them to keep in contact with their diabetes team. This article will focus on the potential adverse pregnancy outcomes associated with diabetes; contraceptive advice for women with diabetes; pre-conceptual advice for women with diabetes; lifestyle management in women of childbearing age; importance of retinal screening before and during pregnancy and GDM to include diagnosis, management and post-natal follow-up.

Pregnancy planning and pre-conception advice

Structured pre-conception advice and care, delivered by a multi-disciplinary team, is advocated as gold standard because early planning allows optimisation of diabetes care and is associated with a 75% decrease in congenital malformations and 66% decrease in perinatal mortality^[7],
[8]
. However, uptake of pre-conception advice remains poor. Murphy et al. found that only 27% of women with pre-existing diabetes who became pregnant had received pre-conception advice^[9]
. This highlights the importance of ensuring that contact from all healthcare professionals with women with diabetes of childbearing age should incorporate advice on the importance of pre-pregnancy planning to ensure good glycaemic control before conception; a medication review; folic acid supplementation at 5mg daily for those actively planning a pregnancy; and the adoption of a healthy lifestyle to promote weight loss and smoking cessation as appropriate^[6]
.

Contraception

The National Institute for Health and Care Excellence (NICE), England’s health technology assessment body, advocates a HbA_1c of 48mmol/mol or lower before conception, and recommends that women are offered contraception as per their needs until their HbA_1c is optimal^[1]
.

In the absence of overt vascular disease, in which case the combined oral contraceptive pill should not be given, contraception choices remain the same as for the general population. The UK Medical Eligibility Criteria for Contraceptive Use offers further information to support healthcare professionals to enable women to make appropriate choices regarding contraception^[10]
.

NICE also advises that women should not try to conceive if their HbA_1c is above 86mmol/mol^[1]
.

HbA1c/self-monitoring of blood glucose

In 2015, the NPDA highlighted that in women with T1D, only 16.2% achieved a first trimester HbA_1c below target level and 9.2% had a HbA_1c >86mmol/mol. The mean HbA_1c was 62.7mmol/mol. For women with T2D, those achieving target for HbA_1c were 38.3%, while 7.9% had a HbA_1c >86mmol/mol. The mean HbA_1c for these women was 56mmol/mol^[2]
. Consequently, healthcare professionals need to promote the benefits and importance of good glycaemic control at conception to these women. One way to help is providing education about self-monitoring of blood glucose (SMBG). All women with pre-existing diabetes planning a pregnancy should be offered SMBG and monthly HbA_1c measurement and review^[1]
, ensuring sufficient quantities of testing strips and lancets are provided, especially to women on multiple daily insulin injections. The desired targets for blood glucose levels should be:

• Fasting: 5–7mmol/mol;
• Pre-meal: 4–7mmol/mol;
• 1 hour post-prandial <7.8mmol/mol;

OR

• 2 hours post-prandial <6.4mmol/mol.

Hypoglycaemia

Achieving a HbA_1c of <48mmol/mol is often at the risk of increased hypoglycaemia. Data show that one in ten women will be admitted to hospital during their pregnancy due to hypoglycaemia^[2]
. Any reduction towards a HbA_1c of 48mmol/mol is beneficial, therefore, women should be advised to achieve a level as close to target, while avoiding hypoglycaemia. No blood glucose level should fall below 4mmol/mol.

Women on insulin and, thus at risk of hypoglycaemia, need to be re-educated about hypoglycaemia prevention and management, the need to observe DVLA regulations^[11]
, and the need to keep a supply of fast-acting glucose available. Glucagon should also be provided to those taking insulin, and education should be given to the woman and her family/friends/carers on how to use it.

Diabetic ketoacidosis (DKA)

A review of ketone monitoring is important for women with T1D, especially if they become unwell, particularly in relation to possible hyperemesis gravidarum, in early pregnancy. Diabetic ketoacidosis may occur at lower blood glucose levels than in non-pregnant women.

Folic acid

Neural tube defects are more common in infants of mothers with diabetes. The NPDA illustrated that only 46.1% of women with T1D were taking the recommended daily dose, while only 22.5% of women with T2D were taking the correct dose, 11.2% were taking the incorrect dose of 400mcg^[2]
.

All women with pre-existing diabetes should take high-dose (prescription only) folic acid 5mg once a day for at least three months before conception and up until 12 weeks’ gestation^[1]
.

Medication review

Many medications associated with diabetes have limited or no evidence to support their use in pregnancy, including statins, angiotensin-converting-enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and most blood-glucose lowering agents. Consequently, in 2015, one study found that 8% of women with T2D became pregnant while taking potentially hazardous medications^[2]
.

All women with diabetes who are planning a pregnancy should receive a medication review to ensure that all oral/glucagon-like peptide-1 based blood glucose-lowering agents, other than metformin, are stopped. Furthermore, they should stop taking statins and be provided with specialist advice on alternatives to ACE inhibitors/ARBs for hypertension management or renal protection.

NICE advises that data from clinical trials are not indicative that the rapid-acting insulin analogues aspart and lispro adversely affect pregnancy or the health of the offspring^[1]
. Fiasp insulin, which received European approval in January 2017, is a faster-acting mealtime insulin that has a licence for use in pregnancy^[12]
.

Intermediate acting isophane insulins are described by NICE as the basal insulin of choice, although long-acting basal analogues can be continued in those who are well controlled and already taking them, which is likely to be most women with T1D.

When reviewing insulin, healthcare professionals should remember to check injection sites, correct injection site rotation and appropriate needle length. The UK Forum for Injection Technique (FIT) advocate that all pregnant women should use 4mm needles^[13]
.

Weight management

Obesity is an independent risk factor for adverse outcomes in pregnancy including hypertension, caesarean section, perinatal mortality, congenital malformations and macrosomia. All women with pre-existing diabetes should be advised to keep active and be involved in regular exercise.

Woman with pre-existing diabetes and a BMI greater than 27kg/m² should be encouraged to look at weight loss before pregnancy; NICE recommends that individualised dietary advice be given and structured education offered^[14]
. Women can be signposted to local weight management services and organisations, such as Diabetes UK, who can provide advice about maintaining a heathy diet and lifestyle (see ‘Box: useful resources’).

Retinopathy

Retinopathy can begin or deteriorate in pregnancy and rapid improvements in glycaemic control may contribute to this. Consequently, all women with pre-existing diabetes should have retinal screening before and during pregnancy.

Renal assessment

Renal assessment is also important for women with pre-existing diabetes. Referral to a nephrologist is recommended if serum creatinine is >120µmol/L, urinary albumin creatinine ratio (ACR) is >30mg/mmol or estimated glomerular filtration rate is <45ml/min/1.73m^[1]
.

Smoking cessation

As with any woman planning a pregnancy, smoking cessation advice where relevant is always essential.

Early referral to an antenatal clinic

NICE guidelines advise to “offer immediate contact with joint diabetes and antenatal clinic services to women with diabetes who are pregnant”^[1]
and in 2015 only 54.6% of women with T1D and 36.2% of women with T2D had their first antenatal contact before 8 weeks’ gestation. Therefore, once pregnant, women should be referred immediately for specialist antenatal care.

Additional advice

Diabetes UK has recently launched a helpful tool to help healthcare professionals support women with diabetes as part of their ‘Information Prescription’ series^[15]
. These are simple A4 sheets of information that are designed for use in primary care and can be linked to general practice IT systems or used as hard copies. They summarise the main advice and allow for individualised care planning and goal setting (see ‘Box: useful resources’).

Gestational diabetes (GDM)

GDM is described as carbohydrate intolerance of varying severity first recognised during pregnancy^[16]
. This can include women with previously undiagnosed diabetes and those who have a transient hyperglycaemia because of pregnancy-induced insulin resistance. Similar to those women with pre-existing diabetes, a pregnancy complicated by GDM is associated with a higher risk of adverse maternal and foetal outcomes, including hypertension, caesarean section, shoulder dystocia and macrosomia^[17]
. Current data suggest that GDM comprises around four per cent of all pregnancies in the UK^[2]
.

It is only in the last decade or so that evidence of the significance of GDM has been established^[18],[19]
, and perhaps the most significant influence on this has been the impact of the HAPO (Hypoglycaemia and Adverse Pregnancy Outcomes) study^[20]
. In this observational study, two-hour 75g oral glucose tolerance tests (OGTTs) were given to pregnant women to determine the relationship of maternal and foetal outcomes in respect of fasting, one-hour and two-hour glucose levels. Results demonstrated increased risks, such as the aforementioned caesarean section rates, macrosomia and neonatal hypoglycaemia, across all three time periods where glucose levels were raised even at minimal levels^[20]
.

Definition

The International Association of Diabetes and Pregnancy Study Groups (IADPSG) Consensus Panel^[21]
developed diagnostic criteria for GDM as follows: 

• Fasting glucose ≥5.1mmol/mol;
• 1-hour glucose ≥10mmol/mol;
• 2-hour glucose ≥8.5mmol/mol.

These criteria were adopted by World Health Organization^[22]
and form the basis of Scottish SIGN Guidance^[23]
, Health Service Executive Guidance in Ireland^[24]
and American Diabetes Association Guidance^[3]
.

In the UK, NICE advocate GDM be diagnosed from a 75g OGTT with: 

• Fasting glucose level ≥5.6mmol/mol;
• 2-hour glucose level ≥7.8mmol/mol^[1]
  .

There is controversy regarding the different definitions, such that the IADPSG guidance may lead to increased numbers and the over treatment of GDM, while NICE guidance may lead to at risk women “falling through the net”^[25]
. The latter has been widely disputed^[26]
.

Consequently, since national and international guidelines differ in their advice on the screening and diagnosis of GDM, it is important to be aware of local guidelines as some maternity units have adapted their own.

When to screen

Universal screening for GDM is not recommended. Women should only be offered an OGGT at 24–28 weeks pregnant if they have any of the following risk factors^[1]
: 

• BMI >30kg/m²;
• Previous macrosomic baby weighing ≥4.5kg;
• Previous GDM;
• Family history of diabetes (first-degree relative with diabetes);
• Minority ethnic origin with a high prevalence of diabetes;
• Glycosuria:
  • 2+ on one occasion;
  • Or 1+ on two occasions.

In addition, all women with a history of GDM should be screened at booking, offered SMBG and followed up at 24 weeks pregnant if their initial OGTT was negative. HbA_1c and or fasting glucose is not recommended for diagnosis of GDM. Diagnosis should only be made from a two-hour OGTT.

Management

On diagnosis of GDM, all women should be seen within one week at a joint diabetes/antenatal clinic and be offered SMBG and lifestyle advice. Diet and exercise are vital in helping to manage GDM; current advice is to follow a low GI diet, referral to a dietician and exercise to include activities such as brisk walking for 30 minutes after meals^[1]
.

Blood glucose monitoring is essential and women may be asked to test up to seven times a day, especially if on multiple doses of insulin. Women are encouraged to aim for the same targets as with women with pre-existing diabetes^[1]
:

• Fasting glucose: <5.3mmol/mol;
• 1 hour post-prandial <7.8mmol/mol;

OR

• 2 hours post-prandial <6.4mmol/mol.

Healthcare professionals should remember that this is a difficult time for the mother with so much information being delivered in a short time frame and the concerns for foetal wellbeing. Some maternity services are offering group education sessions as a way for increased numbers of women to see specialist nurses, midwives and dieticians, as well as promoting group support between mothers with GDM.

Medication

If fasting glucose levels do not remain below 7mmol/L with diet and exercise within 1–2 weeks, metformin should be prescribed^[1]
. There is considerable evidence now supporting the safety and use of metformin in GDM^[27],[28]
. However, if metformin is not tolerated or contraindicated, insulin should be offered.

As previously described, insulin should be offered immediately if plasma glucose levels are above 7mmol/L on diagnosis, if fasting plasma glucose levels are 6.0–6.9mmol/L and there are complications, such as macrosomia (large-for-dates babies) or hydramnios (an excess of amniotic fluid in the amniotic sac).

Glibenclamide can be considered if blood glucose levels are not achieved with metformin and the patient declines or is unable to tolerate insulin^[1]
.

It is important that women are reviewed regularly, have contact numbers for the diabetes/obstetric team and are aware when they need to make contact depending on blood glucose levels/concerns that they may have.

Follow-up

Follow-up of women with GDM is very pertinent for the long-term prevention of T2D because these women have been shown to have up to a 40% chance of developing T2D over 10 years^[29]
. NICE recommends that women with GDM have a fasting glucose level checked six weeks post-delivery and, if this is not taken, a HbA_1c blood test should be performed at thirteen weeks or beyond. Advising women to have a HbA_1c blood test when they take their baby for their three-month immunisations as an aide-memoire may be useful. Furthermore, it is important that women are also reminded to attend an annual screening at their GP practice and that advice is regularly reinforced about the prevention of diabetes via healthy active lifestyles.

Infants of mothers with GDM are at an increased risk of developing metabolic syndrome and diabetes^[30]
, therefore, prevention is paramount in all generations. It is hoped that The National Diabetes Prevention Programme will go some way to help with this^[31]
.

Postnatal diabetes management

Hypoglycaemia

Postnatally, women who have been on insulin or glibenclamide are at an increased risk of hypoglycaemia, especially if breastfeeding. If the woman had pre-existing, insulin-treated diabetes their SMBG readings should be closely observed and insulin doses adjusted accordingly. Reduced doses of insulin are likely to be required. Eating a meal or snack before or during breastfeeding should help to reduce the risk of hypoglycaemia.

Metformin and glibenclamide can be prescribed even if the woman is breastfeeding, however, no other diabetes medications, including those stopped in pre-pregnancy, should be used.

If the woman had GDM, all blood glucose-lowering therapy should be stopped immediately after birth^[1]
, unless there is persistent hyperglycaemia. SMBG can also be stopped.

Breastfeeding

Breastfeeding should be encouraged because in women with GDM it has been shown to reduce the risk of progression to T2D. In one study, it was shown to halve the risk of progression over two years^[32]
. Breastfeeding can also reduce the risk of the baby progressing to T2D in later life.

Conclusion

The increasing prevalence of diabetes and the adverse outcomes associated with pregnancies complicated with diabetes emphasizes the importance of effective clinical care in this population. One way to help achieve this goal is ensuring that all healthcare professionals are all delivering consistent messages and advice to women before, during and after pregnancy.