Section 1: Why is pregnancy with diabetes a special concern?

Numerous outcomes in pregnancy are worse for individuals with diabetes compared to those without diabetes.

For pregnancies complicated by diabetes, there is an increased incidence of preterm birth, stillbirth and neonatal death. Rates of pre-eclampsia are higher and there is greater risk of needing caesarean section. A specific problem at delivery is fetal macrosomia that can lead to shoulder dystocia and obstructed delivery, brachial plexus injury and clavicular fracture. Neonatal problems include respiratory distress syndrome, jaundice and hypoglycaemia, whilst there is an increased risk of congenital abnormalities (1).

Whilst gestational diabetes (i.e. onset of diabetes during pregnancy) is the most common type of diabetes in pregnancy (around 85% of cases), the number of women with type 2 diabetes entering pregnancy has doubled over the past 10–15 years, and for women with type 1 diabetes the figure has increased by a third. For these women, pre-pregnancy care is of great importance in improving outcomes (2).

Disappointingly, the National Pregnancy in Diabetes (NPID) Audit Report 2020 found that 7 out of 8 women with diabetes were poorly prepared for pregnancy (as judged by HbA_1c control, use of folic acid and avoidance of medications that could adversely affect pregnancy). This figure had not improved over the last 7 years (3). There is a clear need to improve the management of pre-pregnancy care in women with diabetes.

Section 2

Georgia, a 33-year-old woman diagnosed with type 2 diabetes two years ago, is planning her first pregnancy and comes to see you for advice.

Georgia takes metformin 1 g twice daily and the combined contraceptive pill. Her HbA_1c is 51 mmol/mol, BP 128/80 mmHg and BMI 31.2 kg/m². She smokes 3–4 cigarettes per day and consumes around 12 units of alcohol per week. Georgia has no known diabetes complications, but has not had retinal screening or a test for microalbuminuria performed within the last 12 months. She has no other significant past medical history.

What lifestyle advice would you give Georgia to prepare for pregnancy?

Section 3

Smoking is associated with numerous adverse outcomes in pregnancy, including low birth weight, increased fetal and neonatal mortality rate, and sudden infant death syndrome (4). Georgia should be strongly encouraged to quit smoking ahead of a pregnancy, and a discussion of possible cessation strategies, including pharmaceutical options, would be appropriate.

There is some evidence that even light alcohol consumption prenatally is associated with being small for gestational age and pre-term delivery (5). Explain to Georgia that no safe lower limit of alcohol is recommended during pregnancy, and so she should try to reduce consumption and, ideally, avoid alcohol altogether.

NICE recommends offering advice on how to lose weight ahead of pregnancy if BMI >27 kg/m² (6). In Georgia’s case, weight loss should be encouraged both to improve glycaemic control and because obesity is linked to a variety of complications during pregnancy and at delivery. You could sensitively try to promote appropriate dietary changes and encourage to follow physical activity recommendations. Women should remain active during pregnancy provided there are no contraindications, but advice is to stay within pre-pregnancy levels.

It would be sensible to recommend to Georgia that she continue her contraception until she has had an opportunity to make the changes discussed previously and ensured that all other preparatory actions are completed.

How would you advise Georgia with regard to taking folic acid?

Section 4

Advise Georgia to take folic acid 5 mg once daily (a prescription is required for this higher dose) as a preventative measure against neural tube defects in the fetus, which are more common in mothers who have diabetes (7). Ideally, the folic acid should be started 3 months before trying to conceive and continued up to 12 weeks of gestation (6).

All of the advice in Sections 3 and 4 holds for type 1 diabetes, as well as for type 2 diabetes. The importance of a planned pregnancy in diabetes cannot be overstated (8). Useful resources for women planning a pregnancy can be found on the Diabetes UK, NHS and Tommy’s websites (9–11).

What foods should Georgia steer clear of with an impending pregnancy?

Section 5

Advise Georgia to avoid soft cheeses and unpasteurised milks because of the risk of listeriosis, which is associated with miscarriage and stillbirth. Raw or uncooked meats, liver products, pâté, game meats and cold cured meats carry a risk of toxoplasmosis, which is linked to miscarriage, intrauterine growth retardation and congenital abnormalities. Fruit, vegetables and salad should be washed before consumption. Food poisoning can occur from raw and uncooked eggs (salmonella) and shellfish. Excess caffeine should be avoided.

Georgia could be directed toward the NHS website covering foods that are safe to eat and foods to avoid in pregnancy (12).

Why is glucose control important going into a pregnancy, and what glycaemic targets would you aim for with Georgia?

Section 6

Organogenesis occurs principally between weeks 3 and 8 of a pregnancy and, because raised glucose levels are teratogenic, it is critical to control periconceptual and early pregnancy glucose levels in order to minimise the risk of congenital abnormality (13). Pregnancy outcomes are related to periconceptual HbA_1c (14).

Explain to Georgia that good blood glucose control starting before conception and continuing throughout the pregnancy reduces (though does not eliminate) the risk of miscarriage, congenital abnormality, stillbirth and neonatal death (6). It also reduces the risk of the baby developing obesity and diabetes later in life (15). Perinatal deaths are, in fact, higher in babies of women with type 2 diabetes than type 1 diabetes (2).

Thus, glycaemic control should be optimised ahead of pregnancy and, if HbA_1c is unduly raised (>86 mmol/mol), NICE recommend that pregnancy should be delayed until satisfactory levels of glycaemia are achieved. It is important, therefore, that safe and effective contraception is available (6).

An HbA_1c of ≤48 mmol/mol is the NICE-recommended target prior to conception, provided this does not cause problematic hypoglycaemia, but any reduction towards this goal is helpful in avoiding complications and reducing the risk of congenital malformations (6). It would be appropriate to aim for this target in Georgia’s case and, in the meantime, offer her access to blood glucose monitoring. A pre-pregnancy glucose range of 3.9–10 mmol/L would be reasonable for Georgia (2). However, individual targets should be set for HbA_1c and glucose levels, most notably to take account of the risk of hypoglycaemia (e.g. if using insulin).

For women with type 1 diabetes planning a pregnancy, blood ketone testing should also be made available to allow testing for ketosis in situations of hyperglycaemia or acute illness (6). The alternatives to capillary glucose monitoring are discussed in Section 11.

NICE guidelines recommend measuring HbA_1c monthly ahead of a pregnancy to ascertain improvement in glycaemic control in response to changes in diabetes treatment (the greatest contribution to HbA_1c comes from the most glucose recent levels) (6). Ensure that “Pre-conception monitoring” is marked on the request form.

Is it safe for Georgia to continue metformin?

Section 7

It is safe for Georgia to continue treatment with metformin (throughout pregnancy) (16), although it is important to note that if this fails to provide satisfactory glycaemic control, then insulin would be the next option. Metformin has been used off-licence in pregnancy for some time in clinical practice. Further reassuring evidence has led to a licence update from the MHRA, recommending metformin as a treatment option in pregnancy (17). The advantages of using metformin instead of or alongside insulin are less weight gain, less glucose monitoring, reduced risk of hypoglycaemia and lower insulin requirements (18). Should gastrointestinal side-effects prove troublesome, the modified-release (MR) preparation of metformin may be tried.

Georgia should be advised to report her positive pregnancy test immediately, so that she can be referred to the joint diabetes/antenatal clinic, where she can expect regular reviews during the pregnancy (and assessment as to whether insulin will be required).

What action would you take over Georgia’s lack of recent retinal and renal screening?

Section 8

Microvascular complications can accelerate during pregnancy. Georgia should be referred for retinal screening (as should all women planning a pregnancy who have not undergone retinal screening within the last 6 months) (6). It is postulated that a rapid optimisation of glycaemic control can trigger a worsening of retinopathy and, ideally, women should be screened and treated before attempting this.

Georgia should also have up-to-date results for renal function and microalbuminuria. If eGFR <45 mL/min/1.73 m², creatinine ≥120 µmol/L or urinary ACR >30 mg/mmol, then referral to nephrology should be considered before discontinuing contraception (6).

Section 9

Emily is a 38-year-old woman with a 4-year history of type 2 diabetes. She has had two children with her ex-partner, but is now in a new relationship and would like to add to her family. She is aware that both her age and diabetes increase the risks of pregnancy, but is determined to go ahead and would like her Mirena coil to be removed.

Emily is a non-smoker and understands the need to avoid alcohol around a pregnancy. She has stable background diabetic retinopathy. Her current medication consists of metformin MR 1000 mg twice daily, sitagliptin 100 mg once daily, atorvastatin 20 mg once daily and ramipril 10 mg once daily.

Recent results: HbA_1c 65 mmol/mol, eGFR 74 mL/min/1.73m², urinary ACR 1.2 mg/mmol; BP 143/87 mmHg; BMI 34.5 kg/m².

You provide lifestyle advice around losing weight and the need to take high-dose folic acid ahead of conception.

What would be your plans for managing Emily’s glycaemic control, given her plans for a future pregnancy?

Section 10

Emily’s HbA_1c is significantly above the NICE target recommended for conception (ideally <48 mmol/mol) and you should explain to her the benefits of tight glucose control in pregnancy (see Section 6).

It is reasonable for Emily to continue with her metformin into pregnancy, but sitagliptin is contraindicated in pregnancy and will need to be stopped. Beyond metformin, the only accepted safe diabetes medication is insulin. Emily should be advised to continue with her contraception until her diabetes medications are stabilised and glucose levels improved. Some more information on diabetes medications in pregnancy is included in Section 14.

Emily is provided with a meter to self-monitor her blood glucose levels in order to build a picture of capillary blood glucose readings throughout the day. She is referred to the hospital pre-conception clinic, where sitagliptin is discontinued, insulin is initiated and follow-up is arranged. (Depending on local arrangements, referral may be made alternatively to the local endocrinology service or diabetes specialist nurses.)

What glucose monitoring arrangements might you expect to be in place for Emily, and what safety advice in regard to hypoglycaemia might you reinforce?

Section 11

Emily has been commenced on a multiple daily insulin dose regimen. She will need to monitor her fasting, pre-meal, post-meal and pre-bedtime glucose levels (i.e. 7 times daily), so her requirement for testing strips will increase.

You could reiterate the symptoms of hypoglycaemia and how to correct this with a fast-acting carbohydrate that should be carried at all times (e.g. dextrose tablets, glucose-containing drink). The aim is to achieve the best possible glycaemic control without problematic hypoglycaemia, and compromises may need to be made (especially if there is hypoglycaemic unawareness) (6,13).

For women with type 1 diabetes, the availability of a glucagon injection to deal with hypoglycaemia offers a further level of protection; family members and carers should be trained to deliver this. Flash glucose monitoring (intermittently scanned continuous glucose monitoring [isCGM]) or real-time continuous glucose monitoring (rtCGM) will usually be offered to women with type 1 diabetes (6,19), and also to those with type 2 diabetes using multiple daily insulin dose regimens (20) (such as Emily) to help optimise glycaemic control and reduce risk of hypoglycaemia. Referral to the Specialist Diabetes Team (diabetes midwives) for education and training is appropriate.

What action would you take in respect of Emily’s treatments for hypertension and hyperlipidaemia?

Section 12

ACE inhibitors are known to be teratogenic and so Emily’s ramipril must be stopped. Reinforce lifestyle measures to help blood pressure, including reduction in salt intake, weight loss and exercise. However, it is likely that Emily’s blood pressure will now be above target (NICE recommends offering treatment for hypertension in pregnancy if BP ≥140/90 mmHg, aiming for a target BP of ≤135/85 (21,22)), so it is a matter of choosing an antihypertensive medication that is safe in pregnancy.

Angiotensin receptor blockers (ARBs), like ACE inhibitors, are contraindicated in pregnancy. Diuretics should also be avoided.

Other antihypertensives do not appear to increase the risk of congenital abnormalities. The three antihypertensives most commonly employed because of their long track record of safety are labetalol, methyldopa and slow-release nifedipine (21). Labetalol is licensed for use in pregnancy and is considered first line by NICE. If labetalol is not suitable, then nifedipine modified-release may be used (although NICE advise using a brand that is not contraindicated in pregnancy – so check SmPC). Methyldopa is a further option, though this may be less efficacious than labetalol and nifedipine, and more prone to cause side-effects. Antihypertensive therapies may need to be used in combination to achieve satisfactory blood pressure control.

Statins are potentially teratogenic and are thus contraindicated in pregnancy.

It is worth mentioning that, for women with chronic hypertension in pregnancy (including diabetes), aspirin 75–150 mg once daily is recommended for use from 12 weeks’ gestation onward (21).

Emily’s ramipril and atorvastatin are discontinued. Her systolic BP is now >150 mmHg and so she is commenced on labetalol.

If Emily had come to see you and was already pregnant (without prior preconception care), how would you have managed the situation?

Section 13

Essentially all the steps outlined in the previous sections are relevant here, except it is appropriate to continue the metformin and sitagliptin until insulin is instituted, given the dangers associated with hyperglycaemia (13). An urgent referral to the specialist diabetes antenatal team should be made with a view to rapid commencement of insulin.

Section 14: Medications for glycaemic control in pregnancy

As mentioned, metformin is considered safe in pregnancy but, even when it is continued, there is a strong possibility that insulin will also be needed to achieve the desired level of glycaemic control.

Insulin is a safe and effective treatment in pregnancy, and for many women with type 2 diabetes a basal bolus regimen of insulin will be required to achieve satisfactory glycaemic control. The insulin doses can be uptitrated bearing in mind that, as insulin resistance increases during the pregnancy, higher doses of insulin are likely to be needed. The supervision of insulin dosage is usually undertaken in the specialist joint diabetes/antenatal clinic. For women taking multiple daily injections of insulin, then continuous subcutaneous insulin infusion (CSII, insulin pump therapy) is an option that may help achieve the necessary glucose control whilst minimising the risk of hypoglycaemia (6).

Glibenclamide, though unlicensed for use in pregnancy, has been shown to be effective in improving glycaemic control (23). It can, however, induce maternal hypoglycaemia and weight gain, and outcomes in gestational diabetes seem to be worse compared to metformin or insulin (24). If metformin therapy does not achieve target, or is not tolerated and insulin therapy is declined, then glibenclamide may, after discussion, be offered as a treatment (6).

Other sulfonylureas should be avoided in pregnancy, as should other classes of medications for type 2 diabetes (i.e. meglitinides, DPP-4 inhibitors, pioglitazone, acarbose, SGLT2 inhibitors and GLP-1 receptor agonists).

Section 15: Pre-conception clinics

There is strong evidence that structured pre-conception care, providing information and monitoring as discussed above, significantly reduces the incidence of congenital malformation and perinatal mortality (13,25–27). Ideally, this should take place several months ahead of conception. Local availability of such services is variable and uptake has been disappointingly low given the clear benefits (1). Primary healthcare professionals should be aware of local arrangements and offer to refer women with diabetes to a structured education programme ahead of trying for a pregnancy (6).

During consultations, the healthcare professional with responsibility for diabetes should always consider the plans for pregnancy of a woman of child-bearing age, and should carefully counsel her regarding the importance of preparation (13), ideally supporting these conversations with printed materials.

Key components to cover in pre-pregnancy advice for women with diabetes are, as discussed above (13):

• Lifestyle advice – diet, exercise, weight, smoking, alcohol
• Folic acid 5 mg once daily for 3 months pre-conception and continued until 12 weeks’ gestation
• Glycaemic control
• Medication review – safety aspects
• Review and management of complications of diabetes
• Contraception until preparations are complete
• Mental and emotional well-being

More information can be found in the journal’s At a glance factsheet: Diabetes before, during and after pregnancy.