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Abstract

Pregnancy complicated by diabetes presents risks for the mother and her baby and a challenge to those responsible for their care. Type 2 diabetes now represents a significant and rapidly increasing proportion of pregestational diabetes. Outcomes of pregnancies complicated by Type 2 diabetes are certainly no better and sometimes worse than for Type 1 diabetes. Perinatal mortality, stillbirths and congenital anomalies are increased between two- and fourfold. Women with Type 2 diabetes and who are of child-bearing age merit special attention for contraception and prepregnancy care. This review considers the implications for women with Type 2 diabetes before, during and after pregnancy.

Keywords

congenital anomaly contraception insulin oral hypoglycemic agents perinatal mortality pregnancy stillbirth Type 2 diabetes

Although it is now 18 years since the St Vincent declaration set a 5-year target of outcomes approximating those of women without diabetes [1], the management of diabetes in pregnancy continues to impose a considerable challenge to achieve that target. Until recently, most publications on the subject concerned Type 1 diabetes, or did not separate Type 2 diabetes for detailed analysis. However, it appears from more recent reports that outcomes of Type 2 diabetes are at least as bad or worse than for Type 1 diabetes.

In the West Midlands, UK, in 182 women with Type 2 diabetes, between 1990 and 2002, the perinatal mortality rate (PMR) was 24.6/1000, stillbirth rate (SBR) 12.2/1000 and neonatal mortality (NMR) 12.4/1000; congenital malformations affected 9.9% of babies [2].

The largest study to date from England, Wales and Northern Ireland reported on 3808 pregnancies in women with pregestational diabetes; of these, 650 had Type 2 diabetes, PMR was 32.3/1000 (95% CI: 18.7–45.9), SBR was 29.2/1000 (95% CI: 16.3–42.2) and NMR 9.5/1000 (95% CI: 1.9–17.1); outcomes were similar to those with Type 1 diabetes [3]. Maternal age-adjusted mortality rates for all women with diabetes were 3.8- (PMR), 4.7- (SBR) and 2.6-times (NMR) higher than the background population. Overall, congenital anomalies were found in 41.8/1000 total births.

Type 2 diabetes is more common in ethnic minority groups, but in one study a significant effect of ethnicity on outcome of diabetic pregnancy was observed, with worse outcomes for babies born to Asian mothers compared with Caucasian mothers [4]. In this study, use of insulin prepregnancy, rather than type of diabetes, appeared to predict adverse outcome.

A study carried out in East Anglia, UK, demonstrated a threefold risk of serious adverse outcome for Type 2 diabetes compared with Type 1 [5]. Their results suggested that treatment with oral hypoglycemic agents (OHAs), lack of folic acid supplements and obesity were associated with malformations. Type 2 diabetic mothers were less likely to have documented prepregnancy counseling. Ethnicity was not found to be a factor in this study.

In Denmark, PMR in offspring of women with Type 2 diabetes was four-times that of women with Type 1 diabetes (nine-times the background population) and congenital anomalies twice as common compared with Type 1 diabetes and the background population [6].

In New Zealand, PMR for women with Type 2 diabetes was 46/1000 compared with 12/1000 for Type 1 diabetes and the background population [7]; in those not diagnosed as having Type 2 diabetes before pregnancy, PMR was 56/1000. Similar findings are reported from Australia [8].

However, a study from Spain comparing 93 patients with Type 2 diabetes and 532 patients with Type 1 diabetes suggests that outcome in Type 2 diabetes is better, provided medical treatment is intensified before conception and during pregnancy [9].

The organ systems affected by congenital anomaly in the offspring of women with Type 2 diabetes are similar to those with Type 1 diabetes (37.6% cardiac, 14.7% musculoskeletal, 9.8% CNS and 16% multiple organ systems) [10,11].

The worldwide increasing prevalence of Type 2 diabetes [12], together with its presentation in younger individuals, has led to an increased proportion of Type 2 diabetes complicating pregnancy [13]. Type 2 diabetes complicated 27% of all diabetes pregnancies in England, Wales and Northern Ireland in 2002–2003 [3]. In Australia, Type 2 diabetes now complicates pregnancy more often than Type 1 diabetes [8]. It has been suggested that fetal exposure to maternal diabetes increases the prevalence of Type 2 diabetes and obesity in offspring [14,15]. Thus, the prevalance of Type 2 diabetes is set to continue increasing for the foreseeable future and the problems of pregnancy associated with this condition will be encountered more frequently.

The largest published study to date was carried out in England, Wales and Northern Ireland by the Confidential Enquiry into Maternal and Child Health (CEMACH). Their project in pregnancy complicated by pregestational diabetes was carried out in three modules, a survey of services [16], a cohort report of 3808 pregnancies in women with Type 1 and Type 2 diabetes who were pregnant in 2002 to 2003 [3], and a confidential panel enquiry reviewing social and lifestyle factors and clinical care in relation to adverse outcomes [17]. A comparison of Type 1 and Type 2 diabetes from the CEMACH reports is shown in Box 1.

Whilst many of the challenges and adverse outcomes are similar in both common types of diabetes, there are significant differences in many respects. Women with Type 2 diabetes are older, multiparous, more obese, present later, come from more socially deprived backgrounds, have black, Asian or other ethnic minority group origins, are less likely to have received prepregnancy counseling and are more likely to be using medication that is potentially harmful to the fetus. Adverse pregnancy outcomes may therefore relate to these factors in themselves, in addition to Type 2 diabetes. Demographic features of local populations may account for some of the observed differences in outcome between centers.

Box 1.

Comparison of Type 1 & 2 diabetes from the Confidential Enquiry into Maternal and Child Health reports

Differences

Glycemic control: glycated hemoglobin measured in the first trimester was lower in Type 2 diabetes and in the panel enquiries was considered ‘suboptimal’ less often.

Hypoglycemia: less frequent in Type 2 diabetes

Retinopathy: less common in Type 2 diabetes, but frequently a new finding. Women with Type 2 diabetes less likely to have had retinal examination in the 12 months before pregnancy and less likely to have retinal assessment in the first trimester

Nephropathy screening: women with Type 2 diabetes are less likely to have had albuminuria assessed

Contraception: less likely to be used in Type 2 diabetes, and they are less likely to receive contraceptive advice postnatally

Folic acid: less likely to be taken in Type 2 diabetes

Similarities

Macrosomia and fetal growth restriction: similar rates

Nephropathy: similar frequency

Planned pregnancy: similar rates

Clinical care during pregnancy

Data from [3,17].

Preconception care

Congenital anomalies are one of the major adverse outcomes of pregnancy in diabetes. Published rates of anomaly vary between 3.4 and 15% of pregnancies in Type 2 diabetes [18]. The wide variation probably reflects whether minor abnormalities are excluded, diligence and duration of follow-up of offspring, and whether only anomalies after a certain gestation are included. Major organogenesis is complete by 42 days of embryo life, but many women present to specialist care after this time. It is imperative that preconception care establishes optimal health for the woman before conception [19].

This includes advice on diet and exercise with lifestyle interventions to optimize weight and glycemic control. It is naive to think that pregnancies are planned or unplanned; between the two extremes are varying degrees of thoroughness of planning and intention. Apart from domestic and social implications, this has little bearing on the outcome of pregnancy for healthy women. In women with diabetes, because of the health implications to mother and baby, they should be encouraged to plan their pregnancy carefully, using contraception that is safe and effective until they wish to conceive and when all measures to minimize risks have been implemented. Very often the most suitable method of contraception is that which the woman herself prefers, as this will be more likely to be employed effectively.

Barrier methods, combined and progesterone-only oral contraceptive pills, long-acting depot progestogens and intrauterine contraceptive devices (IUCDs) are all suitable, although the risks of their use in patients with complications from their diabetes need to be balanced against the risks from pregnancy [101].

Glycemic control

Since poor glycemic control is associated with congenital anomaly, optimization of glycemic control before conception is one of the principle aims of preconception care. There is no level of glycated hemoglobin below which anomalies approximate to the background population, and glycated hemoglobin should not be the only measure by which glycemic control is assessed. Episodes of hyperglycemia may be offset by frequent hypoglycemia, leading to an inappropriately favorable assessment of glycemic control based on glycated hemoglobin alone. It is also possible that brief periods of poor glycemic control at a critical phase of organogenesis may result in an anomaly, but not be reflected in the glycated hemoglobin. High glucose concentrations in animal models have been shown to affect fusion of the spinal cord. This process is brought about through expression of the Pax3 gene, which is not expressed under conditions of oxidative stress such as in hyperglycemia [20]. Altered expression of other genes has also been implicated in defective neural-tube development [21]. It is possible that, in a similar way, other genes concerned with normal development of other organ systems, expressed for less than a day, may be affected by transient episodes of hyperglycemia. Other studies have implicated inhibition of glyceraldehyde-3-phosphate dehydrogenase as a result of oxidative stress associated with hyperglycemia [22], the interaction of oxidative stress and inositol depletion [23] and enhanced mitochondrial production of reactive oxygen species leading to altered activation of protein kinase C [24].

Box 2.

Risks of pregnancy in women with diabetes

Risks to the fetus

Congenital malformation

Spontaneous abortion

Stillbirth

Neonatal death

Excessive fetal growth with risk of birth trauma

Increased likelihood of cesarean section

Intrauterine growth retardation

Respiratory distress

Hypoglycemia

Jaundice

Risks to the mother

Hypoglycemia

Progression of retinopathy

Progression of nephropathy

Pre-eclampsia

Birth trauma

Increased likelihood of cesarean section

For the nonpregnant woman with Type 2 diabetes, after dietary measures, glycemic control is often achieved with oral hypoglycemic agents such as metformin, thiazolidinediones and sulphonylureas.

Metformin

There is no clear evidence that metformin is harmful. It does pass to the fetus [25] and in theory could have fetal effects, but there is no evidence of increase in congenital anomaly [26 –30]. Before conception, it is usually recommended that glycemic control is achieved with insulin, and that OHAs are stopped [19,31,32]. However, metformin is useful to stimulate ovulation in women with polycystic ovary syndrome (PCOS), in whom there is also an increased prevalence of Type 2 diabetes. In such patients, there may therefore be good reason to continue metformin when planning pregnancy. First-trimester miscarriage was reduced in one study [33], but not in another [34]. In a more recent study, out of 214 pregnancies in women with Type 2 diabetes, metformin was taken at some time during 93 pregnancies and throughout pregnancy in 32 women. Even though the metformin group had more risk factors for adverse outcome, there was no increase in pre-eclampsia, perinatal loss and neonatal morbidity [35]. In the only randomized, placebo-controlled study of metformin in pregnancy in 40 women with PCOS, there were fewer severe pregnancy complications in the metformin group [36]. However, there is one report of metformin being associated with increased perinatal loss and pre-eclampsia compared with sulphonylurea and insulin therapy [37].

Sulphonylureas

Sulphonylureas have been associated with an increased risk of fetal malformations and neonatal hypoglycemia. However, it is not clear whether this relates to poor glycemic control or is a direct effect of the drugs. A meta-analysis of studies examining exposure to oral hypoglycemic agents during the first trimester has shown conflicting results [26]. This may be because a number of second-generation sulphonylureas have significantly reduced placental transfer compared with first-generation sulphonylureas. Glibenclamide has the lowest transfer and was not detected in cord blood when used in a study in women with gestational diabetes [38]. Gliclazide and tolbutamide are contraindicated in pregnancy, with particular risk in the third trimester, as they cross the placenta more easily [39]

Box 3.

Prepregnancy preparation

For women of childbearing age with Type 2 diabetes, who engage in sexual activity and who are not using adequate contraception:

Contraception until glycemic control is optimized

Diet and lifestyle changes to reduce weight in the obese and optimize control

Switch to insulin from oral hypoglycemic agents (metformin may be beneficial to stimulate ovulation) under specialist supervision

Discontinue teratogenic medication

Review need for all other medication

Prescribe 5-mg folic acid daily for at least 3 months before stopping contraception

Check thyroid function

Ensure retinas are screened and any treatment is carried out

Inform patient of risks of pregnancy to herself and baby

Inform patient to report positive pregnancy test immediately for referral to specialist care

Glibenclamide has been considered for Type 2 diabetes in pregnancy where insulin is in short supply and a recommendation has been made that the advantage of improving glucose control, with glibenclamide if insulin is unavailable, outweighs a possible low risk of adverse effects [40].

Many drugs routinely used in pregnancy have never been licensed because the appropriate studies have not been undertaken. These drugs may be quite safe to use because they do not cross the placenta or there may be sufficient observational data to support their use safely in pregnancy. The absence of a licence does not equate with a contraindication or caution. Repaglinide is not licensed for pregnancy and is contraindicated for off-label use. Recently, a report of two cases with exposure to repaglinide in the first 6–7 weeks did not identify any embryogenic problems [41].

Thiazolidinediones

The thiazolidinediones (pioglitazone and rosiglitazone) are not licensed for pregnancy and are contraindicated for off-label use. Animal data have shown evidence of teratogenic effects [39]. However, there is evidence of stimulation of ovulation in women with PCOS. Troglitazone (now withdrawn) has been shown to improve insulin sensitivity and result in ovulation [42]. Rosiglitazone has also been shown to have similar effects [43]. The risk of rosiglitazone crossing the placenta appears to increase after 10 weeks gestation [44]. This has implications for counseling women who are incidentally pregnant when already using rosiglitazone and also its potential use for treating subfertility of PCOS. It may be safe to use rosiglitazone to induce ovulation and discontinue the drug as soon as pregnancy is confirmed, but use of the drug beyond 10 weeks should not be advised because of the unknown effects on the fetus [44]. Further research is needed to confirm safety issues.

Insulin

Most clinicians advise that glycemic control be achieved with diet and, if additional therapy is required, insulin. Although formal prepregnancy care is taken up in some cases, oral hypoglycemic agents should be substituted with insulin. There have been no studies to assess ideal regimens for women with Type 2 diabetes planning pregnancy. Until such evidence becomes available, insulin regimens employed should be a matter for negotiation between the woman and her clinician, with the aim of optimizing control.

Humulin® S, Humulin I, Humulin M3 and NovoRapid® are licensed for use in pregnancy. Other insulins are not licensed, but are not contraindicated for use in pregnancy. Insulins do not cross the placenta directly, but antibodies to insulin and insulin–antibody complexes may transfer. Animal insulins should therefore be avoided, as they are more immunogenic. However, particular concern has been expressed with regard to potential hazards from use of Insulin Glargine. Unlike other analogues, Insulin Glargine has been shown to have increased IGF-1 receptor affinity and mitogenic potency compared with human insulin [45]. The safety implications for the fetus of these observations are theoretical and may not be clinically relevant; no adverse pregnancy outcomes have been reported to date.

Optimal control is not simply the lowest possible glycated hemoglobin. Targets should be agreed with each individual, aiming for pre-prandial glucose values of four to six and postprandial levels less than eight. Whilst mild hypoglycemia (defined as not requiring assistance to recognize or treat) can be tolerated, severe hypoglycemia is to be avoided and may require resetting of the targets for blood glucose. Glucagon should be supplied and partners instructed on how to use it.

Folic acid

Animal studies have demonstrated that folic acid administration reduces risk of neural-tube defects [46]. Higher dose (5-mg folic acid) is recommended for 3 months before conception and the first trimester [17,19,31].

Education

Preconception care should include opportunities to discuss the risks of pregnancy and explain the strategies for managing the pregnancy. However, only a few women receive formal prepregnancy counseling [17], and knowledge and understanding of the issues are poor [47]. Before embarking on pregnancy, a woman should be aware of the risks and how to minimize them. Having a baby is an important decision for any woman to make, and is all the more important for a woman with diabetes. A patient thus engaged in her care is better able to plan and prepare for pregnancy.

Screening

Prepregnancy care affords additional opportunities to screen for complications and discuss their implications for pregnancy. Retinopathy may emerge for the first time during pregnancy, especially in Type 2 diabetes, or progress more quickly [17]. Sight-threatening eye disease should be treated and eyes stable before becoming pregnant. Microalbuminuria and proteinuria carry additional risks for the outcome of pregnancy with hypertension, pre-eclampsia and progression of nephropathy.

Hypertension

Many women will be taking angiotensin-converting enzyme (ACE) inhibitors or angiotensin 2 antagonists for hypertension; their value in limiting progression of nephropathy is well established. There are limited data on the effects of ACE inhibitors in human pregnancy; however, they have been reported to cause oligohydramnios, renal tubular dysgenesis, neonatal anuria, hypocalvaria, pulmonary hypoplasia, persistent patent ductus arteriosus, mild-to-severe intrauterine growth retardation and fetal or neonatal death [48]. These developmental anomalies have been attributed partly to their direct effects on the renin–angiotensin system and partly to ischemia due to maternal hypertension and subsequent reduction in fetoplacental blood flow. More recently, a study from Boston (MA, USA) has identified that women with first trimester exposure to ACE inhibitors had an increased risk of malformations in the cardiovascular and CNS [49]. Case reports of women taking angiotensin 2 receptor antagonists suggest a similar spectrum of fetal toxicity, where use in the second and third trimesters of pregnancy has been associated with fetal renal damage, oligohydramnios, skull defects and death. Neither ACE inhibitors nor angiotensin 2 receptor antagonists are licensed for use in pregnancy, and it is generally felt these drugs are contraindicated at all stages of pregnancy [39]. Ideally, they should be discontinued in any woman planning pregnancy and immediately if incidentally found to be pregnant. However, many women may not conceive for some considerable time, during which they will lose the renal protective benefits. This needs careful explanation and discussion during prepregnancy counseling.

Box 4.

Management of Type 2 diabetes during pregnancy

Switch to insulin treatment if not already done so

Review all medication, stop any potentially teratogenic drugs and review need for any unlicensed medication

Continue folic acid for the duration of the first trimester

Add low-dose aspirin

Manage hypertension with appropriate antihypertensives

Monitor renal function and check for proteinuria

Retinal screening in early pregnancy and repeated appropriately according to the findings

Early dating scan

Ultrasound scans for anomalies

Ultrasound scans for growth

Tests of fetal well-being

Consider mode and timing of delivery

Thiazide diuretics are usually avoided in Type 2 diabetes because of their adverse effect on glycemic control. In any case, thiazides and loop diuretics are not recommended in pregnancy as they may cause maternal hypovolemia resulting in reduced placental perfusion [39].

Potassium-sparing diuretics are similarly not licensed for use in pregnancy. The manufacturers of eplerenone state that there is not enough evidence to produce a reliable risk assessment, so caution is required if a prescriber wishes to use this off label. Amiloride is contraindicated owing to limited clinical experience and associations with fetal and neonatal jaundice, fetal bone marrow suppression and thrombocytopenia [32].

None of the calcium channel blockers is licensed for pregnancy, but some (nifedipine and amlodipine) have been used in many centers for some time without adverse outcomes. Schaefer recommends that nifedipine may be used in the second and third trimesters [32]. Diltiazem has been shown to be teratogenic in some animal species and is therefore contraindicated in women of child-bearing age as well as pregnancy [39]. No teratogenic effects of verapamil have been demonstrated, but recommendations are that it should only be used with caution in the second and third trimesters [32].

Methyldopa is not licensed for pregnancy but is widely used off label. It is considered to be the drug of choice for management of hypertension in pregnancy.

Neither hydralazine nor doxazosin is licensed for use in pregnancy. The safety of doxazosin is not established, as data are limited, but animal data suggest low risk. Hydralazine should be avoided, according to the manufacturers, in the first and second trimesters, but is acceptable and has been extensively used for pre-eclampsia and eclampsia in the third trimester [32].

Labetolol is the only β-blocker licensed for treatment of hypertension in pregnancy. Propranolol and atenolol rapidly cross the placenta, but there is no evidence that either drug causes anomalies. Bisoprolol and carvedilol have been used in some centers with no evidence of teratogenic effects. Intrauterine growth retardation, respiratory distress and apnea have been reported and neonatal β-blockade (characterized by bradycardia and hypotension) has been observed after maternal treatment [48]. If β-blockers are used, these adverse effects should be kept in mind.

Cardiovascular disease

Aspirin may already be prescribed for reduction of cardiovascular risk in many women with Type 2 diabetes. A review and meta-analysis of aspirin to assess the effectiveness of reducing pre-eclampsia concluded that it was beneficial in those in a higher-risk group [50]. Insulin resistance, the pathological hallmark of Type 2 diabetes, is associated with pregnancy-induced hypertension, including pre-eclampsia [51]. Aspirin is therefore recommended; large retrospective studies have not indicated any association with increased risk of congenital anomalies [102].

Lipid-lowering agents

Discontinuation of lipid-lowering medication should have little or no effect on the long-term reduction in cardiovascular disease. Congenital anomalies have been reported in first-trimester exposure to statins [52]. Lipid-lowering medication should therefore be discontinued during prepregnancy care.

Review of other medication

Women with Type 2 diabetes may be taking a variety of other drugs. Before conception, an assessment of balance of risks of harm through continuing the drug versus its benefits for the mother should be made. An understanding of whether a drug may be continued until pregnancy is confirmed, running the risk of early exposure, or whether serious harmful effects could occur in early embryogenesis, making recommendations to discontinue therapy important, is essential to consider during pre-pregnancy counseling [48].

Unfortunately, only 17% of units in England, Wales and Northern Ireland provide a structured, multidisciplinary service through which to deliver preconception care [16]. Little more than a third of women receive prepregnancy counseling, have had a test of glycemic control in the 6 months before conception, or started folic acid [3]. Suboptimal preconception care was associated with a poor pregnancy outcome (defined as congenital anomaly or death between 20 weeks gestation and 1 month of age) [17]. Also associated were failure to carry out retinal screening and discuss risks to the fetus and increased risk of cesarean section.

Treatment of diabetes during pregnancy

When the woman has already converted to insulin therapy as part of prepregnancy care, glycemic control is maintained by adjustment of increasing doses of insulin.

Difficulties arise in what to do with regard to the incidentally pregnant woman with no prepregnancy preparation. All but essential drugs should be discontinued. Women using OHAs should not stop them immediately, as the subsequent worsening of hyperglycemia is a clear teratogenic risk. A woman should be reassured that there is no evidence of teratogenicity and should maintain optimal glucose control pending discussion of and transfer to insulin therapy under specialist care. Perinatal mortality and stillbirth were significantly less in women with Type 2 diabetes who transferred from OHAs to insulin during pregnancy, whilst perinatal mortality was not increased with metformin alone started in the second trimester [53]. In this retrospective study, it is difficult to determine the relative safety of metformin versus glibenclamide. It is probably safe to continue metformin and add insulin if necessary. Metformin can be withdrawn gradually in the second trimester as insulin is introduced, avoiding loss of control with hyperglycemia during embryogenesis.

Retinopathy and renal screening schedules should be provided for the duration of the pregnancy [17]. Microvascular complications appear to be less common in Type 2 diabetes in pregnant women [3]. However, there is no reason to suppose that their progression and management should be different from Type 1 diabetes. Identification of or progression to sight-threatening retinopathy may safely be treated with photocoagulation. Nephropathy progresses more quickly during pregnancy and does not necessarily regress after delivery. Proteinuria increases, hypertension is more likely to be problematic and the pregnancy is less likely to carry to term.

Many women who are technically diagnosed as having gestational diabetes, since it is diagnosed for the first time during pregnancy, in fact have undiagnosed Type 2 diabetes before conception. This is a difficult group to identify promptly. There is no reliable method of identifying these women; a high index of suspicion from personal and family history, backed up with fasting or timed blood glucose estimations and, if necessary, glucose tolerance testing is required. A raised glycated hemoglobin in the early weeks of pregnancy is highly suspicious of Type 2 diabetes before conception, but a normal glycated hemoglobin is unhelpful. Subsequent management should be with diet and insulin. Their pregnancies carry similar risks to those with known Type 2 diabetes. After delivery, glucose tolerance does not return to normal.

Obstetric surveillance

Obstetric management of women with Type 2 diabetes does not differ from Type 1 diabetes, and comprises dating scan, developmental scans, growth scans and biophysiological profiling. Screening for anomalies offers the opportunity to discuss with the mother the opportunity to terminate pregnancies with severe life-threatening anomalies. Poor glycemic control or use of drugs with unknown or possible teratogenic effects over the period of embryogenesis are not reasons in themselves to offer termination; the outcome of pregnancy is satisfactory in the most, but the risk of a poor outcome is increased. Timing and mode of delivery needs careful consideration, as for Type 1 diabetes. Use of steroids to promote lung maturity when delivery before 34 weeks is considered will require increased doses of insulin. During labor and delivery, blood glucose should be monitored hourly and separate infusions of dextrose and insulin should be employed if glucose control is not optimal (i.e., below 8 mmol/l) to reduce the risk of neonatal hypoglycemia.

Management postpartum

Breastfeeding should be encouraged, but uptake is low [17]. It may be advisable for women to continue managing their diabetes with reduced doses of insulin rather than resume taking OHAs. However, glibenclamide and glipizide do not appear to be excreted in breast milk and hypoglycemia was not observed in the infants of three women taking either of these OHAs whilst breastfeeding [54]. Little metformin is excreted in breast milk, well below the safety margin; in any case, hypoglycemia with metformin would not be expected [55]. These drugs therefore appear to be compatible with breastfeeding. Most antihypertensive agents are secreted in breast milk and could have neonatal effects. Small amounts of ACE inhibitors are secreted in breast milk, but the American Academy of Pediatrics has classified them as compatible with breast-feeding [39]. Nifedipine is secreted in small quantities, but is compatible with breastfeeding [39].

Contraception has already been considered as part of prepregnancy planning, but should be discussed again, postpartum; tubal ligation or vasectomy may also be appropriate for some. In view of the high cesarean-section rate, the option of tubal ligation at delivery is available to many and should be discussed before delivery.

Conclusion

The outcome of pregnancies complicated by Type 2 diabetes is similar or worse than with Type 1 diabetes. Sexually active women with Type 2 diabetes should be either using contraception or in optimal health for pregnancy. Many of these women are managed in a primary-care, nonspecialist setting. Healthcare professionals should ensure that, before they conceive, patients have access to a multidisciplinary team experienced in the care of women with diabetes in pregnancy. Better outcomes can be achieved with improvements in prepregnancy care and planning for pregnancy.

Future perspective

Already Type 2 diabetes forms a significant proportion of the type of diabetes diagnosed before pregnancy. In the next 10 years it will form the majority in most countries of the world. More experience of managing the condition will enable a better understanding of the safety (and hazards) of drugs commonly used to treat diabetes and its complications. The causes of altered gene expression will be better understood and other means, apart from folic acid supplementation, of reducing the risk of anomalies may be discovered. Developments in biophysiological profiling and other means of detecting the fetus at imminent risk of stillbirth may be revealed.

The target of the St Vincent declaration will not be achieved. The standard set for pregnancy outcome is too optimistic without a cure for diabetes, but progress towards that objective will be made.

Executive summary

Preconception care

Should be undertaken by a multidisciplinary team experienced in management of diabetes in pregnancy.

Safe and effective contraception should be recommended until the woman wishes to conceive and all health measures have been addressed.

Optimize glycemic control with diet and insulin. It may be appropriate to continue metformin in some circumstances. Other lifestyle changes should be recommended to optimize weight.

Prescribe 5 mg of folic acid for at least 3 months before conception and the first 13 weeks of pregnancy.

Provide counseling so that the woman understands the risks to her own and her baby's health and what can be done to minimize the risks.

Ensure that retinal and renal screening have been carried out and that any sight-threatening retinopathy has been treated and the eyes are stable.

Risks and benefits of all medication should be carefully considered and unnecessary or potentially harmful medication discontinued. In some instances, safer alternatives can be used.

Treatment of diabetes during pregnancy

Optimal glycemic control should be maintained by adjusting the insulin regimen and doses. Particular care is needed not to lose glycemic control if changing insulin regimens or discontinuing oral hypoglycemic agents during the period of embryogenesis.

Nonessential or potentially harmful medication should be discontinued, if not already carried out before pregnancy.

Obstetric surveillance

Monitor fetal development and growth.

Careful consideration of timing and mode of delivery.

Maintain tight glycemic control during labor and delivery, if necessary with separate glucose and insulin infusions.

Management postpartum

Encourage breastfeeding and manage diabetes with diet and insulin.

Consider carefully the risks and benefits of medication during breastfeeding.

Discuss appropriate contraception.

Ensure appropriate measures for continued management of diabetes are established, including potential future pregnancy.

Footnotes

Acknowledgement

Grateful thanks are due to Chris Herring, Obstetric Pharmacist, for his assistance in researching the pharmacological aspects of the review.

IPC has been reimbursed by Novo Nordisk Ltd., Takeda UK and Sanofi-Aventis for attendance at several conferences. Merck Sharp and Dohme funded a nurse-led project under the supervision of IPC to reduce cardiovascular risk in Type 2 diabetes.

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Management of Type 2 Diabetes and Pregnancy

Abstract

Keywords

Preconception care

Glycemic control

Metformin

Sulphonylureas

Thiazolidinediones

Insulin

Folic acid

Education

Screening

Hypertension

Cardiovascular disease

Lipid-lowering agents

Review of other medication

Treatment of diabetes during pregnancy

Obstetric surveillance

Management postpartum

Conclusion

Future perspective

Footnotes

Acknowledgement

References