Post-partum care – maternal type 2 diabetes
Prevention of T2DM after GDM has become an increasingly important issue, since there has been a sharp rise in the incidence of women with obesity and GDM.26,47 Epidemiological studies have clearly shown that women with a history of GDM are at increased risk of developing pre-diabetes and T2DM.6,7 In addition, a recent study showed that women with a history of GDM are also at increased risk for the devel-opment of cardiovascular diseases, even in the absence of T2DM.48 The increasing incidence of obesity and diabetes will have a major impact on the medical cost in the upcoming years, and are estimated to increase by £1.9-2 billion/year in the United Kingdom by 2030.49 Therefore, early diagnosis of T2DM and perhaps better ways to identify those women who will develop cardiovascular diseases in women with GDM is important.
Although the current Dutch guidelines provide specific recommendations for the post-partum screening of women with GDM, until recently it was unclear how well these guidelines were implemented.18,19 We found that despite the extensive counselling and treatment in the hospital setting, follow-up of women with a history of GDM was unstructured, and the number of women who were regularly screened for health behaviour or development of T2DM in general practice was very small (Chapter 6). Due to the low numbers of postpartum glucose testing, data on development of T2DM after GDM in the Netherlands are very limited. Recently, these findings are supported by other investigators in the Netherlands.50 The study by Brink et al., also demonstrated that (long-term) postpartum screening was sub-optimal, only 33% of the women in their population were screened in the first year
postpartum.50 Our findings underline the importance to improve communication between primary and secondary care and the awareness among women with a history of GDM.
The long-term postpartum follow-up clearly requires improvement in the Netherlands. In Table 1, we summarized several recommendations to improve the postpartum care for women with a history of GDM.
Moreover, there is clearly more need for lifestyle coaching programs/self-management for women with a history of GDM. These programs can help women to adopt a healthy lifestyle and make them aware about the future risk of T2DM.
Lifestyle interventions after pregnancy can also reduce the risk of having GDM in a future pregnancy.
Neonates of mothers with GDM – foetal programming
There is also growing evidence that obesity and T2DM prevalence is rising in the offspring of mothers with GDM.8-10 Metabolic changes during pregnancy (both under- nutrition and over nutrition) can lead to program adaptations in the foetus metabolism, with potential consequences for growth and metabolism in later life (Chapter 2).51 This topic is still contradictory and awaiting confirmation. Criticisms have suggested that the association between hyperglycaemia in utero and obesity in the offspring may be explained by confounding factors, such as an unhealthy lifestyle or obesity in the parents.52 However, there are data that obesity and T2DM in early adulthood is also more prevalent in offspring of women with type 1 DM, suggesting that hyperglycaemia in utero can contribute to programming of the offspring with a metabolic syndrome fenotype.8
Lifestyle interventions during pregnancy are necessary to achieve normal gly-caemic control and minimize the risk of hyperglycaemia in utero. Moreover, lifestyle interventions after pregnancy are also necessary for both the mother and child.
As already mentioned, in women with a history of GDM lifestyle intervention after pregnancy can reduce the risk of T2DM and having GDM in a future pregnancy. In addition, lifestyle intervention for the mother and their families can stimulate and optimize family lifestyle.
9
TABLE 1. Recommendations to improve the postpartum care for women with a history of gestational diabetes mellitus.
Recommendations Six-weeks postpartum
visit
Internist/GP - Evaluate glucose values, HbA1c, and lipid profile
- Give verbal and written information on future risk of T2DM and lifestyle advices - Give verbal and written advice to visit the GP for annual glucose testing After the postpartum visit
(and for women who did not visit the six-weeks postpartum visit):
- Send a discharge letter to GP, including an advice to invite their patient for follow-up glucose testing – every year for five years
- Send a copy of the discharge letter to the patient with a brochure about the future risk of T2DM. Include information about glucose screening at the GP, healthy weight (BMI calculator), Dutch Food Choice guidelines, Dutch guidelines physical activity, and useful suggestions for help/support to change lifestyle
Long-term follow-up GP
- Mark women with a history of GDM and connect them to a track system for five years
- Send a reminder for follow-up glucose testing to the women – once a year for the next five years
Annual follow-up glucose screening:
- Evaluate glucose values, HbA1c, and lipid profile - Repeat the future risk of T2DM and lifestyle advices - Refer women with overweight/obesity to visit a dietician
- Extra glucose screening preconception in women planning a new pregnancy Public Health
Early Childhood Centers
- Remind women to visit the GP for annual glucose testing
- Organise regional meetings for women with a history of GDM about lifestyle, including diet and physical activity
- Advise and remind women about other regional meeting/activities at the Early Childhood Center useful for women with a history of GDM (i.e. lifestyle, breastfeeding)
- Give information where women can find help/support to change their lifestyle Abbreviations: GDM, gestational diabetes mellitus; GP, general practitioner; T2DM, type 2 diabetes mellitus.
CONCLUSION
In conclusion, in this thesis we have shown that the currently used national guide-line for screening and treatment of GDM is successful in reducing the risk of short-term adverse pregnancy outcomes, but not in reducing the likelihood of having an LGA neonate with a possible unfavourable metabolic profile later in life. In order to further optimize GDM care and pregnancy outcomes, this thesis supports the use of a lower fasting glucose level in the Dutch national guideline for GDM diagnosis. At the moment, there is limited evidence to support a higher 2HG level for the diagno-sis of GDM. We have also shown that the long-term care for GDM is far from optimal and requires further improvement to lower the risk of T2DM after GDM.
Recommendations for further research
In this general discussion there are several topics discussed that deserve further research. First, a randomized controlled trial directly comparing the diagnostic ap-proaches (WHO-1999 criteria versus WHO-2013 criteria) could determine whether treatment of women with mild GDM is beneficial and cost- effective. Secondly, we need more information whether women with a 2HG cut-off value between
≥7.8-≤8.4 mmol/l can be safely left untreated or whether even a stricter 2HG cut-off for establishing the diagnosis of GDM and instituting treatment may further improve pregnancy outcomes. Also the mode of treatment deserve further attention. Insulin therapy is the medication of choice in GDM as recommended in most international guidelines, although drug treatment in guidelines is highly variable. The use of blood glucose-lowering agents in GDM pregnancy has gained considerable interest as an alternative for insulin therapy. On the basis of current evidence, the use of metformin in pregnancy seems to be safe with similar outcomes to those treated with insulin therapy. However, there are uncertainties regarding metformin use and the possible short-term risk of premature delivery and this deserve further research. Thirdly, given the fact that several hospitals in the Netherlands employ a shared-care model between primary and secondary care for GDM, there appears to be a clear need for prospective studies investigating the safety of treating women with GDM who are managed with diet only in primary care. Questions are whether this can be done safely on a large scale, are there better ways to estimate risk of pregnancy-related complications, and what measures need to be taken to ensure proper care for the mother and the newborn in case of unexpected complications, for instance neonatal hypoglycaemia monitoring.
It has to stressed that, if we want to break the vicious circle of obesity, studies on preventive strategies like lifestyle interventions before/ during/ after pregnancy are warranted in the growing number of women with obesity and GDM carrying an
9
increased risk of T2DM after pregnancy. Such strategies well can be cost-effective, as they may reduce the number of referrals to a hospital because of GDM diagnosis, and may limit the need of exogenous insulin treatment. And finally, there is incon-sistency regarding the association between hyperglycaemia in utero and the risk of long-term health consequences for the offspring. Therefore there is an urgent need for long-term GDM-offspring studies regarding the role of foetal program-ming including adequate control for confounding factors. This should also include evaluation of the possible long-term consequences of specific treatments during pregnancy, given the concerns raised about the possible effects of metformin (Chapter 2), a frequently used diabetes drug, on gonadal function in offspring.
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26. Cundy T, Ackermann E, Ryan EA. Gestational diabetes: New criteria may triple the prevalence but effect on outcomes is unclear. BMJ. 2014;11:348-g1567.
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31. Black MH, Sacks DA, Xiang AH, Lawrence JM. The relative contribution of prepregnancy over-weight and obesity, gestational over-weight gain, and IADPSG-defined gestational diabetes mellitus to fetal overgrowth. Diabetes Care. 2013;36:56-62.
32. Dodd JM, Grivell RM, NGUYEN A, Chan A, Robinson JS. Maternal and perinatal health outcomes by body mass index category. Aust N Z J Obstet Gynaecol. 2011;51:136-40.
33. Langer O. Obesity or diabetes: Which is more hazardous to the health of the offspring? J Matern Fetal Neonatal Med. 2016;29:186-90.
34. Langer O. Management of obesity in GDM: Old habits die hard. J Matern Fetal Neonatal Med.
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35. Oteng-Ntim E, Varma R, Croker H, Poston L, Doyle P. Lifestyle interventions for overweight and obese pregnant women to improve pregnancy outcome: Systematic review and meta-analysis.
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36. Zhang C, Tobias DK, Chavarro JE, et al. Adherence to healthy lifestyle and risk of gestational diabetes mellitus: Prospective cohort study. BMJ. 2014;349:g5450.
37. Koivusalo SB, Rono K, Klemetti MM, et al. Gestational diabetes mellitus can be prevented by lifestyle intervention: The Finnish gestational diabetes prevention study (RADIEL): A randomized controlled trial. Diabetes Care. 2016;39:24-30.
38. Medici M, Korevaar TI, Schalekamp-Timmermans S, et al. Maternal early-pregnancy thyroid func-tion is associated with subsequent hypertensive disorders of pregnancy: The generafunc-tion R study.
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39. Korevaar TI, Chaker L, Medici M, et al. Maternal total T4 during the first half of pregnancy: Physi-ologic aspects and the risk of adverse outcomes in comparison with free T4. Clin Endocrinol (Oxf).
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40. Medici M, Timmermans S, Visser W, et al. Maternal thyroid hormone parameters during early pregnancy and birth weight: The generation R study. J Clin Endocrinol Metab. 2012;98:59-66.
41. Bassols J, Prats-Puig A, Soriano-Rodríguez P, et al. Lower free thyroxin associates with a less favor-able metabolic phenotype in healthy pregnant women. J Clin Endocrinol Metab. 2011;96:3717-23.
42. Knight BA, Shields BM, Hattersley AT, Vaidya B. Maternal hypothyroxinaemia in pregnancy is asso-ciated with obesity and adverse maternal metabolic parameters. Eur J Endocrinol. 2016;174:51-7.
43. Yang S, Shi F, Leung PC, Huang H, Fan J. Low thyroid hormone in early pregnancy is associated with an increased risk of gestational diabetes mellitus. J Clin Endocrinol Metab. 2016;101:4237-43.
44. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol. 2008;112:85-92.
45. Haddow JE, Craig WY, Neveux LM, et al. Free thyroxine during early pregnancy and risk for gesta-tional diabetes. PloS One. 2016;11:e0149065.
46. Duran A, Saenz S, Torrejon MJ, et al. Introduction of IADPSG criteria for the screening and diag-nosis of gestational diabetes mellitus results in improved pregnancy outcomes at a lower cost in a large cohort of pregnant women: The St. Carlos gestational diabetes study. Diabetes Care.
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49. Wang YC, McPherson K, Marsh T, Gortmaker SL, Brown M. Health and economic burden of the projected obesity trends in the USA and the UK. Lancet. 2011;378:815-25.
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Samenvatting
S
Zwangerschapsdiabetes
Zwangerschapsdiabetes wordt gedefinieerd als verhoogde bloedglucosewaarden die voor het eerst worden vastgesteld tijdens de zwangerschap. Indien zwanger-schapsdiabetes in het eerste trimester (vóór 12 weken) van de zwangerschap wordt vastgesteld, moet een al aanwezige (type 2) diabetes worden overwogen.
Bij de meeste vrouwen met zwangerschapsdiabetes normaliseren de bloedglucose-waarden na de zwangerschap.1 Zwangerschapsdiabetes komt in ongeveer 14% van alle zwangerschappen voor en het aantal zal naar verwachting blijven stijgen.2
Onbehandelde zwangerschapsdiabetes verhoogt de kans op zwangerschap-scomplicaties zoals een kind met een te hoog geboortegewicht (macrosomie), geboortetrauma, preeclampsie en keizersnede.3-5 Na de zwangerschap hebben vrouwen met een doorgemaakte zwangerschapsdiabetes een verhoogde kans op het ontwikkelen van type 2 diabetes en hart- en vaatziekten.6-10 Ook is er steeds meer bewijs dat kinderen van moeders met zwangerschapsdiabetes op latere leeftijd een verhoogde kans hebben op het ontwikkelen van overgewicht en type 2 diabetes.11-13 Interventie studies hebben aangetoond dat vroege diagnose en adequate behandeling van vrouwen met zwangerschapsdiabetes de kans op zwangerschapscomplicaties kan verlagen.14,15 Echter er is wereldwijd geen duidelijk en uniform beleid rond de diagnose en de behandeling van zwangerschapsdiabe-tes.16
Nederlandse richtlijn voor screening en behandeling van zwangerschapsdiabetes
In Nederland wordt sinds 2010 gebruik gemaakt van de richtlijn “Diabetes Mellitus en Zwangerschap” van de Nederlandse Vereniging voor Obstetrie en Gynaecologie (NVOG) voor de screening en behandeling van zwangerschapsdiabetes. In deze richtlijn wordt geadviseerd om vrouwen met een verhoogde kans op zwanger-schapsdiabetes te screenen tussen 24 en 28 weken zwangerschapsduur met een 75-g orale glucose tolerantie test (OGTT).17 Voor de diagnose van zwangerschaps-diabetes wordt er gebruik gemaakt van de Wereldgezondheidsorganisatie (WHO) diagnostische criteria, welke dateren uit het jaar 1999; een nuchtere glucosewaarde
≥7,0 mmol/l en/of 2-uurs glucosewaarde ≥7,8 mmol/l.17,18
Alle vrouwen gediagnosticeerd met zwangerschapsdiabetes worden behandeld met als hoofddoel het bereiken van normale bloedglucosewaarden tijdens de zwangerschap. De eerste stap in de behandeling is het aanpassen van de voeding.
Als met voedingsadvies niet het gewenste resultaat wordt bereikt, namelijk nor-male bloedglucosewaarden zowel nuchter als na de maaltijd, is insuline therapie de tweede stap.17 Verder adviseert de nationale richtlijn om na de zwangerschap de bloedglucosewaarden te controleren om een eventuele ontstaande type 2 diabetes
in een vroeg stadium op te sporen. Er wordt geadviseerd om bloedglucosecontrole te doen zes weken na de bevalling, en vervolgens dit jaarlijks te herhalen gedurende de daarop volgende vijf jaar.17,19
Internationale richtlijnen voor zwangerschapsdiabetes
In de afgelopen jaren zijn er veel nieuwe bevindingen gerapporteerd met betrek-king tot verhoogde bloedglucosewaarden van de moeder tijdens de zwangerschap en een toegenomen kans op zwangerschapscomplicaties.3,5 Dit heeft geleid tot hernieuwde discussies, zowel in ons land als internationaal, over de meest optimale
In de afgelopen jaren zijn er veel nieuwe bevindingen gerapporteerd met betrek-king tot verhoogde bloedglucosewaarden van de moeder tijdens de zwangerschap en een toegenomen kans op zwangerschapscomplicaties.3,5 Dit heeft geleid tot hernieuwde discussies, zowel in ons land als internationaal, over de meest optimale