11th June 2022, Dr Chee L Khoo
Diabetic retinopathy (DR) will affect at least 1 in 3 of our patients with diabetes. Did you know that DR is the leading cause of irreversible blindness in women of reproductive age? Further, the progression continues up to 12 months postpartum. Type 1 diabetes is on the increase and young type 2 diabetes is definitely on the rise. So, we can expect a lot more women with diabetes, T1 or T2, becoming pregnant. So, how common is DR during pregnancy? Is it a big deal? The burden of DR in pregnancy and its progression rate is hard to estimate but a recent systematic review and meta-analysis ought to shocked you with its numbers.
The pathophysiology
There is a 40% increase in cardiac output during pregnancy and it is thought that this leads to a hyperdynamic circulation state (1). Autoregulatory mechanisms causing compensatory retinal vessel constriction are deranged in diabetics due to decreased renin–angiotensin system, which in turn results in vascular dilatation, increased blood flow, and worsening of DR (2) during pregnancy. Schocket et al proposed that decrease in retinal volumetric blood flow may have worsened DR due to hypoxia and retinal ischaemia (3)
During pregnancy, growth hormone is replaced by placental growth hormone (PGH), which modulates the secretion of pro-angiogenic factor insulin growth factor (IGF). Both have been shown to be increased in those with PDR and cause progression of DR in pregnancy (4,5).
In pregnancy, placenta that is in a highly inflammatory state causes upregulation of pro-inflammatory factors and down-regulation of anti-inflammatory factors, imbalance of which is implicated in the pathogenesis of PDR (6,7). Loukovaara et al. and Immonen et al. showed increased levels of CRP in diabetic pregnant women with progression of retinopathy and in women with worse glycemic control but levels of IL-6 or VCAM-1 were similar in both type 1 diabetic and nondiabetic women (7).
Risk factors for progression of DR in pregnancy
Diabetes Control and Complications Trial (DCCT) (8) and Diabetes in Early Pregnancy study (DIEP) (9) highlighted the factors that contribute to diabetic retinopathy and its progression gestational diabetes (GDM):
- Duration of diabetes
- Metabolic control
- Baseline severity of DR
- Hypertension
- Age of onset (worse in younger diabetic)
- Visual acuity and diabetic macular oedema
So, how significance is DR in pregnancy?
Widyaputri et al examined 18 observational studies in a systematic review and meta-analysis involving 1464 pregnant women with T1D and 262 pregnant women with T2D in 12 countries, most of which were well-resourced countries (10). Overall, the pooled prevalence of any DR in early pregnancy was 52.3 per 100 pregnancies. That number went up to 57.8% by delivery. 6.1 per 100 pregnancies of those were proliferative diabetic retinopathy (PDR). That means a little more than 1 in 2 of your young women with diabetes will have DR in early pregnancy. As a comparison, the overall pooled prevalence estimate in non-pregnant diabetic population was 34.6% (4). These are staggering numbers!
For every 100 pregnancies which did not have DR at baseline, 15.0 developed new DR during the pregnancy. For every 100 pregnancies with non-proliferative DR at baseline, 31.0 worsened (progression) during the pregnancy. 6.3 of those progressed from non-proliferative DR to PDR and amongst women who already had PDR at baseline 37.0 progressed.
DR progression rates per 100 pregnancies were similar between the T1D and T2D groups, except for the development of new DR (T1D groups: 15.8; T2D groups: 9.0). Once a woman has DR, her risk of DR progression is similar in pregnancy irrespective of her diabetes type
In summary, the prevalence of DR is high in our young women with diabetes who become pregnant. It is not unexpected to see more DR in patients with T1D as they would have diabetes duration for longer and often, with poor glycaemic control. However, we are seeing more young T2D and we will be seeing more DR in these patients at baseline.
Diabetes Contraceptive and Prepregnancy Planning (DCAPP) Program
It’s not just DR we need to worry in our young women with diabetes who are in their reproductive years. High rates of congenital malformations exist in South Western Sydney in women with Type 1 and Type 2 diabetes (11% in Campbelltown and 6.8% in Liverpool compared with the background rate of 2%). DCAPP has been designed to develop a more integrated approach supporting women of childbearing age (<50 years) with Type 1 and Type 2 diabetes. Programmes implemented elsewhere have reduced the rates of congenital malformations, miscarriage and stillbirths by up to 70% encouraging us to use the similar approaches. More information on DCAPP can be found here.
Many pregnancies in these women are unplanned. As their GP, it is imperative that we discuss the issue of pregnancy with these women. For those who do not intend to fall pregnant, reliable contraception needs to be in place. Those intended to fall pregnant needs optimisation of their diabetes management including changing their glucose-lowering agents, their anti-hypertensive agents and commencing high dose folic acid (and checking their eyes!). This often necessitate referral to DCAPP. Details for referral to the service can be found on the healthpathways site here.
References
- Thornburg KL, Jacobson S-L, Giraud GD, Morton MJ Hemodynamic changes in pregnancy Semin Perinatol 2000 24 11 4
- Chen HC, Newsom RS, Patel V, Cassar J, Mather H, Kohner EM Retinal blood flow changes during pregnancy in women with diabetes Invest Ophthalmol Vis Sci 1994 35 3199 208
- Schocket LS, Grunwald JE, Tsang AF, DuPont J The effect of pregnancy on retinal haemodynamics in diabetic versus nondiabetic mothers Am J Ophthalmol 1999 128 477 84
- Caufriez A, Frankenne F, Englert Y, Golstein J, Cantraine F, Hennen G, et al. Placental growth hormone as a potential regulator of maternal IGF-I during human pregnancy Am J Physiol 1990 258 E1014 19
- Lauszus F, Klebe JG, Bek T, Flyvbjerg A Increased serum IGF-I during pregnancy is associated with progression of diabetic retinopathy Diabetes 2003 52 852 56
- Adamis AP Is diabetic retinopathy an inflammatory disease? Br J Ophthalmol 2002 86 363 5
- Loukovaara S, Immonen I, Koistinen R, Hiilesmaa V, Kaaja R Inflammatory markers and retinopathy in pregnancies complicated with type I diabetes Eye 2005 19 422 30
- Diabetes Control and Complications Trial Research Group Effect of pregnancy on microvascular complications in the diabetes control and complications trial The Diabetes Control and Complications Trial Research Group. Diabetes Care 2000 23 1084 91
- Chew EY, Mills JL, Metzger BE, Remaley NA, Jovanovic-Peterson L, Knopp RH, et al. Metabolic control and progression of retinopathy. The diabetes in early pregnancy study. National Institute of Child Health and Human Development diabetes in early pregnancy study Diabetes Care 1995 18 6317
- Widyaputri F, Rogers SL, Kandasamy R, Shub A, Symons RCA, Lim LL. Global Estimates of Diabetic Retinopathy Prevalence and Progression in Pregnant Women With Preexisting Diabetes: A Systematic Review and Meta-analysis. JAMA Ophthalmol. 2022;140(5):486–494. doi:10.1001/jamaophthalmol.2022.0050