Introduction
Women with diabetes - regardless of the type of diabetes - must plan a pregnancy to ensure optimal conditions for the child's development and their own health and to reduce the risk of perinatal complications. The main problem with pre-existing diabetes is the development of diabetic embryopathy [1].
Pregnancy in women with manifest forms of diabetes primarily affects women with type 1 diabetes mellitus. However, recent surveys also show a continuous increase in type 2 diabetes mellitus, which, in addition to hyperglycemia, is complicated by obesity-related risks and often by older maternal age [2]. Even among pregnant women with diabetes type 1, a significant increase in BMI has been observed over the last decade. In both T1DM and T2DM, higher maternal BMI and higher blood pressure, in addition to metabolic control and diabetes duration at the start of pregnancy, were associated with poorer pregnancy outcomes. Migrant women and women from low socioeconomic backgrounds account for a significant proportion of women with diabetes type 2, particularly those who were inadequately treated and prepared for pregnancy or whose pre-existing diabetes was only newly discovered during pregnancy. Persistently poor pregnancy outcomes in women with pre-conceptional diabetes are also confirmed in recent population-based surveys [3].
Maternal obesity and inadequate metabolic control are the main modifiable risk factors, while maternal age, duration of diabetes and maternal deprivation are the main non-modifiable risk factors. No differences were found in congenital malformations and stillbirths between women with type 1 and type 2 diabetes, while premature births were more common in type 1 diabetes [4]. However, women with type 2 diabetes had a higher neonatal mortality rate. An HbA1C ≥ 6.5 % in the 3rd trimester, type 2 diabetes, and social disadvantage of the mothers were independent risk factors for perinatal death. Increased attention should be paid to achieve optimal glycaemia in women with type 2 diabetes before and during pregnancy, as these patients often already have additional cardiovascular risk factors, comorbidities, and the risk of complications is often underestimated [4].
According to The Diabetes Control and Complications Trial (DCCT), pregnancy increases the risk of retinal damage by 1.63 times compared to the state of the retina before pregnancy and by 2.48 times compared to similar indicators in non-pregnant women [5].
Potin et al. note that 61.2% of patients with type 1 diabetes mellitus and microvascular changes during pregnancy have DR. However, the occurrence or progression of DR is observed in 9.7% of pregnant women [6].
The worsening of DR during pregnancy is due to a number of factors: pregnancy itself, changes in retinal blood flow, inadequate glycemic control before and during pregnancy, the rapid normalization of blood sugar, the presence and severity of diabetic retinopathy before pregnancy, the duration of diabetes, the presence of hypertension, diabetic neuropathy, and pre-eclampsia [7].
The progression of DR depends considerably on the severity of glucose metabolism decompensation before conception and in the first 6-14 weeks of pregnancy, as well as the rate at which normoglycemia is achieved. The Diabetes in Early Pregnancy (DIEP) study revealed that 10.3% of women with DM1 who had an initial absence of ocular changes and progression of DR during pregnancy had baseline HbA1c level 4 standard deviations above normal. The DCCT study proved that the risk of DR progression in pregnant women with DM1 is directly related to baseline DM compensation [5].
В. Rosenn et al. note that patients with chronic hypertension or pregnancy-related hypertension have a higher frequency of diabetic retinopathy progression. Increased retinal blood flow, corresponding to the hyperdynamic circulatory state in pregnancy, can stimulate endothelial damage and become a significant factor in the progression of the condition [8].
There is a common belief that DR regresses in the postpartum period. The DCCT study indicated the transient nature of the changes occurring during pregnancy [5].
S. Arun and R. Taylor studied women with DM1 for 5 years after childbirth and found that pregnancy does not lead to long-term worsening of DR [9].
However, W. Chan et al. observed pregnant women with an aggressive course of DR and found that in this group of patients, in 81% of cases, the condition progressed to the proliferative stage in the postpartum period. Moreover, the most unfavorable outcomes in the form of traction and rhegmatogenous retinal detachment and neovascular glaucoma were observed when spontaneous regression of the disease was expected after delivery and timely retinal laser coagulation was not performed [10].
The progression of DR may depend on whether retinal laser photocoagulation was performed in the pregestational period. A study of patients with proliferative DR detected in early pregnancy who subsequently underwent laser photocoagulation showed progression and significant visual impairment in 58% of cases. In contrast, among patients in whom retinopathy was detected and treated before pregnancy, only 26% of cases showed progression of DR during the gestational period [11]. The indications for treatment and response to retinal laser photocoagulation in pregnant women are the same as in all patients with diabetes. Pre-conceptional stabilization of glycemia and blood pressure levels is of paramount importance to prevent the manifestation and progression of DR during pregnancy in diabetes. Glycated hemoglobin concentration should be maintained below 6.1% if possible and safe. It is important to monitor the ocular fundus throughout pregnancy - at least twice in different trimesters, as well as in the postpartum period until the process is completely stabilized. If progression of DR is detected, timely treatment, primarily retinal laser photocoagulation, improves visual prognosis [12].
Laser Treatment
It makes sense to advise close supervision in cases where a pregnant woman first develops moderate to severe diabetic macular edema, with a priority on achieving and maintaining adequate glucose control. Two diabetic individuals in the first trimester of their pregnancies were included in a Danish article. They had retinal edema 500–1500 μm in the fovea area. Good glucose management helped both patients improve, and as a result, they did not require any furhter care [13].
Although observation is a good choice for pregnant patients with mild to moderate diabetic macular edema (DME), it is important to observe these women more carefully than non-pregnant adults. If DME does not resolve after a period of follow-up, the first-line treatment option is laser treatment. The ETDRS reported that grid or focused laser treatment of clinically significant macular edema was successful in preventing continued visual disability [13, 14]. According to a study conducted in Copenhagen, two pregnant women diagnosed with type 1 DM and macular edema received targeted laser treatment and did not require any additional medical intervention during their pregnancy. When foveal involvement makes traditional laser therapy unsafe, subthreshold MicroPulse or endpoint management are two further options that could be taken into consideration. Following treatment using a MicroPulse laser, Italian researchers found a substantial short-term improvement in DME and visual acuity [15]. These non-invasive techniques might be useful in situations when traditional laser treatments are inappropriate or potentially dangerous, especially when a woman is newly pregnant [13, 15].
For pregnant patients with DR, panretinal photocoagulation is regarded as a reliable and effective therapy option. It has been shown to be an effective treatment for diabetic retinopathy during pregnancy and remains a vital treatment for stopping disease's progression. When administering PRP to pregnant people, proper scheduling is essential. According to recommendations, PRP therapy may be necessary for pregnant women at earlier stages, especially if their degree of DR approaches severe nonproliferative DR or higher [16].
Intravitreal Steroids in DME
There is little data in the literature on the use of intravitreal steroids during pregnancy, and much of the material available comes from modest research. A collection of research supporting intravitreal steroid usage and evaluation of its safety profiles at different phases of pregnancy may exist, although it is not as extensive as the research supporting certain other therapies. It is critical to recognize the moral difficulties that arise when conducting extensive research on expectant mothers, as these challenges may limit the amount of high-caliber, widely available material. Because of the potential consequences for the developing baby as well as the mother, the safety of any medical intervention during pregnancy is a serious concern.
The use of intravitreal steroids during pregnancy should be decided on a case-by-case basis, carefully balancing the possibility of benefits versus any existing or prospective hazards, given the lack of information [13, 17].
Intravitreal Anti-VEGF Substances
Due to the lack of long-term efficacy evidence for anti-VEGF medication in pregnant patients, it is often used only as an emergency measure during gestation. Anti-VEGF medications, such as bevacizumab, ranibizumab and aflibercept are frequently used to treat a range of eye disorders, particularly retinal illnesses. Because the possible effects on the developing baby are a serious concern, pregnant women are frequently cautious about using drugs that have not been thoroughly investigated for their safety during pregnancy [18].
Consequently, anti-VEGF medication is usually considered only when alternative medical options are not possible or effective for a pregnant woman, and if it is determined that she needs it. Moreover, it is usually preferable to start anti-VEGF medication afterwards in pregnancy, especially in the third trimester. This period was chosen based on the idea of reducing possible hazards to fetal development during the critical early stages of pregnancy. In a patient with foveal-involving diabetic macular edema and a contraindication to steroids, the use of anti-VEGF therapy could be considered. The Diabetic Retinopathy Clinical Research Network study has shown that anti-VEGF therapies are highly effective in the treatment of DME. This study compared the outcomes of anti-VEGF therapy combined with laser treatment versus laser treatment alone. The drug's half-life in the plasma plays a role in deciding which anti-VEGF therapy to choose. Bevacizumab is known to have a longer half-life and to remain in the plasma for a longer period of time. Bevacizumab administered intravitreal has been demonstrated to lower plasma VEGF levels for a minimum of one month. Ranibizumab, on the other hand, has a shorter half-life and is cleared from the plasma quickly. Given that ranibizumab has a shorter half-life, it is considered a viable treatment option for expectant mothers and those who plan to become pregnant soon after receiving an anti-VEGF injection [13, 18, 19].
Women diagnosed with preproliferative DR during pregnancy should be counseled to attend regular eye examinations for at least 6 months postpartum and typically up to 1 year postpartum. This monitoring is important to track the progression of diabetic retinopathy and to ensure timely intervention if necessary. The DCCT study demonstrated that the higher risk of progression of DR during pregnancy persisted for one year after delivery. Several of these women required laser photocoagulation for up to 12 months after delivery [20, 21]. Another study found that DR was more likely to progress 4 months after delivery than during pregnancy. This phenomenon may be related to the successful control of glycaemia during pregnancy, which then decreases in the postpartum period. Dilated fundoscopy should be performed 1-2 months after delivery in those who had treated or untreated DME during pregnancy and in patients with mild, moderate or severe nonproliferative DR. This follow-up examination is recommended to assess the retinal status postpartum and should be continued until 12 months after delivery [22, 23].
Conclusions
Numerous factors affect how DR progresses throughout pregnancy, including the level of retinopathy at conception, the efficacy of medication, the duration of diabetes, the state of glucose regulation prior to pregnancy, and the existence of other vascular complications, such as associated or pre-existing hypertensive conditions. Retinopathy progression is less likely when risk factors are precisely identified, and diabetes is well managed. To protect the wellness of both the fetus and mother's eyes by improving early diagnosis and management of potential ophthalmic disorders, an ophthalmologist consultation is advised for women who have recently been diagnosed with diabetes during pregnancy.
The probability of vision loss is low for those who have mild retinopathy at the beginning of pregnancy; a fundus exam every three months is usually sufficient. Further regular evaluation is advised for patients with mild baseline retinopathy, with ophthalmoscopy carried out at each obstetrician visit. Investigations should be performed every two weeks if there are signs of progression. In situations where high-risk retinal modifications are suspected, laser photocoagulation should be performed immediately, with ophthalmoscopy used to monitor the process. Laser photocoagulation is recommended to be carried out before pregnancy or as soon as significant retinal alterations manifest in women with severe diabetic retinopathy [15, 23].
Competing interests
None declared.
Acknowledgements and funding
No external funding.
Ethics approval
Not needed for this study.
Author’s ORCID ID:
Cristina Șcerbatiuc – https://orcid.org/0000-0002-4512-0626
References
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. JAMA Ophthalmol. 2022;140(5):486-494. https://doi.org/10.1001/jamaophthalmol.2022.0050.
Sarvepalli SM, Bailey BA, D’Alessio D, Lemaitre M, Vambergue A, Rathinavelu J, Hadziahmetovic M. Risk factors for the development or progression of diabetic retinopathy in pregnancy: meta‐analysis and systematic review. Clin Exp Ophthalmol. 2022;51(3):195-204. https://doi.org/10.1111/ceo.14168.
Bourry J, Courteville H, Ramdane N, Drumez E, Duhamel A, Subtil D, Deruelle P, Vambergue A. Progression of diabetic retinopathy and predictors of its development and progression during pregnancy in patients with type 1 diabetes: a report of 499 pregnancies. Diabetes Care. 2020;44(1):181-187. https://doi.org/10.2337/dc20-0904.
Scanlon PH. The English National Screening Programme for diabetic retinopathy 2003–2016. Acta Diabetologica. 2017;54(6):515-525. https://doi.org/10.1007/s00592-017-0974-1.
Nathan DM. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2013;37(1):9-16. https://doi.org/10.2337/dc13-2112.
Potin VV, Borovik NV, Tisel’ko AV. Insulinoterapiia bol’nyh sakharnym diabetom 1 tipa vo vremia beremennosti [Insulin therapy for patients with type 1 diabetes during pregnancy]. Diabetes Mellit. 2009;12(1):39-41. https://doi.org/10.14341/2072-0351-5420. Russian.
Amoaku WM, Ghanchi F, Bailey C, Banerjee S, Banerjee S, Downey L, et al. Diabetic retinopathy and diabetic macular oedema pathways and management: UK Consensus Working Group. Eye. 2020;34(Suppl 1):1-51. https://doi.org/10.1038/s41433-020-0961-6.
Rosen RB, Andrade Romo JS, Krawitz BD, Mo S, Fawzi AA, Linderman RE, Carroll J, Pinhas A, Chui TY. Earliest evidence of preclinical diabetic retinopathy revealed using optical coherence tomography angiography perfused capillary density. Am J Ophthalmol. 2019;203:103-115. https://doi.org/10.1016/j.ajo.2019.01.012
Arun CS, Taylor R. Influence of pregnancy on long-term progression of retinopathy in patients with type 1 diabetes. Diabetologia. 2008;51(6):1041-1045. https://doi.org/10.1007/s00125-008-0994-z.
Chan WC, Lim LT, Quinn MJ, Knox FA, McCance D, Best RM. Management and outcome of sight-threatening diabetic retinopathy in pregnancy. Eye. 2004;18(8):826-832. https://doi.org/10.1038/sj.eye.6701340.
Rafferty J, Owens DR, Luzio SD, Watts P, Akbari A, Thomas RL. Risk factors for having diabetic retinopathy at first screening in persons with type 1 diabetes diagnosed under 18 years of age. Eye. 2020;35(10):2840-2847. https://doi.org/10.1038/s41433-020-01326-8.
Zhang B, Zhang B, Zhou Z, Guo Y, Wang D. The value of glycosylated hemoglobin in the diagnosis of diabetic retinopathy: a systematic review and meta-analysis. BMC Endocr Disord. 2021;21(1):82. https://doi.org/10.1186/s12902-021-00737-2.
Rosu LM, Prodan-Bărbulescu C, Maghiari AL, Bernad ES, Bernad RL, Iacob R, Stoicescu ER, Borozan F, Ghenciu LA. Current trends in diagnosis and treatment approach of diabetic retinopathy during pregnancy: a narrative review. Diagnostics. 2024;14(4):369. https://doi.org/10.3390/diagnostics14040369.
Bakri S, Dedania V. Novel pharmacotherapies in diabetic retinopathy. Middle East Afr J Ophthalmol. 2015;22(2):164-173. https://doi.org/10.4103/0974-9233.154389.
Değirmenci MFK, Demirel S, Batıoğlu F, Özmert E. Short-term efficacy of micropulse yellow laser in non-center-involving diabetic macular edema: preliminary results. Turk J Ophthalmol. 2018;48(5):245-249. https://doi.org/10.4274/tjo.04657.
Gomułka K, Ruta M. The role of inflammation and therapeutic concepts in diabetic retinopathy - a short review. Int J Mol Sci. 2023;24(2):1024. https://doi.org/10.3390/ijms24021024.
Chauhan MZ, Rather PA, Samarah SM, Elhusseiny AM, Sallam AB. Current and novel therapeutic approaches for treatment of diabetic macular edema. Cells. 2022;11(12):1950. https://doi.org/10.3390/cells11121950.
Kohly RP, Muni RH, Kertes PJ. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Evidence-Based Ophthalmol. 2010;11(4):199-201. https://doi.org/10.1097/ieb.0b013e3181f4ce75.
Chandrasekaran P, Madanagopalan V, Narayanan R. Diabetic retinopathy in pregnancy - a review. Indian J Ophthalmol. 2021;69(11):3015-3025. https://doi.org/10.4103/ijo.ijo_1377_21.
Ghanchi F. The Royal College of Ophthalmologists’ clinical guidelines for diabetic retinopathy: a summary. Eye. 2013;27(2):285-287. https://doi.org/10.1038/eye.2012.287.
Pappot N, Do NC, Vestgaard M, Ásbjörnsdóttir B, Hajari JN, Lund‐Andersen H, et al. Prevalence and severity of diabetic retinopathy in pregnant women with diabetes - time to individualize photo screening frequency. DiabetMed. 2022;39(7):e114819. https://doi.org/10.1111/dme.14819.
American Diabetes Association Professional Practice Committee. Management of diabetes in pregnancy: standards of medical care in diabetes - 2022. Diabetes Care. 2021;45(Suppl 1):S232-S243. https://doi.org/10.2337/dc22-s015.
Ong AY, Kiire CA, Frise C, Bakr Y, de Silva SR. Intravitreal anti-vascular endothelial growth factor injections in pregnancy and breastfeeding: a case series and systematic review of the literature. Eye. 2023;38(5):951-963. https://doi.org/10.1038/s41433-023-02811-6.