Hypertension Complicating Diabetic Pregnancies: Pathophysiology, Management, and Controversies

Diabetic Renal Disease and Hypertension in Pregnancy

Management of diabetic renal disease prior to conception and during pregnancy is both complex and controversial. In nonpregnant individuals, the mainstay of management of diabetic nephropathy is inhibition of the renin‐angiotensin system with angiotensin‐converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). 26 , 27 However, both ACE inhibitors and ARBs have well‐established fetotoxic effects when used during the 2nd and 3rd trimesters of pregnancy: renal failure and anuria, with resultant oligohydramnios and pulmonary hypoplasia; skeletal/calvarial abnormalities; and fetal growth restriction. 28 There is conflicting evidence regarding the potential teratogenicity of ACE inhibitors or ARBs when used during the 1st trimester, with one study showing an increased risk of fetal cardiac valve and central nervous system defects after 1st trimester ACE inhibitor exposure 29 but other studies showing no increased teratogenic risk specific to this drug class. 30 , 31 , 32 Further complicating management, pregnancy itself may accelerate progression of clinically significant diabetic nephropathy, particularly when there is already a significant decrease in renal function prior to conception, which may result in progression to end‐stage renal disease earlier than predicted based on the natural course of diabetic nephropathy in nonpregnant patients. 11 , 33 , 34 In addition, pre‐existing maternal nephropathy is associated with significant maternal and fetal morbidity, including preeclampsia, premature delivery, low birth weight, and increased incidence of respiratory distress syndrome and perinatal infant death. 35 The prevalence of fetal complications increases with increasing severity of maternal renal disease. 36 For these reasons, it was previously common practice to discourage pregnancy in women with known diabetic nephropathy. On the other hand, after careful consideration of the possible increased teratogenic risk of limited 1st trimester exposure to ACE inhibitors, 29 , 30 , 31 , 32 the maternal and fetal benefits conferred by their renal‐protective effects may far outweigh the potential risks of short‐term exposure in reliable patients who will discontinue them in early gestation.

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Several studies have shown that treating diabetic women who desire pregnancy with an ACE inhibitor prior to conception, then stopping the medication as soon as pregnancy is known, decreases proteinuria and improves maternal outcome without increased risk to the fetus. In a small uncontrolled study of women with insulin‐dependent diabetes (IDDM) and known nephropathy, 6 to 12 months of treatment with the ACE inhibitor captopril prior to conception appeared to improve maternal‐fetal outcome. 37 Specifically, pre‐conception captopril decreased proteinuria prior to pregnancy, and despite discontinuation of the medication early in the 1st trimester, progression of nephropathy was minimal in most cases and proteinuria reverted back to prepregnancy levels within 3 months postpartum. Neonatal outcome was also improved relative to what would be expected in diabetic mothers with severe proteinuria, with only 1 of 8 births being delivered preterm, 1 SGA, and none with congenital anomalies. 37 A similar study by the same group, in women with IDDM and mild nephropathy (rather than severe nephropathy as in the prior study), half of whom also had pre‐existing hypertension, suggested long‐term renal protection following treatment with captopril for 6 months prior to conception along with strict glycemic control. Moreover, the complications that occurred, including preeclampsia, IUGR, and preterm delivery, occurred at lower rates than expected in pregnancies complicated by diabetic nephropathy. In fact, pre‐existing hypertension was the only significant predictor of these complications. Likewise, none of the offspring from these women exhibited any congenital abnormality despite maternal ACE inhibitor use early in the 1st trimester. 38

Women with diabetic nephropathy should be counseled about the risks of pregnancy and made aware that tight control of glycemia and BP are paramount to minimizing pregnancy complications, including progression of microvascular disease. Ideally, close medical follow‐up should allow these women to continue ACE inhibitor or ARB use as renal‐sparing agents in anticipation of pregnancy, with immediate discontinuation as soon as pregnancy is achieved, to optimize outcomes. Specifically, minimizing progression of diabetic nephropathy during pregnancy is critical to reduce the risk of GH or preeclampsia and associated adverse maternal/fetal outcomes.

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About the Author: Tung Chi