Hypertension and associated complications in pregnant women with chronic kidney disease

Abstract

The growing incidence of obesity and the rising trend of increased age during pregnancy have led to a high number of pregnant women with chronic kidney disease (CKD). Chronic hypertension is commonly associated with CKD and is not only the result of renal damage but is also the cause of declining renal function. Pregnancy and its unique physiological adaptations are affected by a decrease in the filtration capacity of the kidneys. Preeclampsia is a disorder of the vascular endothelium and is exacerbated by endothelial dysfunction resulting from CKD. Blood pressure targets must be strictly maintained owing to overlapping disease pathogenesis and to minimize cardiovascular damage. Moreover, preexisting renal dysfunction poses a challenge in identifying superimposed preeclampsia, which alters the management strategies in pregnancy. Fetal outcomes in patients with CKD are considerably affected by the presence of hypertension. This review is expected to aid in developing a focused and individualized treatment plan for hypertension in pregnant women with CKD to improve pregnancy outcomes and preserve postpartum renal function.

Key Words: Chronic kidney disease; Pregnancy; Hypertension; Preeclampsia; Hypertensive disorders of pregnancy

Core Tip: Hypertension is a strong determinant of pregnancy outcomes in patients with chronic kidney disease. Hence, the success of pregnancy depends largely on the prevention of hypertension and the effective management of patients who develop hypertension and its associated complications. Preeclampsia can lead to a decline in renal function and can worsen preexisting kidney damage. A tailored approach to blood pressure management in these patients can help salvage both the pregnancy and the kidneys.

INTRODUCTION

Hypertension is known to cause deterioration of renal function. It is imperative to arrive at a diagnosis and identify the phenotype of hypertension to prevent the development and progression of kidney disease and avoid the complications of chronic kidney disease (CKD)[1]. Preexisting hypertension, advanced stages of CKD, and proteinuria increase the risk of renal function deterioration in patients with CKD during pregnancy[2]. Women diagnosed with hypertensive disorders of pregnancy are at an increased risk of developing CKD later in life[3,4]. These women generally develop CKD associated with diabetes mellites and hypertension. The risk is exacerbated in women who develop preeclampsia before 37 weeks of gestation, preeclampsia in recurrent pregnancies, or those who are obese before conception and then develop preeclampsia[4]. Hypertension during pregnancy, specifically preeclampsia, amplifies the risk of end-stage renal disease[5,6].

Individually, both CKD and hypertension are risk factors for cardiovascular disease. Controlling blood pressure in patients with CKD not only retards the progression of renal disease but also reduces overall cardiovascular morbidity and mortality[7]. Preeclampsia results in a 3–4-fold increased risk of chronic hypertension as well as a 2-fold increased risk of ischemic heart disease, stroke, and venous thromboembolism[8]. The co-occurrence of hypertension and CKD increases the cardiovascular risk by several folds. This risk is augmented by associated comorbidities, such as diabetes, dyslipidemia, and obesity[9].

Renal outcomes after pregnancy depend on the stage of CKD. While patients with stage 1–2 CKD are expected to have good outcomes during pregnancy, those with advanced stages of the disease are more likely to experience preeclampsia, preterm labor, and growth-restricted babies. In addition, there is an increased risk of renal function deterioration during pregnancy and the postpartum period in patients with stage 3–5 disease[8,10]. In stages 3A, 3B, and 4–5, pregnancy has been shown to exert an effect equivalent to 1.7 years, 2.1 years, and 4.9 years of renal disease in the nonpregnant state, respectively. Moreover, in these patients, the need for dialysis or transplant is advanced by 2–3 years[11]. However, chronic and uncontrolled hypertension, preconception proteinuria, attenuated reductions in serum creatinine of < 10% during pregnancy, and recurrent urinary tract infections are more important risk factors than the disease stage[8,11]. Furthermore, post-transplant patients with CKD exhibit decreased renal physiological adaptation during pregnancy[10]. Dialysis-requiring patients need an increased frequency of the procedure for pregnancy maintenance[10,12].

EPIDEMIOLOGY

Approximately 3%–6% of women in the reproductive age group are affected by CKD, and nearly 3% of pregnant women have CKD[13,14]. Compared with pregnant women without CKD, those with CKD are almost five times more likely to develop gestational hypertension and slightly under nine times more likely to develop preeclampsia[14]. All types of CKD are associated with an increased risk for preeclampsia, with the highest odds ratio being noted for congenital kidney disease[15].

PATHOPHYSIOLOGY

Pregnancy is linked to several physiological renal changes. The serum creatinine level decreases, glomerular filtration rate increases by 50%–80%, and renal blood flow increases. Anatomical alterations include dilation of the urinary tract and an increase in kidney size by approximately 1 cm. The renal tubular function is altered, leading to increased excretion of glucose, bicarbonate, and calcium and decreased serum osmolality[8]. Physiologically, blood pressure starts reducing toward the end of the first trimester and can decrease by 5–10 mmHg below the prepregnancy blood pressure. In the third trimester, the blood pressure increases progressively and reaches the prepregnancy values. In patients with chronic hypertension, a similar pattern may be observed, provided the deterioration in renal function is mild. Hence, these patients may become normotensive in the second trimester, and the antihypertensive drug dosage must be tapered[16].

Renal changes during normal pregnancy may be attenuated or even absent in patients with CKD, depending on the extent of deterioration of renal function[8,17]. Renal hormone synthesis does not increase in patients with CKD, thereby leading to anemia, decreased plasma volume expansion, and vitamin D deficiency[17]. The increased glomerular filtration rate during pregnancy may accelerate the decline in renal function[13]. Arterial hypertension is a common complication in pregnant women with CKD[18]. Hypertension complicating these pregnancies causes dilatation of the afferent arteriole, leading to the transmission of high pressures to the glomeruli, which accelerates renal damage[17]. Hypertensive disorders of pregnancy are believed to occur as a result of placental hypoperfusion. The poor blood supply to the placenta results in the release of antiangiogenic factors into the mother’s blood, leading to systemic endothelial damage, which culminates in hypertension and proteinuria[5]. Glomerular endothelial swelling is a characteristic renal finding in parturients with hypertension. Hypertension during pregnancy has been shown to result in incomplete healing or scarring of the kidney, even in the postpartum period[19]. Reduced renal blood flow in pregnant women with CKD, either due to hemorrhage or the use of nephrotoxic drugs, can lead to rapid impairment of renal function[17].

The above pathophysiological changes have been summarized in Figure 1.

Figure 1 Figure comparing physiological renal adaptations in pregnancy with corresponding changes in pregnant chronic kidney disease patients. CKD: Chronic kidney disease.

PRECONCEPTIONAL CONCERNS

Fertility is diminished in patients with CKD, and only 1.5% of those on long-term dialysis are able to conceive. Approximately one-fourth of patients with CKD who conceive develop hypertension, half of whom develop proteinuria, and many of them experience a decline in renal function during pregnancy[2]. The most common modality of renal replacement therapy in women of reproductive age is hemodialysis. Peritoneal dialysis disturbs the peritoneal milieu and is believed to interfere with ovum pickup, thereby reducing the fertility rates. However, peritoneal dialysis provides the advantages of a stable uterine microenvironment, reduces changes in fluid volume, prevents increases in urea levels, prevents dyselectrolytemia, ensures better hemodynamic stability, avoids falls in hemoglobin levels, and does not necessitate anticoagulation. Uremia is the leading cause of adverse fetal outcomes, and peritoneal dialysis may help reduce these complications. However, kidney transplantation undisputedly improves fertility outcomes, although it is still associated with adverse maternal and fetal events[12]. Patients with CKD who conceive using assisted reproductive techniques have a higher incidence of preeclampsia and fetal growth restriction[20]. Single embryo transfer is recommended to avoid multifetal gestation, which in turn is a risk factor for hypertension and other complications during pregnancy[21].

The blood pressure should be optimized in the preconception period[13,22]. Blood pressure < 140 mmHg/90 mmHg is recommended prior to pregnancy[21]. In the general CKD population, ambulatory blood pressure monitoring has been found to be most effective for diagnosis and follow-up. A systolic blood pressure of < 130 mmHg has been shown to reduce the risk of all-cause mortality[1]. A cutoff of 130 mmHg/80 mmHg is advisable for all patients with CKD[1,9]. Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin 2 receptor blockers (ARBs) are the antihypertensive drugs of choice in the general CKD population. These drugs not only control blood pressure but also decrease proteinuria and impede the progression of renal disease[9]. However, they must be discontinued during pregnancy due to teratogenic risks, such as calvarial hypoplasia and renal dysgenesis, to the fetus. Furthermore, these drugs can cause fetal growth restriction[22]. ACE inhibitors should be discontinued and changed to another drug after confirmation of pregnancy. ARBs should be stopped prior to conception[21].

Women should be advised to avoid high-sodium diets, restrict caffeine intake, and stop smoking[22]. Other comorbidities, such as diabetes and obesity, should also be optimized. Comprehensive preconception counseling should be given to the couple, with information regarding possible maternal and fetal complications. Advanced-stage patients with CKD should be provided with predialysis education[21]. Some pathologies, such as focal glomerulosclerosis, membranoproliferative glomerulonephritis, and reflux kidney disease, are linked to poor renal outcomes. Although normotensive patients with autosomal dominant polycystic kidney disease usually have uneventful pregnancies, those with hypertension are at a risk of complications[2]. Patients with lupus nephritis who have hypertension and positive anti-phospholipid antibodies exhibit poor obstetric outcomes[8].

Preconceptional workup for end-organ damage should be performed. This workup includes baseline serum creatinine, serum electrolytes, blood urea nitrogen, spot urine protein-creatinine ratio or 24-hour values of total urinary protein and creatinine, complete blood count, liver function tests, electrocardiography, and echocardiography[22].

There are a few situations in which pregnancy should be avoided in patients with CKD, which have been listed in Table 1[21,23].

Table 1 Chronic kidney disease patients who should avoid pregnancy.

Chronic kidney disease patients who should avoid pregnancy	Ref.
Atypical hemolytic uremic syndrome if eculizumab is not available	Wiles et al[21]
Patient with active systemic lupus erythematosus or vasculitis	Puri et al[23]

PREDICTION OF PREECLAMPSIA

Preeclampsia is a condition caused by placental hypoperfusion and an imbalance between angiogenic and antiangiogenic factors. A decrease in the maternal serum concentration of placental growth factor (PlGF) between 20 weeks and 42 weeks of gestation has been reported to accurately predict the occurrence of preeclampsia and the need to deliver during the next fortnight in pregnancies complicated by CKD, chronic hypertension, or both[24]. Soluble fms-like tyrosine kinase 1 (sflt-1) is an antiangiogenic factor. A high sflt-1/PlGF ratio is predictive of preeclampsia[25]. Uterine artery Doppler is a good predictor of preterm delivery and, indirectly, adverse neonatal outcomes in patients with hypertensive disorders of pregnancy. However, on its own, it does not predict the occurrence of preeclampsia[26].

The sflt-1/PlGF ratio and uterine artery Doppler findings predict adverse maternal outcomes in patients with CKD but cannot be used to predict perinatal outcomes or deterioration of kidney function. Furthermore, this ratio can aid in predicting severe complications such as eclampsia and placental abruption in patients with CKD[27].

A composite predictive model combining maternal history, mean arterial pressure, uterine artery Doppler, and biochemical markers was proposed. All values were measured between 11 weeks and 13 weeks of gestation. Pregnant women who later developed preeclampsia exhibited a higher mean arterial pressure and uterine artery pulsatility index and lower concentrations of pregnancy-associated plasma protein A and PlGF. The deviations in these values from those of normal pregnancies were significantly greater in the early preeclampsia group than in the late preeclampsia group. In women who developed gestational hypertension, the values did not deviate significantly from those of normal pregnant women. This first-trimester prediction model was able to detect > 90% of early preeclampsia cases, with a false positive rate of 5%[28].

PREVENTIVE STRATEGIES

Patients with CKD are at high risk for preeclampsia, and hence, several preventive strategies have been proposed. The most well-established method is prescribing low-dose aspirin before 16 weeks of gestation[21]. The recommended dose is between 75 mg and 150 mg. However, studies have shown that the effective dose must be > 80 mg[21,29]. Aspirin is believed to aid in the trophoblastic invasion of spiral arterioles and reduce the risk of preeclampsia by 50%[29]. However, aspirin allergy or allergy to nonsteroidal anti-inflammatory drugs are contraindications to low-dose aspirin prophylaxis[30]. Dipyridamole (100 mg) may be administered three times a day instead of aspirin in these patients[8]. Recently, aspirin desensitization has been found to be a safe and effective method to allow allergic women to tolerate aspirin prophylaxis[31].

The role of low-molecular-weight heparin (LMWH) in preeclampsia prevention is disputable. According to a study, heparin increases the excretion of sflt-1[32]. LMWH prophylaxis in women with previous adverse placenta-mediated obstetric outcomes has been documented to prevent recurrence in subsequent pregnancies[33]. This drug should be prescribed before 16 weeks of pregnancy[34]. Nonetheless, there is no evidence that it reduces the incidence of preeclampsia in women screening positive in the first trimester[35]. The combination of LMWH with aspirin has been shown to be more effective than aspirin alone[34]. This combination has been established to prevent preeclampsia, preterm labor, and fetal growth restriction in women at high risk for preeclampsia without thrombophilia[36]. The role of LMWH in thromboprophylaxis in pregnant women with nephrotic-range proteinuria is undisputed. This therapy is even recommended in parturients with non-nephrotic-range proteinuria in the presence of additional risk factors[21].

Oral elemental daily calcium supplementation of 1.5–2 g has been recommended by the World Health Organization for the prevention of preeclampsia in populations with low dietary calcium intake[37]. Statins and metformin are experimental pharmacological interventions used to reduce the risk of preeclampsia. Statins play an anti-inflammatory role and have been proven to reduce the cytokine-mediated release of sflt-1 in animal studies. Furthermore, these drugs improve endothelial function. Pravastatin is the only statin with a potential role in prophylaxis as it does not cross the placenta. Other statins may lead to renal, neurological, and limb anomalies in the fetus. Metformin reduces sflt-1 and soluble endoglin levels and is, therefore, a potential preventive drug[10].

Dialysis-requiring patients have a 50% chance of developing preeclampsia. The incidence of complications can be mitigated by increasing the frequency of dialysis to 5–7 times per week and increasing the duration to > 20 hours[8]. High-intensity hemodialysis of > 36 hours per week with frequent night dialysis is recommended for patients with no residual renal function[38].

DIAGNOSTIC DILEMMAS

As per guidelines, hypertension during pregnancy is defined as “systolic blood pressure ≥ 140 mmHg and diastolic blood pressure ≥ 90 mmHg on the basis of an average of at least two measurements”. If the blood pressure is ≥ 160 mmHg/110 mmHg, the repeat value must be taken within 15 minutes. In all other cases, the measurement should be repeated after 4 hours or on two separate visits to the outpatient clinic. Proteinuria is defined as “≥ 30 mg/mmoL urinary protein creatinine ratio in a spot (random) urine sample or albumin creatinine ratio (ACR) ≥ 8 mg/mmoL or ≥ 0.3 g/day in a complete 24-hour urine collection or ≥ 2+ using urinary dipstick if confirmatory testing is not available”[39].

Patients with CKD are already known to have renal function deterioration. Additionally, these patients might exhibit hypertension and proteinuria, which leads to confusion in the diagnosis of preeclampsia in such patients. To differentiate between a transient rise in blood pressure in women with chronic hypertension or preeclampsia, monitoring the patient on an inpatient basis with blood pressure measurements acquired every 4 hours may be necessary. A workup to rule out other organ dysfunction, as well as fetal heart monitoring and ultrasonography, needs to be performed[22]. Preeclampsia in patients without proteinuria is diagnosed in cases of new-onset hypertension, proteinuria, or maternal organ dysfunction after 20 weeks of pregnancy[21]. Maternal organ dysfunction can include neurological manifestations, hematological complications, pulmonary edema, liver involvement, or acute kidney injury[39]. In patients with CKD and proteinuria, de-novo hypertension, or maternal organ dysfunction beyond 20 weeks, it is used to diagnose superimposed preeclampsia. However, in patients who already exhibit chronic hypertension and proteinuria, maternal organ dysfunction first presenting after 20 weeks of gestation is the only criterion for diagnosis. Estimated glomerular filtration rate equations are not validated in pregnancy. Proteinuria is quantified using spot urine PCR or ACR[21].

The diagnosis of preeclampsia is even more challenging if medical records are not available before 20 weeks of pregnancy, if there is a flare-up of the primary pathology of CKD, or if there is progression of renal disease during pregnancy. A helpful concept for arriving at a diagnosis is that CKD, at least in its early stages, has normal placental development[18]. Abnormal placentation is the primary pathology in preeclampsia, which leads to an imbalance in angiogenic factors, followed by generalized endothelial dysfunction. On the contrary, in CKD, endothelial dysfunction is more localized to the kidney[40]. The sflt-1/PlGF ratio is increased in patients with preeclampsia compared with those having CKD or the normal population[41]. A ratio ≥ 85 has been shown to be strongly associated with the incidence of superimposed preeclampsia as compared with a milder angiogenic imbalance[42]. When the uterine and umbilical artery waveforms were studied, a significant association between abnormal Doppler power and preeclampsia was noted, whereas both were normal in patients with CKD[40].

A renal lupus flare manifests as proteinuria, hypertension, and a decline in renal function. The same constellation of findings can be expected in preeclampsia. A decrease in complement levels is characteristic of a lupus flare, although the levels may be elevated during pregnancy[2]. Lupus flares occur in only 12% of pregnant women with lupus nephritis. Nevertheless, the risk of preeclampsia is up to five times higher in patients with lupus than in the normal population[18].

Renal biopsy is not recommended for diagnosing preeclampsia[18]. This procedure may be performed in patients with sudden unexplained renal function deterioration or those with symptomatic nephritic syndrome. Renal biopsy should preferably be done in the first and early second trimesters and not after 32 weeks of gestation[2,21]. Renal biopsy during pregnancy is associated with a high risk of bleeding complications. The rate of complications in the form of macroscopic hematuria, perirenal hematomas, and the need for blood transfusions are significantly higher after 23 weeks of gestation. In addition, performing a biopsy in the prone position poses more technical difficulties as the pregnancy advances. Hence, the risks and benefits of performing a renal biopsy during pregnancy should be carefully considered, and the procedure must be executed under ultrasonographic guidance[21].

MANAGEMENT IN PREGNANCY

Blood pressure control

A multidisciplinary approach that comprises a consultant obstetrician, a nephrologist, and an expert midwifery team is advocated to manage these pregnancies[8,21]. Blood pressure should be determined regularly during each antenatal checkup, and a target blood pressure of 135 mmHg/85 mmHg is advised. In women known to be hypertensive prior to pregnancy, antihypertensive drugs should be continued during pregnancy unless their blood pressure is persistently < 110 mmHg/70 mmHg or if they develop symptoms of hypotension. Labetalol, nifedipine, and methyldopa are the antihypertensive drugs prescribed during pregnancy[21]. Dihydropyridine calcium channel blockers are the first-line antihypertensive drugs recommended for patients who have undergone renal transplantation[43]. Diuretics are not administered during pregnancy and are not even recommended for fluid volume management in pregnant women requiring dialysis. Ultrafiltration is the best modality for fluid removal, and patients require dialysis almost every day during pregnancy[12]. Care should be taken to avoid overtreatment of blood pressure as it can cause uteroplacental insufficiency. Fetal growth should be carefully monitored for early detection of growth restriction[13].

Administration of magnesium sulfate

Magnesium sulfate should be administered to prevent and treat eclampsia. Furthermore, the drug can be given for fetal neuroprotection if delivery is anticipated in the next 24 hours, up to 33 weeks 6 days of gestation[44]. For patients with decreased renal function, intravenous magnesium sulfate can be prescribed. The loading dose of 4 g iv can be given to all patients. However, the maintenance dose, which is usually given for 24 hours, should be reduced from 1 g iv/hour to 0.5 g iv/hour infusion and can even be stopped based on serum magnesium levels. The level should be maintained at < 3.7 mmoL/L (9 mg/dL)[45]. In patients with CKD, magnesium levels should be checked every 6 hours to prevent toxicity[10].

Management of anemia

A hemoglobin level of 10–11 g/dL should be maintained throughout pregnancy. Parenteral iron and erythropoietin stimulating agents may be required to achieve this target[21]. During pregnancy, the need for erythropoietin-stimulating agents may increase to twice the baseline dose requirement[12]. The response to erythropoietin is reduced in the advanced stage of CKD[46]. The role of erythropoietin in causing hypertension is disputed in pregnancy[47]. However, a rapid surge in the hemoglobin level via the use of recombinant human erythropoietin has been reported to increase the blood pressure during pregnancy[48].

Nutritional considerations

In the early stages of CKD, the protein requirement is comparable to that of a normal pregnancy, i.e., 1.1 g/kg/day[49]. For pregnant women with CKD on dialysis, the recommended protein intake is 1.8 g/prepregnancy weight/day + 20 g/day and the calorie requirement is 23–35 kcal/pregnant weight/day. Water-soluble vitamins can get depleted because of frequent dialysis. Hence, the requirement for these vitamins doubles in patients undergoing dialysis as compared with normal pregnancies[12].

Immunosuppressive drugs

Cyclosporine, tacrolimus, steroids, and hydroxychloroquine can be safely used as immunosuppressants during pregnancy. However, their levels are highly variable because of changing pregnancy physiology. Hence, they should be serially measured to avoid disease flare-ups. Drugs that interfere with their levels, such as macrolide antibiotics, must be avoided[21].

Renal replacement therapy during pregnancy

The recommendations for dialysis in pregnant women with CKD have been summarized in Table 2[50-55].

Table 2 Renal replacement therapy for pregnant chronic kidney disease patients.

Renal replacement therapy
Initiation of dialysis	Blood urea of more than 17 mmoL/L even in the absence of any frank uremic symptoms or absolute indication of dialysis, to prevent foetal death due to azotemia
Haemodialysis vs peritoneal dialysis	Lesser data on successful pregnancy outcomes in peritoneal dialysis patients
	Increased abortion rate during insertion of Tenckhoff peritoneal dialysis catheter
	Challenges to keep the usual dwell volume during peritoneal dialysis. Due to lesser space in the third trimester because of gravid uterus dwell volume needs reductions with concomitant increase in the number of exchanges to achieve the desired clearance
	Peritoneal dialysis: More frequent exchanges to maintain desired BUN
	Tidal peritoneal dialysis helps in reducing drain pain and catheter drain dysfunction due to the gravid uterus
Dialysis adequacy	Target predialysis BUN < 12.5 mmoL/L in hemodialysis. No recommendation established for peritoneal dialysis
	Dialysis duration
	Patients with residual renal function > 20 hours/week
	Patients without residual renal function > 36 hours/week
	Kt/V assessment should not be used in pregnancy
Weekly dry weight assessment to account for weight gain during pregnancy	2nd trimester: 300 g/week weight gain
	3rd trimester: 300-500 g/week weight gain
Segmental bioimpedance for accurate assessment of volume status	It might prevent intradialytic hypotension and subclinical reduction in effective arterial blood volume, which might avert worsening of uteroplacental perfusion and improve foetal outcome
Haemodialysis prescription	Bicarbonate around 25 mmoL/L
	Potassium 3 mmoL/L or more
	Heparin is generally safe in pregnancy

BUN: Blood urea nitrogen.

Delivery considerations

Vaginal delivery is not contraindicated in these patients[8]. Delivery should be planned on the basis of obstetric indications, with refractory hypertension, pulmonary edema, and worsening renal parameters being a few possible renal indications. The intrapartum temperature, heart rate, blood pressure, respiratory rate, oxygen saturation, and early warning score must be assessed. A high early warning score warrants measurement of jugular venous pressure, thorough auscultation of the lungs, and urine output monitoring. Fluid management is imperative to avoid dehydration on the one hand and pulmonary edema on the other. Preeclampsia increases the likelihood of developing pulmonary edema[21].

Patients with chronic hypertension demonstrate an exaggerated response to sympathetic blockade. Neuraxial anesthesia should be given in almost all cases, provided the platelet count is satisfactory. If possible, blood pressure should be controlled prior to intubation[22]. Nonsteroidal anti-inflammatory drugs should not be prescribed for pain relief[21].

All antihypertensive and immunosuppressant drugs administered during pregnancy can be continued after delivery. ACE inhibitors are secreted at very low levels in breast milk and can be started in the postpartum period[22]. The levels of immunosuppressants should be monitored even in the postpartum period to avoid a flare-up[21].

Key points to remember while managing pregnancy in patients with CKD, particularly hypertensive disorders of pregnancy, have been presented in Table 3[8,10,12,21,22,29,30,33,37,38,44,45].

Table 3 Summary of recommendations for prevention and management of hypertension in pregnant chronic kidney disease patients.

Multidisciplinary treating team involving consultant obstetrician, nephrologist and an expert midwifery team
Prevention strategies	Low dose aspirin to be started before 16 weeks pregnancy with dose > 80 mg/ day
	First trimester screening for pre-eclampsia for all chronic kidney disease patients
	Low-molecular-weight heparin prophylaxis in patients with previous adverse placenta-mediated obstetric outcomes
	Oral elemental calcium 1.5-2 g/day
	Dialysis requiring patients: Frequency of dialysis 5-7 times/week, duration > 20 hours/week, anuric dialysis patients should get high intensity dialysis > 36 hours/week
Management of hypertensive disorders	Regular blood pressure charting at every antenatal visit. Maintain blood pressure target < 135 mmHg/85 mmHg
	Magnesium sulphate can be given for prevention of eclampsia. Magnesium levels should be checked every 6 hours, and maintained less than 3.7 mmoL/L
	Maintain haemoglobin levels of 10-11 g/dL
	Recommended protein intake in dialysis patients is 1.8 g/prepregnancy weight/day + 20 g/day. Calorie requirement is 23–35 kcal/pregnant weight/day
	Immunosuppression levels to be regularly monitored and to ensure adequate immunosuppression
	Careful fluid management throughout pregnancy
	Neuraxial anaesthesia is preferred
	To avoid NSAIDs and nephrotoxic drugs

MATERNAL AND FETAL OUTCOMES

The incidence of preeclampsia was found to vary based on the stage of renal disease. While approximately 20% of the patients with creatinine < 125 μmoL/L developed preeclampsia, almost 75% of the women on dialysis developed the condition. Long-term renal outcomes were also worse in patients with higher baseline creatinine[8]. According to a study, 46% of the women with CKD stage 3–5 lost > 25% of their prepregnancy renal function or required renal replacement therapy 1 year after delivery[11].

Higher serum creatinine and worse proteinuria have been reported to correspond to shorter gestational age at delivery and lower birth weight[56]. Chronic hypertension has been observed to be the strongest predictor of preterm delivery before 34 weeks[11]. Among patients with creatinine < 125 μmoL/L, less than one-third delivered preterm and 25% of these women delivered growth-restricted babies. In contrast, > 90% of the women with creatinine values > 180 μmoL/L or requiring dialysis delivered preterm babies. Fetal growth restriction was noted in > 90% of dialysis-requiring mothers[8]. The incidence of “small for gestational age” babies was higher in women who were on peritoneal dialysis rather than hemodialysis. Polyhydramnios was noted in 30%–70% of the pregnancies[12].

Patients with CKD who conceived via assisted reproduction techniques had a higher incidence of preeclampsia, multiple gestations, preterm labor, and low birth weight babies. However, the live birth rates were comparable to those of spontaneous conception[57]. The type of underlying renal pathology has also been shown to determine the outcomes. Patients with congenital kidney disease displayed the highest incidence of preeclampsia, with a greater rate of preterm delivery, both spontaneous and induced. Diabetic nephropathy was observed to be associated with increased caesarean section rates and “small for gestational age” babies[15]. Those with diabetic kidney disease had a 35 times higher risk of mortality than other patients with CKD[14]. Patients with immunoglobulin A nephropathy did not show progression of renal disease after pregnancy, although they exhibited a higher rate of preeclampsia, preterm delivery, and low birth weight babies than the normal population[58].

The effects of CKD on pregnancy, as well as the effects of pregnancy on CKD, have been summarized in Table 4[8,11,12,14,15,56-58].

Table 4 How pregnancy and chronic kidney disease influence each other’s outcomes.

Effect of CKD on pregnancy	Effect of pregnancy on CKD
Increased risk of pre-eclampsia	Loss of renal function
Prematurity	Higher risk of renal replacement therapy requirement in 1 year
Low birth weight
Foetal growth restriction
Polyhydramnios
Still-birth
Increased cesarean section rates (in diabetic nephropathy)
Maternal mortality (higher risk in diabetic nephropathy)

CKD: Chronic kidney disease.

FUTURE RESEARCH POTENTIAL

Few studies have been performed on blood pressure cutoffs in pregnant women with CKD. Continuing antihypertensive medication during pregnancy in patients with chronic hypertension is debatable. On the one hand, there is a risk of over-correction of blood pressure, leading to poor placental perfusion. On the other hand, discontinuing the drugs increases the risk of complications for the mother and necessitates intensive and cumbersome monitoring.

The sflt-1/PlGF ratio has been shown to be correlated with the risk of superimposed preeclampsia and has emerged as a potentially beneficial tool in devising management strategies in patients where the underlying disease can pose difficulties in the diagnosis of preeclampsia. Incorporating these markers in establishing an algorithm for managing pregnancy and delivery via interventional studies will help optimize maternal and fetal outcomes.

Studies regarding the effect of intensive hemodialysis on maternal endothelial function are likely to improve our understanding of preeclampsia in patients with CKD and may also help tailor the approach to dialysis frequency and duration. The role of pravastatin and metformin in preventing preeclampsia should be examined in randomized controlled trials.

CONCLUSION

Pregnancy has become a very real possibility in patients with CKD owing to advances in assisted reproductive techniques and dialysis technology. Hypertension is a key factor in determining the pregnancy outcomes of patients with CKD; hence, clarity in the diagnosis and management of hypertensive disorders of pregnancy will aid in reducing the complications.

ACKNOWLEDGMENTS

We thank our families for their support.