15th July 2024

Renal Conditions and Pregnancy

Renal physiology and dysfunction in pregnancy

Renal physiology

During pregnancy, there is a physiological increase in glomerular filtration rate (GFR), secondary to an increase of approximately 60% in renal blood flow due to increased cardiac output and blood volume. As a result, in pregnant women with normal renal function, creatinine decreases in the first trimester. This can occur as early as the 5th week of pregnancy. During the last few weeks of pregnancy, GFR falls, and therefore creatinine increases, so that renal function returns to baseline shortly postpartum, although GFR can be reduced for up to the first 3 months postpartum. A creatinine above 75µmol/l (0.87mg/dl) should be considered abnormal in pregnancy, indicating renal impairment either secondary to pre-existing renal disease or acute kidney injury. In pregnancy, estimated GFR (eGFR) is not a reliable marker of kidney function.

The increase in GFR in pregnancy can lead to glycosuria in 50% of pregnant women, even with a normal blood sugar, as the kidney tubules are unable to reabsorb all glucose from the filtrate back into the blood. Similarly, mild proteinuria (up to 300 mg over 24 hours) can also occur in pregnancy due to the same mechanism. However, a urine protein creatinine ratio (uPCR) above 30 mg/mmol or a urine albumin creatinine ratio (uACR) above 8 mg/mmol warrants urgent referral to obstetrics.

Other changes during pregnancy occur in the anatomy of the urinary tract itself. The smooth muscle of the renal pelvis relaxes, leading to dilation and a physiological hydronephrosis that requires no intervention or treatment.

Chronic kidney disease

Currently, chronic kidney disease (CKD) affects 3% of pregnancies, and it is likely its incidence will increase. All stages of CKD lead to an increased risk of adverse outcomes, including miscarriage, intrauterine growth restriction and preterm labour. CKD is also a risk factor for pre-eclampsia, the risk and severity of which increases with worsening CKD. For women with progressive CKD, pregnancy accelerates the deterioration of their renal function. Therefore, antenatal counselling and close monitoring during pregnancy is critical. Prior to conception, poorer baseline renal function is associated with lower fertility rates due to lower oestrogen/progesterone, decreased FSH and LH, earlier menopause and often reduced sexual interest.

Women with pre-existing nephrotic range proteinuria (uPCR>300 mg/mmol or uACR>250 mg/mmol) should take low molecular weight heparin when pregnant. This is usually continued until 6 weeks postpartum.

Target blood pressure for women with CKD in pregnancy is below 135/85 mmHg.

Diagnosis and Management

In pregnancy, the following medications can safely continue:

• Tacrolimus
• Hydroxychloroquine
• Azathioprine
• Metformin
• Antihypertensives: Labetalol, Nifedipine, Methyldopa
• Erythropoietin analogues, e.g. Neorecormon and Aranesp (requirement increases in pregnancy)
• Activated vitamin D e.g. Alfacalcidol
• Steroids

Women taking calcineurin inhibitors or steroids during pregnancy should be screened for gestational diabetes.

Prior to pregnancy, administration of the following medications should be discontinued:

• Cyclophosphamide – stop 3 months prior to conception
• Methotrexate – stop six months prior to pregnancy
• Mycophenolate mofetil – stop 3 months prior to conception
• Rituximab – advise to avoid conception for 1 year after treatment (guidance may change)
• ACE inhibitors – can continue until conception
• Angiotensin receptor blockers – should discontinue prior to pregnancy
• Avoid sirolimus/everolimus
• Non-calcium-based phosphate binders
• Cinacalcet
• Diuretics should not be used to treat hypertension in pregnancy but can be used for symptomatic fluid overload

Contraception after cessation of medication before the safe time for conception; this time is known as the “washout period”. For women with CKD, oestrogen-containing contraceptives are usually contraindicated as they lead to increased risks of hypertension, as well as thromboembolism (especially for women with antiphospholipid syndrome or the nephrotic syndrome) and cervical malignancy (especially for women on immunosuppression). Progesterone based systems e.g. the Mirena coil and progesterone-only pill are acceptable. The copper intrauterine device can also be used.

If breastfeeding, the following medications can still be administered:

• Steroids
• Azathioprine
• Hydroxychloroquine
• Tacrolimus
• Everolimus

Renal conditions, such as glomerulonephritides, can present de novo in pregnancy. These can present very similarly to pre-eclampsia, with new proteinuria and renal impairment. However, pre-eclampsia does not lead to haematuria or the presence of red cell casts in the urine. Renal biopsy can be performed antenatally, although between 23-28/40 weeks, there is the highest risk of complications. After 28 weeks, most common presentations are haematomas and loin pain post procedure. A new presentation of nephrotic syndrome or acute glomerulonephritis may warrant a renal biopsy, although this must be balanced against the risks of biopsy and whether it will change treatment.

Increasingly, it is recognised that despite impaired fertility, women with end stage renal disease (ESRD) can become pregnant, although the rate of perinatal death is 50% for women established on dialysis, and 25% for those who start dialysis while pregnant. Women aiming to conceive should change from peritoneal dialysis (PD) to haemodialysis (HD) during pregnancy, as this reduces the risk of prematurity.

For women with progressive renal dysfunction, dialysis, i.e. haemodialysis, should be initiated with a urea level of 17 mmol/L or above, as urea is foeto-toxic. A target urea below 12 mmol/L should be aimed for. This usually requires more intensive dialysis. For anuric women on dialysis (i.e. those with no residual renal function), the target should be 36 hours of dialysis a week (usual dialysis regimens are 9-12 hours). This intense dialysis can lead to hypophosphataemia in the mother, which increases the risk of cervical shortening, and therefore, this must be replaced on dialysis.

Women with renal transplants should wait 1-year post transplant before conceiving. Women with SLE should be at least 6 months into remission on stable treatment before conceiving.

References

• Harel Z, McArthur E, Hladunewich M, Dirk JS, Wald R, Garg AX, Ray JG. Serum Creatinine Levels Before, During, and After Pregnancy. JAMA. 2019 Jan 15;321(2):205-207. doi: 10.1001/jama.2018.17948. PMID: 30644975; PMCID: PMC6439761
• Wiles K, Chappell L, Clark K, Elman L, Hall M, Lightstone L, Mohamed G, Mukherjee D, Nelson-Piercy C, Webster P, Whybrow R, Bramham K. Clinical practice guideline on pregnancy and renal disease. BMC Nephrol. 2019 Oct 31;20(1):401. doi: 10.1186/s12882-019-1560-2. PMID: 31672135; PMCID: PMC6822421
• National Institute for Health Care Excellence. Urinary tract infection (lower): antimicrobial prescribing London: NICE; 2018.(NICE Guideline No. 109). Available from: https://www.nice.org.uk/guidance/ng109/chapter/recommendations
• Say L, Chou D, Gemmill A, Tunçalp Ö, Moller AB, Daniels J, Gülmezoglu AM, Temmerman M, Alkema L. Global causes of maternal death: a WHO systematic analysis. Lancet Glob Health. 2014 Jun;2(6):e323-33. doi: 10.1016/S2214-109X(14)70227-X. Epub 2014 May 5. PMID: 25103301

Pre-eclampsia

Pre-eclampsia is a major contributor to global maternal morbidity and mortality. It occurs in around 5% of pregnancies.

Characterisation and diagnosis

Pre-eclampsia is a hypertensive disorder of pregnancy. It is defined as a new diagnosis of hypertension (systolic >= 140mmHg/diastolic >= 90mmHg) after 20 weeks of pregnancy, with organ dysfunction, manifested as one of:

• Proteinuria – detected via dipstick and confirmed by albumin: creatinine ratio above 8 mg/mmol or protein: creatinine creatinine ratio above 30 mg/mmol
• Maternal organ dysfunction
• Renal insufficiency – new rise in creatinine
• Hepatic impairment – increased liver transaminases
• Neurological complications – signs elicited on examination and the progression to eclampsia with seizures
• Uteroplacental dysfunction – foetal hypoxia, growth restriction, premature labour, placental abruption or in-utero demise caused by oxidative stress

For women with known CKD, diagnosing pre-eclampsia is more complicated.

• In cases where there is pre-existing non-proteinuric CKD, superimposed pre-eclampsia should be should be suspected after 20 weeks if new hypertension develops (systolic >= 140mmHg/diastolic >= 90mmHg) with new proteinuria or other evidence of maternal organ dysfunction.
• For women with CKD who have either pre-existing hypertension and/or proteinuria, there is no increase in either of these that are diagnostic for pre-eclampsia.
• However, women with chronic hypertension and proteinuria that develop severe, sustained hypertension (systolic >= 160mmHg/diastolic >= 1100mmHg) should be investigated for superimposed pre-eclampsia.
• Women with pre-eclampsia and CKD are at increased risk of pulmonary oedema peripartum.

Most cases of pre-eclampsia are based on the above clinical diagnostics. Increasingly, biomarkers also play a role in diagnosis. The National Institute for Health Care and Excellence (NICE) recommends offering tests for placental growth factor (PIGF) in suspected PET between 20 to 35 weeks’ gestation.

Clinical presentation

Patients with PET may complain of visual blurring, headaches, right upper quadrant pain and pedal oedema.

Risk factors

Although the aetiology of PET remains unclear, NICE guidelines outline the risks associated with development of PET. These can be divided into:

• History of previous hypertensive disorder during pregnancy
• Pre-existing hypertension – PET can be superimposed onto existing disease
• Concurrent maternal disease
• Chronic kidney disease
• Diabetes
• Maternal factors
• Nulliparity
• Increased maternal age (>40)
• High body mass index (BMI)
• Positive family history

Management

Women at high risk for pre-eclampsia, including women with chronic kidney disease, should start prophylactic aspirin (75-150mg) from 12 weeks’ gestation, reducing the risk of developing pre-eclampsia by 10%. Early detection of adverse foetal outcomes is monitored through increased frequency of antenatal scanning and obstetric clinics. Pre-eclamptic mothers should also monitor their blood pressures at home with pharmacological treatment started for blood pressure consistently 140/90mmHg or above. Renal and liver function tests should be measured two to three times per week, depending on the severity of hypertension.

Severe hypertension (>/=160/110 mmHg) should be treated in hospital under close obstetric monitoring and agents include oral nifedipine, methyldopa or oral/intravenous labetalol. Ultimately, timely delivery of the baby is the only curative management, balancing gestation for optimal in-utero development with maternal outcomes. Birth before 37 weeks is not indicated if blood pressure remains lower than 160/110 mmHg.

Follow-up

Blood pressure monitoring should continue after birth, daily for the first two days and once between day three and five. Anti-hypertensives should be continued postnatally for a similar time period. The adverse effects of pre-eclampsia have been shown to carry on into adult life, with a baby of a preeclamptic pregnancy having a higher relative risk of hypertension in later life. Key vascular changes lead to adverse cardiac remodelling and long-term cardiovascular morbidity. Future pregnancies should be closely monitored and other risk factors and concurrent diseases, such as diabetes, should be screened. Patients should have a follow up urine protein creatinine ratio to check for resolution of proteinuria. If it persists, patients should be referred to nephrology.

References

• Duhig KE, Myers J, Seed PT, Sparkes J, Lowe J, Hunter RM, Shennan AH, Chappell LC; PARROT trial group. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. 2019 May 4;393(10183):1807-1818. doi: 10.1016/S0140-6736(18)33212-4. Epub 2019 Apr 1. PMID: 30948284; PMCID: PMC6497988
• Hypertension in pregnancy: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2019 Jun 25. PMID: 31498578
• Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369(9575):1791-8
• Davis EF, Lazdam M, Lewandowski AJ, Worton SA, Kelly B, Kenworthy Y, Adwani S, Wilkinson AR, McCormick K, Sargent I, Redman C, Leeson P. Cardiovascular risk factors in children and young adults born to preeclamptic pregnancies: a systematic review. Pediatrics. 2012 Jun;129(6):e1552-61. doi: 10.1542/peds.2011-3093. Epub 2012 May 21. PMID: 22614768

Urinary Tract Infections in Pregnancy

Urinary tract infections (UTIs) in pregnancy are potentially severe as they are associated with developmental delay, cerebral palsy and infant death. Please note that unlike in non-pregnant individuals, the presence of bacteria in the urine without symptoms – i.e. asymptomatic bacteriuria (ASB) – is not a benign condition in pregnancy, as it is a risk factor for pyelonephritis and premature labour. ASB should be treated with antibiotics.

NICE guidelines for antibiotics for UTIs in pregnancy are as follows:

• First line: nitrofurantoin – avoid at term due to risk of neonatal haemolysis or if significant renal impairment (pre-pregnancy eGFR <45 ml/min)
• Second line: amoxicillin 500mg three times a day for 7 days or cefalexin 500mg twice daily for 7 days

For ASB, nitrofurantoin, amoxicillin and cefalexin can all be used, based on culture/sensitivity results.

Trimethoprim, although commonly used to treat UTIs, is a folate antagonist and, therefore, should be avoided in the first trimester. Manufacturer advice is to avoid trimethoprim altogether in pregnancy. Other antibiotics to treat UTIs contraindicated in pregnancy include quinolones, such as ciprofloxacin and levofloxacin. Gentamicin should be avoided, due to a small risk of foetal ototoxicity.