Pregnancy and Renal Disease

Pregnancy in Renal Disease

Ideally, all women with significant chronic kidney disease who wish to become pregnant should receive pre-conception counselling. Counselling ensures the patient is aware of the maternal and fetal risks and allows the physician time to optimise the patient’s medications and minimise their risk factors.  As with any pregnancy, folic acid should ideally be commenced pre-conceptually to reduce the risk of neural tube defects. Women with chronic kidney disease who become pregnant should ideally be looked after by a team who have expertise in renal disease in pregnancy.  Regular reviews are recommended for close monitoring of maternal renal function, signs of pre-eclampsia and fetal well-being. Thanks to advances in renal replacement therapy, obstetrics and neonatal care, the number of live infants born to mothers with chronic kidney disease is continually improving (1).

 

Fertility in Renal Disease

Conception rates decrease with worsening renal function. Nevertheless, even women in end-stage renal failure can become pregnant, with reports of annual pregnancy rates of 0.5% in women of childbearing age on dialysis (2). The effect of CKD on menstruation and fertility is hypothesised to be proportional to the degree of renal impairment, however the effect of very mild renal dysfunction remains unclear. 

The principal cause of reduced fertility in CKD is thought to be hormonal, with impaired function of the hypothalamic-pituitary-ovarian axis. Women on dialysis have high levels of luteinising hormone, likely secondary to an acquired hypothalamic defect in gonadotrophin releasing hormone pulsatility. This prevents the luteinising hormone surge required for ovulation from occurring, which leads to anovulatory menstrual cycles (3,4). 

Fertility is also affected by psychosocial issues such as lower libido; with body image, concurrent disease and fatigue secondary to anaemia, and suboptimal nutrition all suspected to contribute (5).  The time commitment to dialysis and relationship issues that can be associated with this may also play a role in reduced conception rates (6). 

Renal transplantation restores fertility and reduces both maternal and fetal risk.  Pregnancy is not recommended within 12 months of transplantation in order to minimise the risk of acute rejection, and to ensure stable graft function with established doses of maintenance immunosuppression (6-8).

 

Risks of Pregnancy

Our understanding of CKD progression in pregnancy is somewhat limited due to relatively few studies with small sample sizes, especially in more advanced renal impairment. Even mild renal failure increases the risk of poor outcomes for both mother and baby, with a quarter of these women experiencing problems during pregnancy (1).  The risks increase significantly with declining renal function, increasing proteinuria, and worsening hypertension (9,10).

However, broadly speaking, women with mild renal impairment should be reassured that the risk of pregnancy causing long-term renal problems is low, with less than 3% suffering a permanent deterioration in function (1).  However, this risk may rise to around 50% in women with more advanced renal failure at the time of conception (11).  

Maternal complications include hypertension, pre-eclampsia and decline in renal function, whilst fetal complications include growth restriction, medication-related congenital anomalies and preterm delivery. An increment in all complications is observed with worsening renal function (22).

 

RRT and Pregnancy

Pregnancy is uncommon in women on dialysis and there appears to be no difference in conception rates between those on peritoneal dialysis and those on haemodialysis (11). In haemodialysis, it has been observed that successful obstetric outcomes are more likely with more frequent or intense treatments (11,12).  It must be remembered that the woman’s dry weight must be continually reassessed as they normally gain 0.45kg/week after the second trimester (5). 

In women with renal transplants, graft function seems relatively unaffected if the initial renal function has been good.  These pregnancies are still not without their problems, however; according to the UK Transplant Pregnancy Register, 50% of babies were born prematurely and over half were of low birth weight (13, 14).  The graft itself is not injured by vaginal delivery and rarely causes a problem during Caesarean Section (8).

For women with CKD which progresses during pregnancy, the indications for initiating haemodialysis mirror those outside of pregnancy and include fluid overload, hyperkalaemia and metabolic acidosis resistant to medical management. However, the most common trigger for dialysis initiation in pregnancy is the fetotoxicity of urea. Emerging evidence suggests dialysis should be considered when maternal urea reaches 15mmol/L, although there is no firm consensus on this (15).

 

Fetal Growth

Studies have shown that the majority of babies whose mothers have renal impairment are born prematurely, at less than 37 weeks gestation (5, 16, 17). Indeed, the average gestational age at delivery has been reported at 32.4 weeks in women with chronic renal disease and 35.6 weeks in renal transplant recipients (11,13).  There are many reasons for this, with intervention for pre-eclampsia and intrauterine growth retardation being common.  Obstetricians may also have a lower threshold for induction of labour given the high-risk nature of the pregnancy.  It is therefore unsurprising that the birth weight of babies born to women on dialysis is significantly lower than that of a baby born to a healthy mother at term, with the average being 1.5 – 1.9kg compared to 3.5kg (5, 10, 17). 

Among haemodialysis patients, polyhydramnios is more common than in the general population. Monthly ultrasound monitoring of fetal growth and amniotic fluid volume from 24 weeks has therefore been advocated to identify those at high risk of poorer outcomes (6). 

 

Pre-eclampsia

Pre-eclampsia is particularly prevalent in women with renal impairment.  The risk of pre-eclampsia is doubled in women with mild renal failure and as many as 80% of those with severe renal failure will experience it (1).  Preterm delivery therefore frequently occurs due to concerns about the adverse effect on fetal growth.  Pregnant women with renal disease should therefore be advised to seek medical advice if they have any of the symptoms of pre-eclampsia, such as severe headache, visual disturbances, upper abdominal pain, or sudden oedema of the hands, feet or face (18).  A daily dose of 75mg or 150mg  of aspirin is considered beneficial in high-risk women with CKD. This us usually commenced from 12 weeks gestation and continued until delivery (13, 18, 21).

The target range for blood pressure in patients with pre-eclampsia is a systolic of 110-140mmHg and diastolic of 80-90mmHg (1,18) (below 140/90). Blood pressure control is complicated by the teratogenicity of many anti-hypertensive medications commonly used in renal impairment. Many renal physicians therefore tolerate higher blood pressures than usual targets during pregnancy, in the absence of good evidence on the risks versus benefits of this approach.  

 

Proteinuria

Proteinuria worsens in pregnancy, not only because of increase in GFR. It may become much worse and reach nephrotic levels increasing the already elevated risk of venous thromboembolism. Proteinuria can be estimated using urinalysis and quantified by sending a urine specimen for protein:creatinine ratio (PCR).  A PCR of greater than 30mg/mmol (i.e. higher than non-pregnancy upper limit of normal) represents significant proteinuria (18).  In patients with proteinuria before pregnancy, it can be expected that the level of proteinuria will rise to some degree during pregnancy without that necessarily indicating pre-eclampsia.  

 

Blood Pressure

Patients with renal disease are often on a multitude of medications, some of which are known to be teratogenic.  It is important that women who want to conceive have their medications reviewed.

ACE inhibitors and angiotensin II receptor blockers (ARBs) are both damaging to the fetus in mid-pregnancy due to their deleterious effect on fetal development, including pulmonary hypoplasia and neonatal anuria (4). Where there are strong indications for them (high risk of deteriorating function in a patient with significant proteinuria), and particularly if fertility is lowered so that withdrawing them may mean years without them, an alternative strategy is to discuss the balance of risk and aim to stop the drug as soon as pregnancy is confirmed. The risks in early pregnancy are probably very low (18). 

Alternative anti-hypertensives that can be used in pregnancy include labetalol, nifedipine and methyldopa.  Other beta-blockers, such as atenolol have been associated with growth restriction and other fetal adverse effects; however labetalol is regarded as safe (19).

 

Immunosuppressants

In renal transplant patients, immunosuppressive medications are vital to the survival of the graft.  Most of the commonly used medications – such as prednisolone, tacrolimus, ciclosporin and azathioprine – are regarded as safe in pregnancy (1), however, mycophenolate mofetil (MMF) and sirolimus are not recommended due to their association with congenital abnormalities (8,20).  MMF has been linked to the development of cleft lip and palate, diaphragmatic hernia and congenital heart defects (1). Female partners of male patients treated with mycophenolate mofetil or mycophenolic acid should use highly effective contraception during treatment and for 90 days after the last dose.

 

In practice, all non-essential medications should be avoided during pregnancy.  However, the physician must keep in mind the risks versus benefits of discontinuing individual medications, and this should be discussed with the patient. The fetus is at greatest risk of contracting congenital abnormalities from the 3rd to the 11th week of gestation, when all the major organ systems are formed, and some medications may be used with caution in later pregnancy if maternal health necessitates it (1). 

 

ESA and Iron

Women with significant renal impairment may require erythropoietin and parenteral iron supplementation to address the anaemia that may result as a consequence of both pregnancy and renal failure.  Both erythropoietin and iron are safe during pregnancy and breastfeeding, although parenteral iron should be avoided in the first trimester.

 

Breastfeeding

Breastfeeding is preferred, however it may be contraindicated if the mother is taking certain medications that can pass into breast milk and harm the baby.  For example, breastfeeding is contraindicated if the mother is taking mycophenolate, ciclosporin or ACE inhibitors (with the exception of enalapril and captopril) (8,18).  

Although breastfeeding has not been advised if the mother is taking tacrolimus, due to lack of evidence for safety in neonates, the amount of tacrolimus that is transferred into breast milk appears to be trivial, so it is likely that the risk is low (19).  Furosemide and thiazides are safe to take when breastfeeding (1). 

 

Useful Links

  1. https://www.breastfeedingnetwork.org.uk
  2. https://www.sps.nhs.uk/articles/ukdilas

References

  1. Davison JM, Nelson-Piercy C, Kehoe S, Baker P, editors.  Renal Disease in Pregnancy, 1st ed.  London: RCOG Press, 2008  
  2. Hou S.  Pregnancy in chronic renal insufficiency and end-stage renal disease. Am J Kidney Dis 1999; 33:235-252.
  3. Schmidt RJ, Holley JL. Fertility and conception in endstage renal disease. Adv Renal Repl Ther  1998; 5:38-44. 
  4. Lim VS. Reproductive function in patients with renal insufficiency. Am J Kidney Dis 1987; 9:363-7 5.
  5. Giatras I, Levy DP, Malone FD, Carlson JA, Jungers P.  Pregnancy during dialysis: case report and management guidelines. Nephrol Dial Transplant 1998; 13:3266-72
  6. McKay DB, Josephson MA et al. Women’s Health Committee of the American Society of Transplantation. Reproduction and transplantation: report on the AST Consensus Conference on Reproductive Issues and Transplantation. Am J Transplant 2005; 5:1592-9. 
  7. McKay DB, Josephson MA.  Pregnancy in recipients of solid organs – effects on mother and child.  N Engl J Med 2006; 354:1281-93
  8. EBPG Expert Group on Renal Transplantation.  European Best Practice Guidelines for Renal Transplantation. Section IV.10.  Long-term management of the transplant recipient – pregnancy in renal transplant recipients.  Nephrol Dial Transplant 2002; 17 Suppl 4:50-55. 
  9. Imbasciati E, Gregorini G, Cabiddu G, Gammaro L, Ambroso G, Del Giudice A, Ravani P.  Pregnancy in CKD stages 3 to 5: fetal and maternal outcomes.  Am J Kidney Dis 2007; 49:753-62.
  10. Hayslett JP.  Interaction of renal disease and pregnancy.  Kidney Int 1984; 25:579-87
  11. Okundaye I, Abrinko P, Hou S.  Registry of pregnancy in dialysis patients.  Am J Kidney Dis 1998 31:766-73.
  12. Jungers P, Chauveau D.  Pregnancy in renal disease.  Kidney Int 1997; 52:871-85.
  13. Sibanda N, Briggs JD, Davison JM, Johnson RJ, Rudge CJ.  Pregnancy after organ transplantation: a report from the UK Transplant pregnancy registry.  Transplantation 2007; 83:1301-7.14.
  14. First MR, Combs CA, Weiskittel P, Miodovnik M.  Lack of effect of pregnancy on renal allograft survival or function.  Transplantation 1995; 59:472-6.
  15. Edison RJ, Muenke M.  Central nervous system and limb anomalies in case reports of first-trimester statin exposure.  N Engl J Med 2004; 350:1579-82. 
  16. Jones DC, Hayslett JP.  Outcome of pregnancy in women with moderate or severe renal insufficiency.  N Engl J Med 1996; 335:226-32. 24. British National Formulary.  61st edition, March 2011. London: BMJ Group & Pharmaceutical Press.
  17. Kyle PM.  Drugs and the fetus.  Curr Opin Obstet Gynecol 2006; 18:93-9. 
  18. National Institute for Health and Clinical Excellence. Hypertension in Pregnancy – the management of hypertensive disorders during pregnancy. NICE Clinical Guideline 107. August 2010. 
  19. French AE, Soldin SJ, Soldin OP, Koren G.  Milk transfer and neonatal safety of tacrolimus.  Ann Pharmacother  2003; 37:815-8. 
  20. Sifontis NM, Coscia LA, Constantinescu S, Lavelanet AF, Moritz MJ, Armenti VT.  Pregnancy outcomes in solid organ transplant recipients with exposure to mycophenolate mofetil or sirolimus.  Transplantation 2006; 82:1698-702.  
  21. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, Forest JC, Giguère Y.  Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis.  Obstet Gynecol 2010;116:402-1423.
  22. Piccoli GB, Cabiddu G, Attini R, Vigotti FN, Maxia S, Lepori N, Tuveri M, Massidda M, Marchi C, Mura S, Coscia A, Biolcati M, Gaglioti P, Nichelatti M, Pibiri L, Chessa G, Pani A, Todros T. Risk of Adverse Pregnancy Outcomes in Women with CKD. J Am Soc Nephrol. 2015 Aug;26(8):2011-22. doi: 10.1681/ASN.2014050459. Epub 2015 Mar 12. PMID: 25766536; PMCID: PMC4520166.