Two pregnancies after simultaneous pancreas–kidney transplantation: A case report

Abstract

Simultaneous kidney–pancreas transplantation can successfully restore fertility in women with type 1 diabetes mellitus and kidney failure. There have been few cases of pregnancy after simultaneous kidney–pancreas transplantation, and a second pregnancy is rare. We report a case of two live births in rapid succession in a simultaneous kidney–pancreas transplantation recipient, complicated by pre-eclampsia but with excellent fetal and graft outcomes. The first pregnancy was achieved with IVF, while the second was achieved naturally. Simultaneous kidney–pancreas transplantation with stable pre-pregnancy graft function enabled this patient to achieve successful pregnancy. However, both pregnancies were complicated by transient renal graft dysfunction and pre-eclampsia precipitating pre-term birth.

Introduction

Simultaneous pancreas–kidney transplantation (SPKT) is an excellent means of restoring long-term normoglycaemia, kidney function, and fertility in women with type 1 diabetes and end-stage kidney disease (ESKD). Experience of SPKT pregnancies remains limited by the infrequency of pregnancies in this small cohort.^1,2 There have been five case series published thus far, with fewer than 10 cases of more than one pregnancy following SPKT reported.^1–5 In the Australia and New Zealand Dialysis and Transplantation Registry (ANZDATA), there have been 18 SPKT pregnancies reported.⁶ This case study describes the outcomes of two pregnancies in rapid succession in an SPKT recipient and discusses the issues unique to SPKT pregnancies.

Case description

A Caucasian female with a congenital horseshoe kidney was diagnosed with type 1 diabetes mellitus at 11 years of age. Her disease was complicated by hypertension, nephropathy, retinopathy, gastroparesis and recurrent urinary tract infections (UTIs). By age 29, she developed end-stage kidney failure secondary to poorly controlled diabetes.

She underwent haemodialysis for four months, and subsequently received a cadaveric pancreas–kidney transplant, with enteric pancreatic anastomosis, and three antigen mismatch (at HLA A, DR and DQ loci). This was complicated by two episodes of severe transplant pyelonephritis and borderline cellular rejection. At two years post-transplant, her immunosuppression changed from mycophenolate, tacrolimus and prednisolone to azathioprine (125 mg), tacrolimus and prednisolone (7.5–10 mg) prior to attempting conception, with considerable pre-pregnancy planning with a multidisciplinary team. After the immunosuppression change, she retained stable kidney and pancreatic allograft function and no donor specific antibodies.

Table 1 summarizes the clinical characteristics of both pregnancies.

Table 1.

Clinical characteristics during pregnancy.

	Pregnancy 1	Pregnancy 2
Age at pregnancy (years)	32	34
Fasting plasma glucose (mmol/L)	3.7–4.6	3.0–5.1
Preconception HbA1c (%)	4.9–5.3	5.3
Pre-conception blood pressure (mmHg)	130/80, no therapy	120/70, no therapy
Pre-conception creatinine (µmol/L)	96	91
Pre-conception urine protein (dipstick)	Trace	Trace
Peak urine PCR in third trimester (mg/mmol)	170	42
BP in pregnancy (mmHg)	120–140/60–80 until 35 weeks – no treatment; 160/100 at 35 weeks; Pre-delivery 190/110 Resolved post-partum	105–140/50–90 until 35 weeks – no treatment; pre-delivery 150/95; resolved post-partum
Delivery method	Emergency CS	Emergency CS
Gestation (weeks)	36	35
Birthweight (g)	2610	2520
Growth percentile at birth adjusted for gestation	40	64

PCR: protein-creatinine ratio; BW: birth weight; CS: caesarean section.

IVF was undertaken to achieve the first pregnancy at three years post-transplantation. IVF was used due to paternal low sperm count and failure to conceive after 18 months. A single cycle of IVF was undertaken following ovulation induction, which resulted in seven embryos frozen and one embryo implanted. She commenced aspirin 100 mg daily and calcium 1200 mg daily from the first trimester for pre-eclampsia risk-reduction, and clinical monitoring with weekly blood pressure checks and, at minimum, monthly kidney function and whole blood tacrolimus levels monitoring (Figure 1). Tacrolimus blood concentrations fell in the second trimester requiring a dose increase to maintain a concentration of 4–5 µg/L. Results of oral glucose challenge tests at 15 and 28 weeks were normal.

Figure 1.

Monitoring of serum creatinine in both pregnancies.

Early pregnancy was uncomplicated apart from UTI with multi-resistant Klebsiella pneumoniae treated with fosfomycin. By 22 weeks’ gestation, she developed mild hypertension treated with methyldopa 250 mg twice daily. Fetal growth ultrasound at 34 weeks was normal. At 36 weeks, she was hospitalized for sudden severe hypertension (BP 190/100 mmHg) with a rise in serum creatinine to 125 µmol/L and oliguria, suggestive of super-imposed pre-eclampsia. There were no features of kidney transplant obstruction, HELLP syndrome or unstable pancreatic graft function. Hypertension was treated acutely with intravenous labetalol and oral nifedipine. She also received a magnesium sulphate infusion. An emergency caesarean section was performed with delivery of a healthy male infant. Kidney function and blood pressure improved to baseline within days of delivery, and anti-hypertensives were ceased. She successfully breastfed the first child.

A second unexpected pregnancy occurred within a year of her first pregnancy, having continued on azathioprine (125 mg), prednisolone (7.5–10 mg) and tacrolimus. She had mild anaemia (haemoglobin 98 g/L), which was successfully treated with iron supplements. Haemoglobin rose to 109 g/L and the iron supplements were ceased by 21 weeks’ gestation. There was no UTI or hypertension. Kidney graft function remained stable until the third trimester (Figure 1), and glycaemic control remained normal throughout. She developed presumed super-imposed pre-eclampsia at 35 weeks’ gestation, with hypertension and serum creatinine rise to 133 µmol/L. The delivery decision in the second pregnancy was prompted by concern for the graft and desire to preserve long-term kidney function. A healthy female infant was delivered by caesarean section. She was breastfed with no issues. Kidney function and blood pressure returned to baseline. No new donor-specific HLA antibodies developed by three months post-partum. Her pre-existing diabetic retinopathy was previously treated with laser, followed by anti-VEGF injections, and reassuringly there was no progression of the retinopathy during either pregnancy.

Discussion

In severe diabetic nephropathy with advanced kidney failure, fertility is dramatically reduced by hormonal dysfunction, with substantial risks of maternal and fetal complications during pregnancy, including fetal loss and malformations.⁷ SPKT can restore fertility and improve the opportunity for successful pregnancy outcomes. We report a case of two rapidly successive pregnancies after SPKT, with overall good maternal, graft and fetal outcomes, complicated by superimposed pre-eclampsia and graft dysfunction necessitating early (but not very pre-term) delivery.

Preconception planning and shared decision making are important for women with kidney disease contemplating pregnancy, as there are competing risks of proceeding with pregnancy versus guilt and distress at not achieving motherhood.^8,9 Pre-conception kidney allograft function is a key determinant of adverse obstetric and fetal outcomes, particularly pre-eclampsia.¹⁰ Counselling prior to the first pregnancy enabled appropriate modification of immunosuppression, followed by a period of observation to ensure both kidney and pancreatic graft function was satisfactory.

This case is notable as assisted reproduction was required to achieve pregnancy. Infertility is often multifactorial but has been attributed to ongoing hormonal imbalance post-transplantation.² IVF pregnancies in kidney-transplant (KT) recipients have maternal and fetal outcomes comparable to other KT pregnancies,¹¹ but has rarely been reported for SPKT recipients.

The optimal timing of pregnancy after a kidney transplant is after the second post-transplant year.¹² Australian women have a median transplant-pregnancy interval of over three years, and increased graft loss after pregnancy has not been demonstrated.¹³ Worse preconception graft function and function during pregnancy are associated with increased risk of graft dysfunction and loss over time in kidney transplant¹⁰ and SPKT recipients.⁵ Hence, the development of an acute kidney injury during pregnancy in our case prompted concern for longer-term graft outcomes, but reassuringly kidney function returned to baseline after each pregnancy. There are minimal data on the longer-term risks of short intervals between pregnancies in transplant recipients, but in this case the short interval was well tolerated.

Both pregnancies ended in pre-term birth due to pre-eclampsia. Pre-term birth occurs in more than 70% of KT and SPKT pregnancies.^4,10,14 This is often due to concern regarding fetal growth or declining maternal health (particularly graft dysfunction or superimposed pre-eclampsia) and subsequent iatrogenic delivery rather than preterm labour or membrane rupture. Vaginal birth is uncommon in SPKT pregnancies;⁴ however, there is no anatomical contraindication and should be encouraged, provided there is no obstetric contraindication.¹⁵

Pre-eclampsia is estimated to complicate 29–33% of kidney transplant pregnancies in Australia,^10,16 and remains common in SPKT pregnancies.^1–3 Pre-eclampsia is inherently difficult to diagnose in transplanted women with background hypertension and kidney dysfunction. In our patient, the development of new hypertension and kidney graft dysfunction suggested super-imposed pre-eclampsia, prompting delivery in both pregnancies. Our patient had a pre-conception serum creatinine (<110 umol/L) that placed her at lower risk for adverse pregnancy outcome according to studies where serum creatinine was used to risk-stratify transplant pregnancies,^17–20 and also did not have chronic hypertension. However, for the second pregnancy, pre-eclampsia in a previous pregnancy was recognised to be a strong predictor of likely recurrence in transplanted women.²⁰

In conclusion, SPKT with stable pre-pregnancy graft function enabled this patient to achieve successful pregnancy. The risks of SPKT pregnancies appear similar to those in KT recipients; graft stability remains essential to minimizing these risks. Furthermore, early management of hypertensive disorders is essential, with worsening kidney function considered an indication for early delivery.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

Written patient's consent was obtained. The Royal Adelaide Hospital, Women's and Children's Hospital and Flinders Medical Centre Human Research Ethics Committee also approved publication.

Guarantor

SJ.

Contributorship

1. Fadak Mohammadi – Preparation of manuscript.

2. Stephen McDonald – Involved in patient care, preparation and suggestions to write the manuscript.

3. Erin Clark – Involved in patient care, preparation and suggestions to write the manuscript.

4. Shilpa Jesudason – Involved in patient care, preparation of manuscript.

Consent has been taken from all the authors before submission.