Systematic review of pregnancy and renal outcomes for women with chronic kidney disease receiving assisted reproductive therapy

An initial search of the online databases identified 3520 records of which 1616 were duplicates. Titles and abstracts of the remaining 1904 records published between 1995 and 2020 were screened, leading to 32 publications being quantitatively analysed (Fig. 1) including 23 case reports, three case series, four retrospective studies, one population-based retrospective study and 1 questionnaire.

Fig. 1figure 1

There were 68 women for whom a total of 84 fertility treatment cycles were analysed (35 women with data extracted from case reports or series, 32 from retrospective studies and 1 from other publication types). Fertility treatment cycles included IVF/ICSI cycles, OI cycles, IUI cycles, frozen embryo transfer cycles and auto-transplantation of cryopreserved ovarian tissue.

Demographic and baseline characteristics

The median age of women with CKD at the time of pregnancy was 32.5 years (IQR 30.0, 33.9 years; Range 25–45 years). Ethnicity was not reported in any of the studies. Clinical characteristics are described in Table 2.

Table 2 Demographic and clinical data of CKD women who had fertility treatmentRenal data and outcomes

A substantial proportion of women had renal transplants (n = 52, 76.5%) with a median time from transplantation to fertility treatment of 4.5 years (IQR 4.0, 7.0 years). For women without transplants (n = 16), eight had early CKD (Stage 1 = 6, Stage 2 = 2) and two patients were established on dialysis prior to conception.

The pre-pregnancy, median serum creatinine (N = 30) was 88 µmol/L (IQR 71, 106 µmol/L); first trimester (N = 4) 115 µmol/L (IQR 97, 133 µmol/L), second trimester (N = 10) 69 µmol/L (IQR 49, 106 µmol/L), third trimester (N = 16) 113 µmol/L (IQR 84, 164) and post-partum (N = 4) 168 µmol/L (IQR 137, 198 µmol/L). Median serum creatinine levels before, during and after pregnancy are summarised in Table 3.

Table 3 Median serum creatinine and eGFR in each pregnancy trimester

The overall pre-pregnancy median estimated glomerular filtration rate (eGFR) was 75.0 ml/min/1.73m2 (IQR 61, 99 ml/min/1.73m2) and it was 67 ml/min/1.73m2 (IQR 51, 76.0 ml/min/1.73m2) in women with kidney transplants (N = 30) and 99.0 ml/min/1.73m2 (IQR 86.0, 120.0 ml/min/1.73m2) in women with CKD without transplants (N = 9). Ten women who reported creatinine changes met criteria for AKI (6 – Stage 1, 1-Stage 2; 3- Stage 3). All stage 3 AKI episodes required emergency haemodialysis / haemofiltration. Factors contributing to AKI included atypical haemolytic uraemic syndrome (aHUS), non-aHUS thrombotic microangiopathy, nephrotic syndrome relapse, pre-eclampsia (N = 5), OHSS (N = 2) and unknown (N = 2).

Women were also taking many other medications including antihypertensives (nifedipine, labetalol, metoprolol, losartan, quinapril, methyldopa), aspirin, acyclovir, co-amilozide, insulin, calcitriol, omeprazole, atorvastatin and erythropoietin including teratogenic co-trimoxazole. The causes of CKD for women undergoing fertility treatment, and the immunosuppressive medications taken by women with kidney transplants (N = 52) are listed in Table 2.

Type and cause of infertility, fertility treatment and outcomes

The cause of infertility was reported for 28 out of 68 women (41.2%). Of those reported, the most common cause was tubal (n = 7, 25%). Anovulatory disorders occurred in 6 women (21.4%) including polycystic ovary syndrome. Secondary infertility was identified in 5 women (17.9%). Male factor was identified in 2 cases (10.7%). Other causes included primary ovarian failure / premature ovarian insufficiency (n = 2, 7.1%), endometriosis (n = 2, 7.1%), low ovarian reserve (n = 1, 3.6%), genetic abnormalities (n = 1, 3.6%) and 1 reported as unexplained (3.6%).

The majority of women had IVF or ICSI (54/68; 79.4%). One woman had an auto-transplant of cryopreserved ovarian tissue which led to a spontaneous pregnancy, one woman had a medicated frozen embryo transfer cycle after a previous IVF cycle to create the transferred embryo, one woman used donor eggs, seven women (10.1%) had OI and two women had IUI (2.9%).

OI regimens varied, most commonly using clomiphene citrate and human menopausal gondatropin with many different protocols used for IVF mid-luteal pituitary downregulation and antagonist approaches. Controlled ovarian stimulation medications included Follitropin alfa, follitropin beta, urofollitropin, Human Chorionic Gonadotropin (HCG), gonadorelin analogues and LHRH agonist triggers. When reported, luteal support was given in intramuscular, vaginal and rectal forms. The median duration of controlled ovarian stimulation was 11 days (IQR 10.5, 11 days).

Fertility and obstetric outcomes are summarised in Table 4. The number of embryos transferred was unknown in 27 women, and the reported number of embryos ranged from one to six. In 12 cases a single embryo was transferred, and a double embryo transfer was reported in 12 cases.

Table 4 Fertility and pregnancy outcomes of Chronic Kidney Disease (CKD) patients receiving Assisted Reproductive Technology (ART) treatment compared with cohorts of women with CKD with spontaneous conception and women with kidney transplant who had spontaneous pregnancies and women who had ART following kidney transplantation

There were 84 fertility cycles from 68 patients. The overall pregnancy rate per fertility cycle was 60/84 (71.4%) and live birth rate of 51/60 (85%). Live birth rate was determined as the number of pregnancies which ended with at least 1 live birth. In total there were 70 babies: there were 13 sets of twins, including a triplet pregnancy that was reduced to twins and a quintruple pregnancy that was reduced to twins. There were 3 sets of triplets including a quadruplet pregnancy that was reduced to triplets. There were 35 singletons borne including 2 sets of twins which reduced to singletons spontaneously. Of the pregnancies that did not continue to live birth: there were 12 miscarriages, 1 ectopic pregnancy and 2 stillbirths. This is summarised in Fig. 2.

Fig. 2figure 2

Overview of fertility cycles, pregnancies and fetal/neonatal outcome numbers

Four women (4/54; 7.4%) developed Ovarian Hyperstimulation Syndrome, three of whom developed AKI. One woman also developed pancreatitis and OHSS three weeks after embryo transfer and was successfully treated with intravenous fluids, methylprednisolone, heparin and albumin.

Obstetric outcomes

Twenty-six/68 (38.3%) women were complicated by hypertensive disorders of pregnancy including pre-eclampsia (N = 18; 26.5%) and gestational hypertension (N = 8; 11.8%). Other complications included obstetric cholestasis (N = 1), anaemia (N = 3), DVT (N = 1) and urinary tract infection (N = 1). The most common mode of delivery was caesarean Sect. (41/68; 60.3%). Four (5.9%) women had vaginal deliveries and mode of delivery was not reported for 23/68 (33.8%).

Preterm delivery (< 37 weeks’ gestation) occurred in 24/68 (35.3%) women. Overall median gestational age of delivery was 34 weeks (IQR 30, 36) and median birth weight was 1658 g (IQR 1190, 2295); Singletons only: 2322 g (IQR 1812, 2649). Median intergrowth centile for singletons was 55.8 (IQR 15.1, 60.5), 23.5 (IQR 11.7, 23.7) for twins and 12.0 (IQR 16.8, 39.9) for triplets. Low birth weight (< 2500 g) was present in 29/68 (42.6%) of women.

Fetal and long-term outcomes

There were 14 neonate admissions to a neonatal intensive care unit with median stay of 52.5 days (IQR 16.5, 81.5). Five out of 70 (7.1%) neonates had congenital malformations which included an ear malformation, inguinal and umbilical hernias, hydrocele and phimosis. Fourteen offspring were followed up for up to four years. One child developed hyperactivity disorder.

Comparison between the outcomes in the renal transplantation cohort and non-transplant group

We further subdivided the fertility and pregnancy outcomes of the patients according to transplant status as shown in Table 4. In addition, we compared the outcomes with previous literature published on spontaneous pregnancies in patients with CKD and patients who had had spontaneous pregnancies with renal transplant [21, 22].

The majority of the women in our cohort had had renal transplant ( 52 women). Only 16 women had not had renal transplant, of whom 15 had pregnancies. When comparing the non-transplant patients who had ART with non-transplant patients with spontaneous pregnancies we observed that the live birth rate (86.7% vs 68.9%) and miscarriage rate (13.3% vs 4.9%) were not significantly different but the multiple pregnancy rate (60% vs 3.4%) in the ART group was significantly higher (p < 0.001) [21]. The rate of pre-eclampsia in the ART CKD cohort (6/15, 37.5%) was much higher than the spontaneous pregnancy CKD cohort (95/731, 13.0%) (p < 0.002). The mean gestational age was lower in the ART CKD women ( 27.6 weeks, cf. 36.9 weeks) as was the mean singleton birth weight (2319 g, cf. 2803 g) which were both statistically significant (p < 0.05) [21].

There were 52 women who had ART after having a kidney transplant. This cohort was compared to women with kidney transplant with spontaneous pregnancy and is summarised in Table 4 [22]. The live birth rate and miscarriage rate (11.1% cf 15.4%) were similar as was the stillbirth rate. The mean gestational age was significantly lower in the ART cohort compared to the spontaneous pregnancy cohort (32.2 weeks cf 34.9 weeks) (p < 0.001)and the mean singleton birth weight was also significantly lower at 2014 g compared to 2470 g (p < 0.001) [22].

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