Pregnancy outcome of five patients with renal amyloidosis regarding familial Mediterranean fever

Abstract

Familial Mediterranean fever (FMF) is an autosomal recessive disease affecting mainly patients of the Mediterranean basin and its major complication is the development of renal AA amyloidosis. On the other hand pregnancy with amyloidosis is not common; nevertheless, amyloidosis will complicate pregnancies also with the underlying disease and may cause terrible perinatal morbidities and mortalities. We report here the cases of five pregnant women and their pregnancy outcomes, who have been diagnosed with FMF complicated by renal amyloidosis. In the five cases, we observed that increased pregnancy complication such as small for gestational age, intrauterine growth restriction, preeclampsia and preterm birth.

• Hypertension
• intrauterine growth restriction
• preeclampsia
• pregnancy outcome
• renal disease in pregnancy

Introduction

Amyloidosis is a generic term that refers to the extracellular tissue deposition of beta-sheet fibrils, many of which circulate as constituents of plasma. There are many forms of these fibrils. Primarily accumulation of immunoglobulin light chain fragments is called primary amyloidosis (AL) and accumulation of serum amyloid A is called secondary amyloidosis (AA).1 Amyloidosis can occur due to many etiologic databases. AA amyloidosis is the result of a reactive process due to deposition of serum amyloid A protein and this condition may complicate chronic diseases related to inflammation such as rheumatoid arthritis, chronic infections or diseases; or familial Mediterranean fever (FMF).2 Clinical symptoms of amyloidosis vary widely according to the accumulated protein and the deposited site of protein. Additionally, the underlying disease also has a critical role on the symptoms.3

Pregnancy with amyloidosis is not common; nevertheless, amyloidosis will complicate pregnancies also with the underlying disease and may cause terrible perinatal morbidities and mortalities. In that aspect, we tried to highlight the importance of the disease control for preventing chronic sequels like amyloidosis regarding pregnancy outcomes.

Materials and methods

In this study, we retrospectively analyzed all of the pregnancies between January 2001 and May 2013. We evaluated patients with known amyloidosis and excluded the patients who are not fully followed at our institute during pregnancy. Additionally, we followed the patients postoperatively 2 months and by an office visit we checked the patients for complications. Patients’ demographics, period of primary disease, duration of pregnancy, birth weight, laboratory values, APGAR scores, perinatal and maternal complications, medications as drug, and comorbid diseases, and pregnancy outcome were recorded.

For the statistical analysis of the data, the Statistical Package for the Social Sciences (SPSS) 17.0 (SPSS Inc., Chicago, IL) was used. Data were summarized as frequencies and percentages. The significance in difference between two related samples is calculated with non-parametric Wilcoxon signed rank test. Significance was set to p < 0.05.

Results

We retrospectively analyzed 20,181 pregnancies and found five patients with known renal amyloidosis. The total number of pregnancies from these five patients was also five (0.031%) in that 12 years’ time. All patients have histologically proven diagnosis of renal amyloidosis. All of those five patients had FMF as an underlying disease, and we found 50 pregnancies (0.24%) that have FMF (with/without amyloidosis) for the same period.

The median age of these five patients was 27.0 (ranging between 19 and 36). Three of these five patients were primiparous and one of them had previously pregnancy with medical abortion because of renal amyloidosis. The mean gestational age for patients was 34.0 weeks and only 2 patients (2/5) had preterm delivery at the 30th and 28th weeks. These two pregnancies were also complicated with preeclampsia and intrauterine growth restriction (IUGR).

While evaluating the patients it was obvious that three patients (3/5) had IUGR pregnancies and these three patients were having chronic hypertension for years. The other two patients did not have chronic hypertension. These three patients had also amyloidosis for 6, 8, and 6 years, respectively. The renal protein loss for the preeclamptic patients had increased during pregnancy the others did not have an abnormality.

Except these three babies, one was small for gestational age (SGA), however, she was born vaginally at the 37th week. Only one baby had low APGAR score and she was intubated at the 5th min. She was severe growth restricted and a preeclamptic mother baby. Cesarean section was the preferred way of delivery (4/5) because of maternal (previous cesarean section, placenta previa marginalis) and fetal complications (preeclampsia, IUGR).

Only one patient (1/5) had postoperative complication, severe postoperative wound infection, and needed transfusion and dialysis. That patient had preeclampsia as an additional risk factor. All of these details are given at Table 1.

Table 1. Clinical features and pregnancy outcomes of five cases with renal amyloidosis.

Patient no.	Age (years)	Parity	FMF duration (years)	Amyloidosis (years)	Comorbid disease	Gestational age (weeks)	Delivery indications	Birth weight	Mode of delivery	APGAR score
1	25	G2Y1	11	6y	Bronchiectasis, HT	37	Previous CS, IUGR	2110 g	CS	10
2	27	G1P0	10	2y	None	38	Previa marginalis	2710 g	CS	10
3	36	G1P0	18	8y	HT	30	Preeclampsia, IUGR	1270 g	CS	8
4	33	G2A1	14	6y	HT	28	Preeclampsia, IUGR	870 g	CS	Intubated
5	19	G1P0	8	1y	None	37	SGA	2230 g	Vaginal	10

Note: HT; hypertension, CS; cesarean section, IUGR; intrauterine growth restriction, SGA; small for gestational age.

We also evaluated renal function of the patients before pregnancy, during pregnancy and after pregnancy. Although not statistically significant, we detected a marked increase in serum creatinine levels and proteinuria in two patients (case no: 1 and 3). Details are given at Table 2.

Table 2. Serum creatinine and proteinuria levels of the patients.

	Before pregnancy		During pregnancy		After pregnancy
Patient no	Serum creatinine (mg/dL)	Proteinuria (mg/24 h)	Serum creatinine (mg/dL)	Proteinuria (mg/24 h)	Serum creatinine (mg/dL)	Proteinuria (mg/24 h)
1	2.7	2910	2.6	4025	3.1	7161
2	1.2	288	1,1	250	1,5	265
3	2.0	3900	1.8	5701	2.29	4884
4	1.2	305	1.6	1254	1.1	395
5	1.1	270	0.9	340	1.1	310

Discussion

FMF is an autosomal recessive disease and has periodic inflammation signs like peritonitis, pleuritis, and arthritis with fever. Some races like Turks, Armenians, Arabs, and non-Ashkenazi Jews have an increased risk of developing FMF.4 It could be seen as 0.2% in affected populations and the risk of being a mutation carrier is higher than that,4 at our data the incidence of FMF was 0.24%, a bit more than the literature, as far as our concern being a tertiary center probably has a role on that.

Most patients of FMF have their first attack at the early childhood and 90% of the cases would have an attack before 20 years of age.5 Over 90% of our patients with FMF and all of the patients with amyloidosis (100%) had the initial manifestation before the age of 20.

Inflammatory attacks of FMF may cause vital morbidities if not controlled and treated carefully. Moreover secondary amyloidosis (AA) is such a great reason for morbidity and mortality that it is commonly encountered in kidneys and relatively less seen in other tissues.6 All the patients at our institute had renal amyloidosis during pregnancy.

FMF may cause adverse outcomes to a pregnancy and may also increase the perinatal and maternal complications by chronic effects and acute attacks. The rate of preterm delivery and miscarriages were higher before the colchicine treatment,7 our clinical experience shows that although FMF is independently influencing complications than general population, colchicine has great effects on the perinatal and maternal outcomes of patients with FMF.

Colchicine is a mitotic inhibitor and makes microtubule growth inhibition. FMF is a well-known disease for colchicine treatment and being used since 1970s.8 Although colchicine crosses transplacentally, Rabinovitch et al. reported its safety for pregnancy and fetus in a study after 10 years of follow-up period and they found fewer complications for the colchicine users.9 Nearly all of our patients were using colchicine during pregnancy and we did not find any abnormalities related to colchicine for FMF patients.

Colchicine is very important for disease control, prevents the renal disease and may delay the occurring of amyloidosis.10 Although colchicine has a role on the control of disease deterioration, it does not have an effect after end stage renal disease.11 All of our patients with a diagnosis of amyloidosis used colchicine during pregnancy. From the three patients with chronic hypertension and FMF (3/5), two of our patients (2/3) had deteriorated renal functions during pregnancy and they developed preeclampsia; and that situation resulted in preterm delivery. However, after birth one of these patients needed dialysis. It has been reported that the level of creatinine and proteinuria at the time of conception is the cornerstone for predicting complications for patients with FMF complicated with amyloidosis.12

Pregnancy with renal amyloidosis would be complicated with spontaneous abortion, stillbirth, IUGR, oligohydramnios or progression in renal disease.7 Amyloidosis based on the initial renal function may adversely affect pregnancies and additional comorbid diseases especially chronic hypertension may aggressively deteriorate the situation like two of our patients.12 It takes between 2 and 13 years from the beginning of nephropathy to end stage renal disease5 and the time from the diagnosis of amyloidosis may also contribute to the progression of the disease.

Three of our patients who were complicated with IUGR had amyloidosis for more than 5 years. In these three patients, we detected relationship between development of IUGR and increasing proteinuria levels (Table 2). Since there are only few patients in this case series, there seems to be no statistically significant change in proteinuria or serum creatinine levels before and after pregnancy. Although patients who developed preeclampsia seems to have a worsening renal functions, this is not proved statistically most probably due to low number of cases. New studies are required to prove these changes.

Preeclampsia is more common in women with advanced maternal age. This situation is an independent risk factor for preeclampsia.13 We observed worse pregnancy outcome in two patients (case no: 3 and 4). These two patients had advanced maternal age during pregnancy compared to other patients. Our findings are consistent with the literature.

Conclusion

FMF is a common disease and amyloidosis is the inevitable end of this condition if not controlled and treated on time. Colchicine is the main focus of this process. Amyloidosis is irreversible and complicates severely especially in pregnancy. However, the time from the beginning of amyloidosis and underlying comorbid disease like chronic hypertension will make the process accelerated.

Declaration of interest

There are no disclosures of interest.