Familial Mediterranean fever during pregnancy: An independent risk factor for preterm delivery☆

1. Introduction 

Familial Mediterranean fever (FMF) is an autosomal recessive disorder affecting mainly Jews, Armenians, Arabs and Turks. The disease is manifested by short and self-limiting attacks of fever, peritonitis, pleuritis and arthritis [1], [2]. Ninety-five percent of the patients report abdominal pain as the principal manifestation of the disease. This abdominal pain is localized at first at the lower part of the abdomen, then spreads throughout the entire abdomen. The differential diagnosis for such pain includes inflammatory processes like appendicitis, gallbladder disease, acute pancreatitis, porphyria, chronic inflammatory disease of the intestine, and in women, gynecological events such as rupture or torsion of ovarian cysts, bleeding from a follicle or corpus luteum cyst, ectopic pregnancy, and endometriosis [1], [2]. Pregnant women having this pain should be evaluated for septic abortion, contractions and placental abruption.

The use of colchicine as the treatment of FMF started in the early 1970s. This drug is used to prevent and decrease the severity of FMF attacks [3], and as studies show, 60–75% of patients with FMF respond with complete remission while only 5–10% are non-responders [4]. In the 1970s, patients who regularly took the drug were advised to discontinue it 3 months before planning conception and during pregnancy, because of concern that treatment during pregnancy might cause chromosomal abnormalities [4]. Today, because treatment withdrawal may exacerbate symptoms, the general recommendation is that colchicine should be continued during pregnancy. Researchers are divided in recommending amniocentesis on a routine basis to determine the fetal karyotype [1], [2], [5]. Some sporadic studies have shown that the drug is safe during pregnancy [3], [9]. Moreover, a study comparing pregnant women treated and untreated with colchicine during pregnancy showed that there was no significant difference in malformation rates [6].

There is a risk that peritonitis during the pregnancy may lead to eventual abortion or preterm delivery [1]. In the 1970s, before the use of colchicine, pregnancy wastage rates were higher in women with FMF than in the general population. Today, however, the course and outcome of pregnancies are considered comparable with that of the general population [1]. Few studies have investigated the influence of FMF complications (amyloidosis and nephrotic syndrome) on pregnancy [6], [7], [8], [9], [10] and the effect of colchicine on fetal malformations [3], [4], [5]. Nonetheless, little is reported regarding perinatal outcome of patients with FMF, and there is still no population-based study comparing pregnancies of women with and without FMF.

The present study was designed to investigate pregnancy outcome of patients with and without FMF. During an 18-year-period, we were able to examine a relatively large number of women with FMF, and investigate their pregnancy complications.

2. Materials and methods 

A population-based study comparing all pregnancies of women with and without FMF was conducted. The deliveries occurred between the years 1988 and 2006 at the Soroka University Medical Center. This is the sole hospital in the Negev, in the southern part of Israel. FMF was pre-diagnosed according to the referral documents, according to the ICD9 codes 277.3 or 277.31; Familial Mediterranean fever.

Data were collected from the computerized perinatal database that consists of information recorded directly after delivery by an obstetrician. Only four skilled medical secretaries examined the information routinely before entering it into the database. Coding was done after assessing the medical prenatal care records as well as the routine hospital documents. These procedures assured maximal completeness and accuracy of the database.

The following clinical characteristics were evaluated: ethnicity (i.e. Jewish or Bedouin Arabs), maternal age, parity, gestational age, and birth-weight. The following obstetrical risk factors were examined: previous cesarean deliveries (CD), recurrent abortions (two or more consecutive spontaneous abortions), fertility treatments (either ovulation induction or in vitro fertilization), hypertensive disorders (preeclampsia, eclampsia and chronic hypertension), gestational diabetes mellitus, smoking, and premature rupture of membranes (PROM). In addition, the following risk factors were investigated during routine third trimester ultrasound screening: polyhydramnios (amniotic fluid index >24cm), oligohydramnios (amniotic fluid index ≤5cm) and intra-uterine growth restriction (IUGR; estimated weight below the 10th centile for gestational age) [11]. The following labor characteristics and perinatal outcomes were assessed: CD, Apgar score less than 7 at 1 and 5min, congenital malformations, perinatal mortality and post-partum hemorrhage. The local ethics institutional review board approved the study.

Statistical analysis was performed with the SPSS package 14 edition (SPSS, Chicago, IL). Statistical significance was calculated using the Chi square test for differences in qualitative variables and the t-test for differences in continuous variables. Stratified analysis using the Mantel–Haenszel technique was used to assess the association between FMF and PTD while controlling for possible confounders. A multivariable logistic regression model, with backward elimination, was constructed in order to find independent risk factors associated with maternal FMF and to evaluate the association between FMF and CD while controlling for confounders. Odds ratios (OR) and their 95% confidence interval (CI) were computed. P<0.05 was considered statistically significant.

3. Results 

During the study period there were 175,572 deliveries, of which 239 occurred in patients with FMF. Table 1 shows the clinical characteristics of women with and without FMF. In the FMF group there were significantly higher rates of PTD (<37 weeks). While analyzing PTD <34 weeks gestation, no significant differences were noted between the groups (OR=0.4; 95% CI 0.07–1.7; P=0.161, data not shown in the table). These PTD were mostly induced (OR=2.1; 95% CI 1.2–3.7; P=0.012). Also, a higher rate of LBW was noted in the FMF group as compared to patients without FMF. The FMF parturients had lower parity, but no statistically significant differences were noted between the groups regarding maternal age. Finally, patients with FMF were more likely to be Jewish as compared to Bedouin Arabs.

Table 1. Clinical characteristics of women with and without FMF

	Characteristics	FMF (n=239) (%)	No-FMF (n=175,572) (%)	P
	Ethnicity: Jewish	92.9	54.5
	Bedouins	7.1	45.5	0.000
	Maternal age <19	0.9	1.3
	19–35	86.2	86.1
	>36	12.9	12.6	0.853
	Gestational age ≤36	12.6	7.8
	37–39	83.7	87.4
	>40	3.8	4.8	0.021
	Spontaneous PTD	11.7	8.1	0.092
	Induced PTD	13.7	7.0	0.012
	Parity: 1	24.7	20.2
	2–4	53.6	48.2
	>5	21.8	31.7	0.004
	Birth weight <2500g	12.1	7.8
	2500–4000g	86.2	87.3
	>4000g	1.7	4.9	0.005

Data are expressed as means±standard deviation (S.D.), or numbers and percentages.

Obstetric risk factors are presented in Table 2. There were statistically significant higher rates of recurrent abortions, smoking and fertility treatments among parturients with FMF as compared with non-FMF patients. No significant differences were noted between the groups regarding previous CD, hypertensive disorders, gestational diabetes, PROM, IUGR, polyhydramnios, and oligohydramnios.

Table 2. Obstetric risk factors of patients with and without FMF

	Characteristics	FMF (n=239) (%)	No-FMF (n=175,333) (%)	OR	95% CI	P
	Previous CD	10.9	11.4	0.9	0.6–1.4	0.785
	Recurrent abortions	11.3	5.4	2.2	1.5–3.23	<0.001
	Fertility treatments	5.4	1.9	3.0	1.7–5.3	<0.001
	Hypertensive disorders	7.1	6.1	1.2	0.7–1.9	0.506
	Gestational diabetes	6.3	6.8	0.9	0.5–1.5	0.769
	Polyhydramnios	4.6	4.2	1.1	0.6–2.0	0.741
	Oligohydramnios	3.3	2.4	1.4	0.7–2.8	0.357
	IUGR	3.8	2.1	1.8	0.9–3.6	0.071
	Smoking	3.3	1.4	2.46	1.21–4.99	0.011
	PROM	7.5	6.6	1.15	0.7–1.8	0.564

CD=Cesarean delivery; IUGR=intra-uterine growth restriction; PROM=premature rupture of membranes. Data are presented as percentages, odds ratios (OR), 95% confidence intervals (CI) and P-values for statistical significance.

Table 3 presents the pregnancy and labor complications and outcomes of patients with and without FMF. Higher rates of CD and malpresentation were found among FMF patients. No significant differences were noted between the groups regarding perinatal outcomes such as low Apgar scores, congenital malformations, post-partum hemorrhage, fetal distress, placenta previa, placental abruption or perinatal mortality.

Table 3. Pregnancy and labor complications and outcomes of patients with and without FMF

	Characteristics	FMF (n=239) (%)	No- FMF (n=175,333) (%)	OR	95% CI	P
	Cesarean delivery	18.0	12.8	1.5	1.1–2.0	0.017
	Apgar 1min <7	2.5	4.0	0.6	0.3–1.4	0.252
	Apgar 5min <7	0.4	0.6	0.7	0.1–5.4	0.783
	Perinatal mortality	0.8	1.3	0.6	0.1–2.6	0.544
	Post-partum hemorrhage	0	0.5	0.99	0.998–0.999	0.263
	Malpresentation	9.6	5.4	1.87	1.21–2.88	0.004
	Fetal distress	2.1	2.4	0.88	0.36–2.14	0.781
	Placenta previa	0.8	0.4	2.0	0.5–8.06	0.319
	Placental abruption	0	0.7	0.99	0.998–0.999	0.185
	Congenital malformations	4.6	4.8	1.0	0.5–1.7	0.888

Data are presented as percentages, odds ratios (OR), 95% confidence intervals (CI) and P-values for statistical significance.

Using a multivariable analysis, with backward elimination, the following conditions were significantly associated with FMF (Table 4): preterm delivery, fertility treatments, recurrent abortions, labor induction and malpresentations. Using another multivariable analysis, with CD as the outcome variable, controlling for malpresentations, failure of labor to progress and failed induction, the association between FMF and CD lost its significance (OR=1.2, 95% CI 0.8–1.8, P=0.388; data not shown in a table).

Table 4. Multiple logistic regression model, with backward elimination, of factors associated with FMF

	Characteristics	Odds ratio	95% CI	P
	Preterm delivery (<37 weeks)	1.5	1.1–2.2	0.045
	Fertility treatments	2.5	1.4–4.4	0.001
	Recurrent abortions	2.2	1.5–3.2	<0.001
	Malpresentation	1.9	1.5–2.5	<0.001
	Labor induction	1.8	1.2–2.8	0.007

CI=Confidence interval. Data are expressed as odds ratio, 95% confidence interval and P-values for statistical significance.

Stratified analysis (the Mantel–Haenszel technique) was used to assess the association between FMF and PTD while controlling for possible confounders such as labor induction, fertility treatments, recurrent abortions and placental abruption. None of those variables explained the higher incidence of PTD in the group of patients with FMF (Table 5).

Table 5. Crude and adjusted OR (the Mantel–Haenszel technique) for the association between FMF and PTD

	Variables in analysis	Odds ratio	95% CI	P
	Crude OR for PTD	1.7	1.1–2.5	0.002
	OR for PTD adjusted for
	Labor induction	1.7	1.2–2.5	0.005
	Fertility treatments	1.6	1.1–2.3	0.016
	Recurrent abortions	1.6	1.1–2.4	0.011
	Placental abruption	1.7	1.2–2.6	0.003
	Cesarean delivery	1.6	1.1–2.3	0.022

Data regarding treatment during pregnancy were collected from the delivery files of the 239 FMF patients (Table 6). Most patients (66%) were indeed treated with colchicine (0.5–2mg/day) during pregnancy.

Table 6. Treatment characteristics of patients with FMF

		Number of patients	%
	Not treated	26	11
	No data available	43	18
	Discontinue treatment during pregnancy	31	13
	Colchicine treatment during pregnancy	139	58
	0.5mg×1 day	7	5
	0.5mg×2 day	96	69
	0.5mg×3 day	21	15
	0.5mg×4 day	15	11

4. Comment 

Our study design differed extensively from most other studies investigating pregnancy outcome of patients with FMF. While the latter mostly investigate the influence of colchicine treatment, or compared the pregnancy outcome of FMF patients who took colchicine to FMF patients who discontinued the drug, we performed a population-based study, enabling us to describe independent risk factors associated with FMF. To the best of our knowledge, based on searching Medline using the words “pregnancy” and “FMF” over the last 15 years, this is the largest study that has been published regarding FMF during pregnancy. Furthermore, it is the first study comparing pregnancy outcome between parturients with and without FMF.

The major finding of our study is that FMF is an independent risk factor for preterm delivery. FMF is characterized by recurrent short attacks of serositis and fever, and these attacks may lead to early contractions and abortions [1], [2], [6]. Our study supports this concern. It is still unclear, though, if the preterm delivery is due to the peritonitis and the fever, which lead to contractions, or is the consequence of the pregnant women coming with acute stomachache which leads the medical team to suspect placental abruption or other complications necessitating delivery.

FMF was significantly associated with higher rates of recurrent abortion. It may be related to the high fever and the signs of peritoneal irritation during the attacks [6], or may be an outcome of complications of the disease such as amyloidosis. High demand for ovulation induction and in vitro fertilization was previously found among patients with FMF [1], [2]. Similarly, we found high rates of fertility treatments in the FMF patients (5.4%) as compared to the non-FMF patients (1.9%). The cause of this association is still unclear [1], [2].

Higher rates of CD were found among FMF patients. Interestingly, other studies did not compare the rates of CD in patients with and without FMF. However, in a recent study [6], the CD rate was compared between treated and untreated FMF patients. It was found that the general rate of CD in FMF patients was 16.8%. The higher number of CDs in the treated group was thought to be attributed to a more liberal approach to CD and the apprehension concerning this group [6]. Likewise, in our study the rates of CD among FMF patients (18%) were comparable to the latter study. Nevertheless, after controlling for confounders such malpresentations, failure of labor to progress and failed induction, FMF was not found to be an independent risk factor for CD. Thus, it seems that it is the association with other risk factors, and not the FMF per se, that leads the obstetrician to perform a cesarean delivery.

A main finding of our study was that perinatal outcome of FMF patients was comparable to the general population. No significant differences were noted between the groups regarding perinatal outcomes such as low Apgar scores (<7) at 1 and 5min (2.5% vs. 4.0%, P=0.253 and 0.4% vs. 0.6%, P=0.783; respectively), or perinatal mortality (0.8% vs. 1.3%, P=0.544). This is surprising considering the higher rate of preterm delivery, and the disease-associated complications which might pose a risk for adverse perinatal outcome. Also, no significant differences were noted between the groups regarding congenital malformations, regardless of the use of colchicine (4.6% vs. 4.8%, P=0.888). Most patients continued their treatment during pregnancy, and no significant differences were noted regarding congenital malformations (5.2% vs. 4.9%, P=0.838). Thus, it seems that colchicine may not increase the actual risk for malformations during pregnancy.

In conclusion, FMF is an independent risk factor for preterm delivery. Nevertheless, perinatal outcome is comparable to the general population.