Narcolepsy and pregnancy: a retrospective European evaluation of 249 pregnancies

Authors

Errata

This article is corrected by:

  1. Errata: Corrigendum Volume 23, Issue 2, 239, Article first published online: 14 March 2014

Correspondence

Karel Šonka MD, DSc, Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Katerinska 30, Praha 2, Prague, Czech Republic.

Tel.: +420 224965550;

fax: +420 224922678;

e-mail: ksonka@lf1.cuni.cz

Summary

In a retrospective cohort study undertaken in 12 European countries, 249 female narcoleptic patients with cataplexy (= 216) and without cataplexy (= 33) completed a self-administrated questionnaire regarding pregnancy and childbirth. The cohort was divided further into patients whose symptoms of narcolepsy started before or during pregnancy (308 pregnancies) and those in whom the first symptoms of narcolepsy appeared after delivery (106 pregnancies). Patients with narcolepsy during pregnancy were older during their first pregnancy (< 0.001) and had a higher body mass index (BMI) prior to pregnancy (< 0.01). Weight gain during pregnancy was higher in narcoleptic patients with cataplexy (< 0.01). More patients with narcolepsy–cataplexy during pregnancy had impaired glucose metabolism and anaemia. Three patients experienced cataplexy during delivery. The rate of caesarean sections was higher in the narcolepsy–cataplexy group compared to the narcolepsy group (< 0.05). The mean birth weight and gestational age of neonates were within the normal range and did not differ across groups. Neonatal care was affected adversely by symptoms of narcolepsy in 60.1% of those with narcolepsy during pregnancy. This study reports more obstetric complications in patients with narcolepsy–cataplexy during pregnancy; however, these were not severe. This group also had a higher BMI and higher incidence of impaired glucose metabolism during pregnancy. Caesarian section was conducted more frequently in narcolepsy–cataplexy patients, despite cataplexy being a rare event during delivery. Furthermore, symptoms of narcolepsy may render care of the infant more difficult.

Introduction

Narcolepsy is a rare, disabling and chronic sleep condition, affecting 0.02–0.18% of the population in western European countries and the United States (Longstreth et al., 2007). It is characterized by excessive daytime sleepiness (EDS). Cata-plexy (a sudden loss of postural tone when awake) divides the disease into two nosological entities: narcolepsy with cataplexy (NC, 70–90% patients) and narcolepsy without cataplexy (N). Low cerebrospinal fluid (CSF) hypocretin-1 levels, caused by selective loss of hypocretin (orexin)-producing neurones in the prefornical hypothalamus due to possible autoimmune mechanisms, are reported in 95% of NC patients (Baumann and Bassetti, 2005). In addition to their crucial role as regulators of sleep and wakefulness, hypocretin neurones have been shown to play an important role in energy homeostasis. Narcolepsy occurs as frequently in women as in men. In most cases, the age of onset is between 15 and 40 years, thereby affecting many women in their childbearing years.

Narcolepsy patients often require daily medication to control EDS and cataplexy. Many of these drugs are designated Class C in pregnancy, and there are no published data regarding their effect on the developing fetus or neonates. Prematurity, low birth weight and withdrawal symptoms have been reported in infants born to women taking amphetamines for recreational purposes or as part of an addiction disorder, but no reports exist in the context of narcolepsy (Littner et al., 2001). Indeed, how pregnancy affects the course of narcolepsy (and vice versa) is poorly documented and researched.

Data about multiple sclerosis, another autoimmune disease of the brain, have shown no association with adverse pregnancy or birth outcomes (Jalkanen et al., 2010; van der Kop et al., 2011) but, conversely, pregnancy influences the course of the disease: the relapse rate is typically reduced during late pregnancy and increased in the postpartum period (Confavreux et al., 1998; Saraste et al., 2007).

Except for one small case-series (Maurovich-Horvat et al., 2010), only two case reports and two guideline papers have been published on narcolepsy and pregnancy. In the first case report, Ping et al. (2007) reported a 32-year-old Chinese woman with NC who developed status cataplecticus during childbirth, requiring an emergency caesarean delivery. Williams et al. (2008) described a pregnant patient with glutaric aciduria type II and narcolepsy, who underwent elective delivery at term to avoid cataplexy during labour. The reviews devoted to pregnancy in narcolepsy by Hoover-Stevens and Kovacevic-Ristanovic (2000) and Hoque and Chesson (2008) are expert opinion papers with no patient cohort data or any case report experience.

Only one study to date has reviewed narcoleptic women retrospectively, and shown a significantly higher total number of (not severe) pregnancy complications in women in whom narcolepsy symptoms started before pregnancy compared to women who developed symptoms after delivery (Maurovich-Horvat et al., 2010). The main limitation of the study was the small sample size from two Czech and one Slovak sleep centres.

This European multi-centre study aimed to collate information on pregnancy, childbirth and the puerperium in narcoleptic women, with and without cataplexy, and symptom onset before or after pregnancy. Our hypothesis was that women with narcolepsy and cataplexy at the time of pregnancy would have more difficult pregnancies and experience more complications during labour.

Methods

The study was conducted in 16 European sleep centres in Austria, the Czech Republic, Denmark, France, Germany, Italy, the Netherlands, Poland, Slovakia, Spain, Switzerland and the United Kingdom.

To explore the number and course of pregnancies in enrolled patients, current treatments for narcolepsy and possible complications, a questionnaire was compiled in English (Appendix 1). Participating sleep centres subsequently translated it into local languages, as required, and it was distributed to NC and N female patients by mail or during routine outpatient visits. Participating centres also provided further information on patients' diagnoses. Information was anonymized and data were entered into a dedicated database. The study was approved by Institutional Review Boards in the Austrian and German sleep centres. Specific ethical approval was not required in the other participating countries.

Patients were diagnosed according to the American Academy of Sleep Medicine criteria (American Academy of Sleep Medicine, 2005) by participating centres. Using all collated questionnaires, the same parameters were compared between the N and NC groups, symptomatic women (whose symptoms of narcolepsy started before or during pregnancy) and asymptomatic women (in whom the first symptoms of narcolepsy appeared after delivery), and between NC symptomatic patients and NC asymptomatic patients. Comparison between symptomatic and asymptomatic N patients was not possible, due to the limited number of N patients.

Patients who gave birth prior to the first appearance of narcoleptic symptoms had the details of that particular pregnancy/pregnancies and their experiences classified under the asymptomatic group. If they subsequently carried a diagnosis of narcolepsy and became pregnant, the details of this next pregnancy/pregnancies were classified under the symptomatic groups.

We have no information about the onset of narcolepsy in five women (information on seven children). These latter data were used only when comparing NC versus N patients (and not symptomatic versus asymptomatic). Because the response rates and the absolute numbers for each questions differed, we have indicated in the tables accompanying the text where response rates have fallen below 75% of the number of women surveyed.

Statistical analysis

To compare continuous variables, we used Student's t-test for normally distributed data and the Mann–Whitney U-test for non-normally distributed variables. Normal distribution was tested using the Shapiro–Wilk's test. The chi-square statistic and Fisher's exact test were used to compare discrete variables. Statistics controlled for age were performed by analysis of covariance (ancova), using the age as covariate. Statistical significance was taken at < 0.05 and all tests were two-tailed.

Results

Participants

In total, 458 questionnaires were sent out to patients attending the centres, of which 310 were returned (68% response rate). Of these, 61 were completed inadequately, leaving 249 questionnaires for analysis.

The mean age of respondents was 49.1 ± 14.9 [standard deviation (SD)] years. The diagnostic criteria for NC and for N were met by 216 and 33 patients, respectively.

In the NC group, HLA status was available for 144 subjects, with 93.1% being human leucocyte antigen (HLA) DQB1*06:02-positive. In the N group, HLA status was available for 18 subjects, with 72.2% being HLA DQB1*06:02-positive. The NC and N patients reported a total of 421 pregnancies and 426 children, respectively, with five pairs of twins.

We did not find any differences between the NC and N groups in terms of age at first pregnancy, age of narcolepsy onset, time between first pregnancy and first symptom onset, time between first pregnancy and participation in the study. Symptomatic and NC symptomatic patients were younger when the questionnaire was completed and at narcolepsy onset, and older at the time of first pregnancy, irrespective of whether or not cataplexy was present, compared to their asymptomatic counterparts (Table 1).

Table 1. Characteristics of patients
 NCN P SymptAsympt P NC
SymptAsympt P
  1. NC, group of patients with diagnosis of narcolepsy with cataplexy; N, group of patients with diagnosis of narcolepsy without cataplexy; Sympt, group of patients in whom the first symptoms of narcolepsy appeared before or during pregnancy; Asympt, group of patients, in whom the first symptoms of narcolepsy appeared after pregnancy; NS, non-significant, > 0.05; Bold value indicates significance.

Total number of patients216331766815556
Total number of pregnancies3665530810627386
Total number of children3715531110827688
Age at the first pregnancy (years)26.9 ± 6.424.6 ± 7.5NS28.1 ± 6.522.9 ± 5.3 <0.001 28.2 ± 6.623.3 ± 4.4 <0.001
Age of narcolepsy onset (years)22.0 ± 10.222.8 ± 11.8NS17.1 ± 5.634.4 ± 9.8 <0.001 17.3 ± 5.734.4 ± 9.7 <0.001
Years between first pregnancy and symptom onset4.7 ± 13.31.3 ± 14.6NS10.8 ± 8.4−11.9 ± 14.3 10.8 ± 8.7−11.5 ± 9.3
Years between first pregnancy and assessment21.5 ± 16.425.4 ± 14.4NS18.9 ± 16.230.0 ± 13.0 <0.001 18.5 ± 16.429.8 ± 13.1 <0.001
Current age (years)48.9 ± 15.150.3 ± 13.6NS47.3 ± 15.452.9 ± 12.3 <0.05 47 ± 15.553.1 ± 12.4 <0.01

Pregnancy

There were no significant differences across groups in the percentage of patients with one or more abortions before pregnancy, in the number of pregnancies preceded by abortion (spontaneous or induced) and in the number of pregnancies preceded by spontaneous abortion (Table 2).

Table 2. Characteristics of patients and their pregnancies
 NCNP (P*)SymptAsymptP (P*)NC
SymptAsymptP (P*)
  1. NC, group of patients with diagnosis of narcolepsy with cataplexy; N, group of patients with diagnosis of narcolepsy without cataplexy; Sympt, group of patients in whom the first symptoms of narcolepsy appeared before or during pregnancy; Asympt, group of patients in whom the first symptoms of narcolepsy appeared after pregnancy; BMI, body mass index; NS, non-significant, > 0.05; P*, age at birth adjusted P-value. Bold value indicates significance.

Patients with one or more abortions before pregnancy (%)26.412.1NS2620.9NS27.623.6NS
Number of pregnancies preceded by abortion5414NS69 5NS5815NS
Number of pregnancies preceded by spontaneous abortion433NS37 9NS349NS
BMI before pregnancy23.4 ± 4.224.0 ± 3.4NS (NS)23.9 ± 4.522.4 ± 2.7<0.01 (<0.05)24.0 ± 4.622.1 ± 2.6 <0.01 (<0.01)
Weight increase during pregnancy (%)25.1 ± 15.417.6 ± 8.5 <0.001 (<0.01) 23.7 ± 14.425.8 ± 16.7NS (NS)24.4 ± 1527.6 ± 17.1NS (NS)
BMI before delivery29.1 ± 5.528.1 ± 4.3NS (NS)29.3 ± 5.528.1 ± 5.0<0.05 (<0.01)29.5 ± 5.628.1 ± 5.1 <0.05 (<0.001)
BMI 1 year after delivery25.2 ± 5.424.8 ± 4.3NS (NS)26.0 ± 5.723.3 ± 3.5<0.001 (<0.001)26.0 ± 5.823.2 ± 3.5 <0.001 (<0.001)
Smoking during pregnancy (%)23.41.1NS17.334.0<0.0119.335.5 <0.01

Patients in the symptomatic and NC symptomatic groups had a higher body mass index (BMI) prior to pregnancy (< 0.001). The weight increase during pregnancy was significantly higher in the NC group than in the N group (< 0.01), but the BMI before delivery showed no intergroup differences. Before delivery and 1 year after delivery, the BMI was higher in the symptomatic than in the asymptomatic groups (< 0.05, < 0.001), mirrored in the NC, symptomatic and NC asymptomatic groups (< 0.05, < 0.001) (Table 2). As the patients in the symptomatic and NC symptomatic groups were older, on average, we carried out the same analysis controlling for age, but the results remained the same.

Smaller proportions of women in the symptomatic and NC symptomatic groups smoked during pregnancy compared to the asymptomatic group.

Medication for narcolepsy was used during 29 pregnancies in the NC group (11.9%) and two pregnancies in the N group (7.7%). Of the total number of women surveyed, 150 stated that they did not use any medication throughout their pregnancies and 75 were missing responses.

In the NC patient group, medication was taken during the first trimester in 19 pregnancies, with continued use into the second trimester in two pregnancies. In five pregnancies, medications were used throughout the entire pregnancy. Medications used during pregnancy by women in the NC group were as follows: modafinil (twelve pregnancies), methylphenidate (six pregnancies), clomipramin (three pregnancies), phenmetrazine (three pregnancies), phenterminum resinatum (two pregnancies), sodium oxybate (one pregnancy), amphetamine (one pregnancy), fluoxetine (one pregnancy) and phendimetrazine (one pregnancy). Two mothers in the N group used modafinil during their respective single pregnancies. There was no difference in complication rates within the groups between those using and not using medication.

The NC symptomatic group had significantly more pregnancies with one or more complications than the NC asymptomatic group (< 0.001). The prevalence of anaemia during pregnancy was significantly higher in NC patients than in N patients, in the symptomatic than in the asymptomatic groups and in the NC symptomatic than the NC asymptomatic groups (< 0.05). Impaired glucose metabolism during pregnancy (gestational diabetes mellitus or impaired glucose tolerance) was more frequent in the NC symptomatic group (< 0.05) (Table 3). No patients reported type 1 or type 2 diabetes mellitus prior to pregnancy.

Table 3. Complications during pregnancy
 NCN P SymptAsympt P NC
SymptAsympt P
  1. NC, group of patients with diagnosis of narcolepsy with cataplexy; N, group of patients with diagnosis of narcolepsy without cataplexy; Sympt, group of patients in whom the first symptoms of narcolepsy appeared before or during pregnancy; Asympt, group of patients in whom the first symptoms of narcolepsy appeared after pregnancy; NS, non-significant, > 0.05; Bold value indicates significance.

  2. a

    Responder rate between 70.0 and 74.9%.

  3. b

    Responder rate between 69.9 and 65.0%.

Pregn. with at least one complication (%)32.229.6NS33.524.4NS34.720.6 <0.001
Lower limb oedema (%)13.37.5aNS14.27.1NS14.97.3NS
Anemia (%)10.32.6b <0.05 10.7a2.4 <0.05 11.52.9 <0.05
Impaired glucose metabolism (%)4.8a9.8NS6.8a2.3NS6.4a0 <0.05
Hypertension (%)6.5a7.9bNS5.7a9.6NS5.9a8.7NS

From expectant NC and N mothers not using medication, 5.8% experienced an improvement in the severity of their sleep attacks during their first trimester, 61.4% experienced no change and 32.8% had a worsening of their sleep attack. During the second trimester, improvement in the severity of sleep attacks was reported in 16.8% of the pregnancies, no change in 57.3% and a worsening in 25.9%. During the third trimester, improvement in sleep attack severity was experienced by 9.6% of expectant mothers, no changes in 53.9% and worsening in 36.5%.

Patients who withdrew from medication during the first trimester of pregnancy admitted to no change in the severity of sleepiness in 40.1% case, a worsening in 40.1% and an improvement in 18.2% cases. Information about the severity and frequency of other symptoms of narcolepsy during pregnancy were insufficiently documented to undertake meaningful analyses.

Delivery

The World Health Organization (WHO) defines the normal term for delivery as between 37 and 42 weeks (http://data.euro.who.int/hfadb/). The average duration of gestation was normal for all groups, and the difference between the individual groups was not significant (Table 4). Pregnancies were shorter than 37 weeks in 12.6% of NC, in 5.0% of N, in 13.3% of symptomatic groups and in 7% of asymptomatic groups, respectively. Normal gestation was exceeded in 8% pregnancies in NC women, 0% in N women, 7% in symptomatic and 1% in asymptomatic women. No differences across groups were found in the prevalence of induced delivery and spontaneous delivery. We have no information about the influence of medication on delivery. The most common reason for inducing labour across all groups was overdue delivery (33 pregnancies) and fetal distress (11 pregnancies). In three cases, labour was induced on account of a diagnosis of narcolepsy; in one case, fear of cataplexy was the reason. In the NC group, significantly more patients underwent caesarian section than in the N group (< 0.05), the most common reasons being fetal distress, prolonged delivery, breech birth, failed induction of labour or the caesarian section was planned due to obstetric complications (placental problems, overly large or small baby, umbilical cord abnormalities, multiple births, hypertension, heart disease, injuries in the pelvic area, etc.). A diagnosis of narcolepsy was cited as the reason for caesarian section in two cases. Additionally, in five cases, a caesarian section was performed out of concern for possible cataplexy. Of those latter five women, three were medication-free throughout pregnancy, one was on clomipramine throughout her pregnancy and one used modafinil and citalopram in the first trimester.

Table 4. Characteristics of deliveries
 NCN P SymptAsympt P NC
SymptAsympt P
  1. NC, group of patients with diagnosis of narcolepsy with cataplexy; N, group of patients with diagnosis of narcolepsy without cataplexy; Sympt, group of patients in whom the first symptoms of narcolepsy appeared before or during pregnancy; Asympt, group of patients in whom the first symptoms of narcolepsy appeared after pregnancy; NA, not available; NS, non-significant, > 0.05; Bold value indicates significance.

  2. a

    Respondent rate between 70.0 and 74.9%.

  3. b

    Respondent rate between 69.9 and 65.0%.

Duration of pregnancy (weeks)38.4 ± 6.438.0 ± 6.6bNS38.2 ± 6.838.8 ± 5.0bNS38.3 ± 6.738.8 ± 5.3aNS
Spontaneous delivery (%)69.869.1NS72.763.6NS72.863.6NS
Induced delivery (%)27.529.1NS25.133.3NS25.032.9NS
Caesarian section (%)18.96.1 <0.05 17.613.4NS18.915.4NS
Cataplexy during delivery (%)0.9NANS1.1NANA1.2NANS

Three patients reported cataplexy during delivery (0.9% of NC pregnancies). In all cases, childbirth started spontaneously. In one case a forceps delivery was performed and one baby was born by caesarean section. Of these three women, one had used modafinil and clomipramin in the first trimester.

No differences were found across groups for complications during or after delivery (bleeding, fetal distress, etc.), or for complications regarding the fetus/newborn (suffocation, amniotic fluid aspiration, umbilical cord around the neck, etc.). The most common cause for resuscitation (23 cases) was asphyxia (eight cases).

One baby died during spontaneous delivery in the 42nd week of pregnancy. The 25-year-old mother (NC symptomatic) had a normal pregnancy and used no medication for narcolepsy throughout. No further details are known about this death.

Newborns

The weight and length of the babies fell within the normal range (3426.5 ± 589.8 g, 50.7 ± 2.8 cm), and did not differ significantly across groups. Fifty-five per cent of the babies were boys, 45% girls, with the sex distribution showing no intergroup differences. The most common neonatal complication after delivery was jaundice (11.8%).

There was only one severe complication involving a neonate who experienced asphyxia during labour at 43 weeks. This resulted in psychomotor retardation. The cause of asphyxia was not clear. The NC mother was 35 years old, the pregnancy was uneventful and she did not take any medication, smoke or consume alcohol throughout pregnancy.

Puerperium

Mothers in the symptomatic groups breastfed children more frequently than in the asymptomatic group (< 0.05). Furthermore, more children of the symptomatic and NC symptomatic mothers were breastfed for longer than 1 year (< 0.005) (Table 5).

Table 5. Duration of breastfeeding among narcoleptic women
 NCNa P SymptAsympta P NC
SymptAsympt P
  1. NC, group of patients with diagnosis of narcolepsy with cataplexy; N, group of patients with diagnosis of narcolepsy without cataplexy; Sympt, group of patients in whom the first symptoms of narcolepsy appeared before or during pregnancy; Asympt, group of patients in whom the first symptoms of narcolepsy appeared after pregnancy; NS, non-significant, > 0.05; Bold value indicates significance.

  2. a

    Respondent rate between 70.0 and 74.9%.

Breastfeeding (%)77.063.9NS78.567.1 <0.05 79.769.1NS
Breastfeeding until 6th month (%)48.041.7NS47.049.4NS47.850.0NS
Breastfeeding until 12th month (%)19.913.9NS19.816.5NS19.819.2NS
Breastfeeding exceeding 12th month (%)9.18.3NS11.71.3 <0.01 12.20 <0.01

However, significantly more symptomatic women received psychological treatment because of symptoms such as sadness, fatigue, insomnia, appetite changes, crying episodes, anxiety or irritability during the months following childbirth (< 0.05), although this result may have a limited value due to the low response rate for this question (Table 6). Five women (three in the NC symptomatic group, one in the symptomatic group and one in the asymptomatic group) reported depression prior to pregnancy, but none of them took any antidepressants as expectant mothers.

Table 6. Psychological problems during puerperium
 NCbNc P SymptbAsymptb P NC
SymptaAsymptb P
  1. NC, group of patients with diagnosis of narcolepsy with cataplexy; N, group of patients with diagnosis of narcolepsy without cataplexy; Sympt, group of patients in whom the first symptoms of narcolepsy appeared before or during pregnancy; Asympt, group of patients in whom the first symptoms of narcolepsy appeared after pregnancy; NS, non-significant, > 0.05.; Bold value indicates significance.

  2. a

    Respondent rate between 70.0 and 74.9%.

  3. b

    Respondent rate between 69.9 and 55.0%.

  4. c

    Respondent rate between 54.9 and 40.0%.

Managed the problems alone (%)83.772.7NS80.893.6 <0.05 81.594.8 <0.05
Thought of finding a specialist, but never did (%)12.118.2NS15.03.2NS14.43.5NS
Under psychiatric care (%)4.39.1NS4.23.2 <0.05 4.11.7 <0.05

The baby care was influenced by at least one symptom of narcolepsy in 60.1% of the symptomatic group and 14.1% of the asymptomatic group admitted excessive daytime sleepiness. Women in the symptomatic and NC symptomatic groups had problems due to excessive daytime sleepiness at a rate of 46.9 and 47.3%, respectively, followed by sleep attacks during feeding or nursing (33.9 and 34.3%), fear of being impaired by any of their narcoleptic symptoms (14 and 13%), cataplexy while holding the baby (12 and 14%) and automatic behaviour while nursing or travelling (6 and 0%).

Discussion

This is the first detailed multi-centre questionnaire study providing information on pregnancy, delivery, childbirth and the puerperium in a large number of narcoleptic women. We also confirmed our hypothesis that women with NC at the time of their pregnancy suffered a higher rate of pregnancy-related complications than those who did not, but there was no increase in significant problems in labour or throughout the puerperium.

Pre-pregnancy and pregnancy

Spontaneous abortions occur in 10–15% of clinically recognized pregnancies, and it is well established that women with certain autoimmune conditions have a high frequency of fetal wastage (Faussett and Branch, 2000). This was not observed in our groups, but it should be borne in mind that the autoimmune process in NC may be time-limited.

Patients in the symptomatic groups had a higher BMI prior to pregnancy (< 0.01), before delivery (< 0.05) and 1 year after delivery (< 0.001) compared to patients in the asymptomatic groups. This observation is in line with earlier studies if we were to loosely consider the asymptomatic groups as controls (Schuld et al., 2002).

The percentage weight increase during pregnancy was significantly higher in the NC group than in the N group (< 0.001), but the BMI before pregnancy and 1 year after delivery did not differ between these two groups. This latter findings contradict a study by Sonka et al. (2010), showing a higher BMI in NC patients versus the N patients. However, Sonka et al.'s study included men; furthermore, patients in N and NC groups were younger in our study both before pregnancy and 1 year after delivery than patients in the study published by Sonka et al. The reasons for the greater weight increase in NC pregnant women are unclear.

Unsurprisingly, the majority of women in our study did not use medication for narcolepsy during pregnancy. Importantly, and interestingly, neither patients nor physicians reported any adverse side effects or outcomes related to ongoing medication use throughout the reported pregnancies.

In terms of maternal complications during pregnancy, the NC symptomatic group had a significantly higher prevalence of anaemia and impaired glucose metabolism (< 0.05), among other complications, than the NC asymptomatic group. Not surprisingly, the higher prevalence of impaired glucose metabolism in the NC symptomatic group during pregnancy was associated most probably with the higher recorded BMI. Hypocretin deficiency may, hypothetically, contribute to metabolic dysregulation; however, recent studies do not confirm increased prevalence of impaired glucose tolerance or diabetes mellitus in non-pregnant narcoleptic patients (Beitinger et al., 2012; Engel et al., 2011).

The WHO estimates that 18% of women from the industrialized countries become anaemic during pregnancy (World Health Organization (WHO), 1992). The prevalence of anaemia during pregnancy was higher in the NC and symptomatic groups; there did not appear to be any documented reason for this.

Narcolepsy and pregnancy

Regarding the narcoleptic symptoms during pregnancy, the majority of women who did not receive any medication reported little change in the severity of their sleep attacks. Severity trend of excessive daytime sleepiness appeared unrelated to the stage of the pregnancy. However, the data from our questionnaires preclude any generalization as to the kind of fluctuation in the course of pregnancy.

Delivery

Contrary to expectation (Hoque and Chesson, 2008), only three patients were documented to experience cataplexy during delivery in our group. Thus, the frequency of cataplectic attacks throughout pregnancy may not necessarily translate to an increased risk of cataplexy during delivery.

In European Union (EU) countries, the rate of caesarian section increased from 6.9% in 1999 to 31.5% in 2007 (http://data.euro.who.int/hfadb/). In our study, women with NC underwent statistically significantly more caesarean sections than women without cataplexy. The higher elective caesarian rate for narcoleptic women may be attributable to potentially unwarranted wariness on behalf of obstetricians (Williams et al., 2008).

Newborns

Babies born to mothers with N and NC did not have more complications requiring resuscitation during delivery, and their weight and length were within the normal range.

Puerperium

The last survey on breastfeeding in Europe in 2000 revealed that the average number of infants breastfed to 3 months was 65.4% and to 6 months was 53.5% (http://data.euro.who.int/hfadb/). From our data, neither cataplexy nor sleepiness placed any limitations on breastfeeding. Although the evidence is currently sketchy, patients who wish to return to taking their medications are still advised to give up breastfeeding. Estimates of postpartum depression in the general population range from 6.5% to more than 12% in western countries (Gaynes et al., 2005). In our symptomatic groups, significantly more patients received formal psychological treatment than in the asymptomatic groups after delivery (< 0.05). This is of interest, because depression is present in a significantly higher proportion in narcoleptics than in people without narcolepsy (Dauvilliers et al., 2009; Jara et al., 2011).

Because our study did not contain more detailed questions regarding postpartum depression, we cannot determine the prevalence of subclinical and clinical depression. However, one of the most pertinent findings in our study was the restriction that narcolepsy symptoms placed on the care of the infant. In the symptomatic groups, more than half the patients reported some difficulties coping with their baby. As expected, the main concerns centered on EDS, followed by sleep attacks during feeding or nursing.

Even patients in the asymptomatic group reported excessive daytime sleepiness, which corresponds with the data published by Montgomery-Downs et al. (2010), which show that in non-narcoleptic mothers, severe sleep disturbances may occur during the first 3 postpartum months, causing increased sleepiness which may complicate child care.

Limitations of the study

The limitations of this questionnaire-based study are centred largely on the rate of response, the possibility of recall bias and the heterogeneity inherent in pan-European medical practice. Although it is impossible to control for all biases, perhaps the strongest argument arises from the fact that because pregnancy and delivery are such milestone events in the life of a woman, precise age-independent memory recall is very likely to be high. Additionally, with a low incidence and prevalence of narcolepsy itself, retrospective cohort studies are more feasible within a shorter time-scale and form the basis of most clinical studies in this area. Finally, twice-matched controls (age and age of delivery) were difficult to obtain in this study, and it is hoped that patients asymptomatic at the time of their pregnancy act loosely as a valid comparative population.

Conclusion

Our data suggest that women with narcolepsy have pregnancy outcomes comparable to the women in general population. Because only a small percentage of the women used medication during their pregnancy, there are insufficient safety data and no firm conclusions can be drawn from our reported observations. Additionally, women with narcolepsy may require more psychological and practical child-care support from families during the postpartum period. Overall, our findings are positive: pregnancy should not be discouraged in narcoleptics.

Acknowledgements

We are grateful to all the patients who participated in this study. E.M.H., D.K., S.N. and K.Š. were supported by the Czech Ministry of Health grant IGA NT 13238-4/2012 and by Charles University grant PRVOUK-P26/LF1/4.

Appendix 1

Distribution of questionnaires among participating countries

CountryDistributed questionnairesReturned questionnairesAccepted questionnaires
Austria222222
Czech Republic1067264
Denmark503814
France201813
Germany672827
Italy705240
Netherlands191313
Poland966
Slovakia887
Spain393531
Switzerland18148
United Kingdom3044

Questionnaire about the pregnancy, delivery and newborn in patients with diagnosis of narcolepsy

Please fill in separate forms for each pregnancy, and circle one or more answers where applicable. Please feel free to skip any questions which are inconvenient.

Narcolepsy has been connected to altered endocrine and metabolic functions. Pregnancy in narcoleptic women would be of huge interest, since the bodies of pregnant women undergo several changes (hormonal, physical, cardiovascular, respiratory, metabolic, renal) to ensure the growth of the fetus.

Since narcolepsy symptoms in many cases start in adolescents or young adults, possible interaction of pregnancy and narcolepsy may be a major concern for females of child-bearing potential. Our aim with this questionnaire is to collect enough data which helps us find out the potential effect of narcolepsy on pregnancy, and allows us to give relevant information to the future mothers with narcolepsy.

Name or patient code:

1. Pregnancy: Order of pregnancy – 1. 2. 3. 4. 5. more:

1.1. Did you have a high risk pregnancy?

2. No

1. Yes -----> If yes, the reason/s was/were: (please circle)

  1. High blood sugar during the pregnancy
  2. Infection
  3. Symptoms of narcolepsy
  4. Poor growth of baby while in womb
  5. Twin pregnancy
  6. Preterm bleeding
  7. Preterm contraction
  8. In vitro fertilization (test tube baby)
  9. Others (specify):

1.2. Have you ever had an abortion before this pregnancy?

2. No

1. Yes ----->

  1. Total number:……………
  2. Spontaneous:……………
  3. Induced because of medical reasons:

1.3. How much did you weigh before the pregnancy (around the time of your last menstruation)? ………………kg

1.4. How much weight did you gain from the beginning until the end of the pregnancy? …………….kg

1.5. How much weight did you lose up to 1 year after the delivery?……………kg

1.6. Did you experience any restrictions in physical activity during the pregnancy?

2. No

1. Yes-----> If yes, the reason/s was/were:

  1. Hypertension
  2. Preterm bleeding
  3. Preterm contraction
  4. Twin pregnancy
  5. Others (specify):

1.7. Did you have any restrictions on your diet during the pregnancy?

2. No

1. Yes -----> If yes, your diet was:

  1. Diabetic
  2. Low salt
  3. High magnesium
  4. Others (specify):

1.8 What was your marital status at time of pregnancy?

  1. Married
  2. Cohabiting
  3. Single
  4. Divorced
  5. Widow

1.9. Did you smoke during the pregnancy?

2. No

1. Yes-----> How many cigarettes/day? …………………..

1.10. Did you drink alcoholic beverages during the pregnancy?

2. No

1. Yes----->

  • How often? ……………
  • How many units per day? (1 unit= 0,5l beer=0,2 wine=0,05l spirits) …………..

1.11. Did you take any medicines, vitamins or medical supplements during the pregnancy or one month before pregnancy?

2. No

1. Yes-----> If yes, please specify:

NameHow many pillsHow oftenHow longWhen (indicate the month of pregnancy)

1.12. Did you use any treatment for sleepiness or cataplexy during and/or before this pregnancy?

2. No

1. Yes ----->If yes, please specify:

 Yes (please include dosing per day and month of pregnancy)No (please include the discontuniation of the drug relative to last menstruation)
1 - Modafinil (Vigil)
2 - Sodium oxybate (Xyrem)
3 - Amphetamine
4 - Metamphetamine
5 - Metylphenidate (Ritalin)
6 – Pemoline
7 - Clomipramine
8 - Protriptyline
9 - Imipramine
10 - Desipramine
11 - Fluoxetine
12 - IVIg
13 - Fenmetrazine/Dexfenmetrazine
Other:

1.13. Did you suffer from any diseases since the beginning of the pregnancy?

2. No

1. Yes -----> If yes, please specify:

  1. Problems with thyroid gland
  2. Arterial hypertension
  3. Ischemic heart disease
  4. Type1/Type 2 diabetes mellitus
  5. Depression
  6. Other psychiatric problems
  7. Epilepsy
  8. Asthma
  9. Other diseases :

1.14. Did you have any health complications during the pregnancy?

2. No

1. Yes -----> If yes, please specify:

  1. Oedema
  2. Anemia
  3. Impaired glucose tolerance
  4. Diabetes mellitus
  5. Arterial hypertension
  6. Preeclampsia (pregnancy induced hypertension with protein in the urine)
  7. Others

1.15. Symptoms of narcolepsy BEFORE the pregnancy and therapy:

1. Excessive daytime sleepiness yes/no

2. Naps per week ……………….

Symptom (before the pregnancy) No Yes (Please specify the frequency of symptoms!)
<1/year1-6/yearMonthlyWeekly2-6/weekDaily>2-6/day>7/day
  1. a

    Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening.

  2. b

    Sleep paralysis is a temporary inability to talk or move when waking.

  3. c

    Automatic behaviour means that a person continues to function or work during sleep episodes, but awakens with no memory of performing such activities.

Sleep attacks
Cataplexy
Hypnagogic hallucinationa
Sleep paralysisb
Automatic behaviorc

1.16. Symptoms of narcolepsy during the pregnancy

1. Excessive daytime sleepiness yes/no

2. Naps per week ……………….

Symptom (during the pregnancy)No Yes (Please specify the frequency of symptoms!)
<1/year1-6/yearMonthlyWeekly2-6/weekDaily>2-6/day>7/day
  1. a

    Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening.

  2. b

    Sleep paralysis is a temporary inability to talk or move when waking.

  3. c

    Automatic behaviour means that a person continues to function or work during sleep episodes, but awakens with no memory of performing such activities.

Sleep attacks
Cataplexy
Hypnagogic hallucinationa
Sleep paralysisb
Automatic behaviorc

1.17. Symptoms of narcolepsy AFTER the delivery

1. Excessive daytime sleepiness yes/no

2. Naps per week ……………….

Symptom (after the delivery)No Yes (Please specify the frequency of symptoms!)
<1/year1-6/ yearMonthlyWeekly2-6/weekDaily>2-6/day>7/day
  1. a

    Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening.

  2. b

    Sleep paralysis is a temporary inability to talk or move when waking.

  3. c

    Automatic behaviour means that a person continues to function or work during sleep episodes, but awakens with no memory of performing such activities.

Sleep attacks
Cataplexy
Hypnagogic hallucinationa
Sleep paralysisb
Automatic behaviorc

1.18. Tendency of symptoms development during the pregnancy

SymptomFrequency of symptoms (durint this pregnancy)Yes (please specify the tendency)
Improvement best in:Deterioration worst inNo changes
1-3 month4-6 month7-9 month1-3 month4-6 month7-9 month1-3 month4-6 month7-9 month
  1. a

    Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening.

  2. b

    Sleep paralysis is a temporary inability to talk or move when waking.

  3. c

    Automatic behaviour means that a person continues to function or work during sleep episodes, but awakens with no memory of performing such activities.

Sleep attacks          
Cataplexy          
Hypnagogic hallucinationa          
Sleep paralysisb          
Automatic behaviorc          

2. Delivery

2.1. Beginning of delivery

1. Spontaneous

2. Induced ----->the reason was:

  1. Fetal stress
  2. Fetal infection
  3. Over term
  4. Other

2.2. Length of delivery from the first contractions (h):

2.3. Complications during the delivery:

2. No

1. Yes ----->the cause was:

  1. Cataplexies
  2. Bleeding
  3. Presence of signs in pregnant women that the baby was not well
  4. Other

2.4. Caesarian section:

2. No

1. Yes -----> the cause was:

  1. Twin birth
  2. Breech birth
  3. Prolonged labor
  4. Failed induction of labor
  5. Preterm birth
  6. Planned due to obstetric reason
  7. Presence of signs in pregnant women that the baby was not well
  8. Other

3. Newborn

(In case of twin pregnancy, please fill out the questions 3.1-3.6 separately for each baby.)

3.1. Date of birth

3.2. Sex:

  1. Male
  2. Female

3.3. Length of pregnancy (week + day): ………… weeks + ……..days

3.4. Weight, length of baby …………kg ………….cm

3.5. Head circumference at birth………….cm

3.6. APGAR score

3.7. Resuscitation of the baby

2. No

1. Yes -----> please specify the cause:

  1. Suffocation
  2. Amniotic fluid aspiration
  3. Bradycardia (slow heart rhythm)
  4. Other (specify):
  5. Unknown

3.8. Other complications

2. No

1. Yes -----> please specify the cause:

  1. Newborn jaundice
  2. Anemia
  3. Infection
  4. Other (specify)
  5. Unknown

4. Childbed

4.1. Did the symptoms of narcolepsy complicate the care of baby?

2. No

1. Yes- -----> please circle all applicable:

  1. Excessive daytime sleepiness
  2. Sleep attack during feeding or nursing
  3. Cataplexy while holding baby
  4. Automatic behavior while nursing or traveling
  5. Fear of beeing impaired with any of the narcoleptic symptoms
  6. Other (specify)

4.2. What fits you best regarding symptoms such as sadness, fatigue, insomnia, appetite changes, crying episodes, anxiety, and irritability after childbirth?

  1. I was thinking of looking for psychotherapy or a doctor but I never did it.
  2. I was in psychological treatment during the months following the birth of my baby.
  3. I did not experience those feelings during that time, or I did it but in some way I managed the situation (speaking with other mothers, attending a self-help group, spending more time with my partner, etc.)

4.3. Did you breastfeed your baby?

2. No

1. Yes -----> how long?

  1. 0 - 6 months
  2. 7-12 months
  3. >13 months

Please fill in the following form only once

1. Mother

1.1. Date of birth

1.2. Education:

  1. Primary school
  2. Secondary school/grammar school
  3. University

1.3. Current height (cm); current weight (kg)

1.4. Current comorbidities

  1. Problems with thyroid gland
  2. Type 1/ Type 2 dabetes mellitus
  3. Arterial Hypertension
  4. Ischemic heart disease
  5. Stroke
  6. Hyperuricaemia
  7. Headache
  8. History of head injury
  9. Forgetfullness
  10. Depression
  11. Other psychiatric problems
  12. Epilepsy

Other diseases:

1.5. Menopause:

2. No

1. Yes -------> since age:

2. Narcolepsy (mother)

2.1. Age at onset of narcolepsy symptoms: ……..

2.2. Current symptoms----->

  1. Without medication:
  2. On medication (give the list of the drugs):

2.2.1. Excessive daytime sleepiness:

2. No

1. Yes ----->

  1. 1 - Since? ……(years)
  2. Naps/week
Symptoms No Yes Please specify
Age of onset (years) The current frequency of symptoms!
<1/year1-6/yearMonthlyWeekly2-6/weekDaily>2-6/day>7/day
  1. a

    Hypnagogic hallucinations are vivid, often frightening, dreamlike experiences that occur while dozing, falling asleep and/or while awakening.

  2. b

    Sleep paralysis is a temporary inability to talk or move when waking.

  3. c

    Automatic behaviour means that a person continues to function or work during sleep episodes, but awakens with no memory of performing such activities.

Sleep attacks
Cataplexy
Hypnagogic hallucinationa
Sleep paralysisb
Automatic behaviorc

Medical diagnoses – to be filled by the physician. Please check patient's self – reported comorbidities

1. ICSD – 2 diagnoses

  1. Narcolepsy with cataplexy
  2. Narcolepsy without cataplexy
  3. Idiopathic hypersomnia
  4. Other

2. Sleep comorbidity (please circle)

  1. RLS
  2. PMLS
  3. OSA
  4. RBD

3. HLA II DQB1*0602 positive

  1. No
  2. Yes

Ancillary