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Keywords:

  • Epilepsy;
  • Pregnancy;
  • Seizures;
  • Antiepileptic drugs

Summary

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information

Purpose

To analyze seizure control, dose adjustments, and other changes of antiepileptic drug (AED) treatment during pregnancy in a large cohort of women with epilepsy entering pregnancy on monotherapy with carbamazepine, lamotrigine, phenobarbital, or valproate.

Methods

Seizure control and AED treatment were recorded prospectively in 3,806 pregnancies of 3,451 women with epilepsy taking part in European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), an international AED and pregnancy registry.

Key Findings

Of all cases, 66.6% remained seizure-free throughout pregnancy. Generalized tonic–clonic seizures (GTCS) occurred in 15.2% of the pregnancies. Women with idiopathic generalized epilepsies were more likely to remain seizure-free (73.6%) than women with localization-related epilepsy (59.5%; p < 0.0001). Worsening in seizure control from the first to second or third trimesters occurred in 15.8% of pregnancies. The AED dose was increased during pregnancy in 26.0% and a second AED added to the initial monotherapy in 2.6% of all pregnancies. Seizures were more likely to occur in the first trimester in pregnancies with an increased drug load (35%; increased dose and/or addition of another AED) than in pregnancies without an increased drug load (15.3%) (p < 0.0001). Compared with other monotherapies, pregnancies exposed to lamotrigine were less likely to be seizure-free, 58.2% (p < 0.0001); had more GTCS, 21.1% (p < 0.0001); had a greater likelihood of deterioration in seizure control from first to second or third trimesters, 19.9% (p < 0.01), and were more likely to require an increase in drug load, 47.7% (p < 0.0001). The mean dose increases from the first to third trimesters were 26% for lamotrigine, 5% for carbamazepine, 11% for phenobarbital, and 6% for valproate. There were 21 cases of status epilepticus (10 convulsive): none with maternal mortality and only one with a subsequent stillbirth.

Significance

Although the majority of women remain seizure-free throughout pregnancy, our data suggest that a more proactive approach to adjusting the dose of all AEDs in pregnancy should be considered, in particular for those pregnancies with seizures occurring in the first trimester and those exposed to lamotrigine, to reduce the risk of deterioration in seizure control.

The management of epilepsy in pregnancy is particularly challenging because any risk–benefit assessment needs to take into account the needs of not only the woman with epilepsy but also the potential adverse effects on the embryo and fetus (Tomson & Battino, 2012). Specifically, the risks to the offspring from prenatal antiepileptic drug (AED) exposure need to be balanced against fetal and maternal risks imposed by uncontrolled seizures. Epilepsy is a serious condition and seizures can have profound effects on maternal health, occasionally including maternal mortality (Cantwell et al., 2011). Moreover, frequent generalized tonic–clonic seizures (GTCS) during pregnancy have been associated with poorer postnatal cognitive development of the child (Adab et al., 2004; Cummings et al., 2011).

We recently reported rates of major congenital malformations after monotherapy exposure for the four most frequently used AEDs based on data from European and International Registry of Antiepileptic Drugs and Pregnancy (EURAP), an international prospective epilepsy and pregnancy registry (Tomson et al., 2011). We found an increase in malformation rates with increasing doses for all four investigated drugs: carbamazepine (CBZ), lamotrigine (LTG), phenobarbital (PB), and valproate (VPA). Because the general treatment strategy has been to identify, before pregnancy occurs, the lowest effective dose of the most appropriate AED for the woman's epilepsy syndrome or seizure type (Harden et al., 2009), our data provided the prescriber with an estimate of the teratogenic risks associated with use of four specific treatments, taken in monotherapy, within certain dose ranges. However, these risk estimates were based on the dose used at the time of conception, and did not take subsequent dose adjustments into account.

In the present study we analyzed seizure control, dose adjustments, and other treatment changes in relation to the type of AED and dose categories defined at conception, using the same study cohort as in our previous analysis of teratogenic risks.

Patients and Methods

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information

Inclusion criteria and study procedures

EURAP is an observational study that was set up in 1999 and that relies on the collaboration of investigators from 42 countries. Its primary objective is to compare the prevalence of major congenital malformations in offspring exposed to AEDs in utero. Pregnancies are deemed eligible for prospective assessment when women who have taken AEDs at the time of conception are enrolled before gestation week 16 and fetal outcome is known. Follow-up data are collected by the treating physician each trimester, at birth, and at 12 months after birth. Recorded data include demographics, several potential risk factors for teratogenic outcome, information on type of maternal epilepsy, and occurrence of seizures. Seizures are classified by the treating physician as either GTCS (including primary and secondary generalized seizures) or other seizure types. In each trimester report, seizure types are quantified separately into one of six predefined categories (no seizures, less than one per month, monthly, weekly, more than weekly, and daily). Occurrence of status epilepticus is recorded separately and classified as convulsive or nonconvulsive. Details on the study methodology have been published previously (The EURAP Study, 2006; Tomson et al., 2011), including eligibility criteria and the methods used to determine the dose–range categories for comparing the teratogenic risks of CBZ, LTG, PB, and VPA (Tomson et al., 2011). Of the 3,909 pregnancies included in that analysis (Tomson et al., 2011), 103 ended prematurely due to induced abortions (n = 41), or stillbirths (n = 62). Hence, prospective information on medication changes or seizure control up to the time of delivery was available for 3,806 pregnancies in 3,451 women.

Statistical analysis

Results were expressed as proportions. Study end points included occurrence of seizures and GTCS (expressed as present or absent), changes in number or doses of AEDs, and changes in seizure frequency (expressed as increase or decrease, using seizure frequency in the first trimester as reference). A change in seizure frequency was defined as a switch from one frequency category to another. In the case of mixed seizure types, the greater change was recorded when one seizure type increased and the other decreased. The relationships of the above end points with three covariates (type of epilepsy, type of AED, and dose groups) were investigated by means of two chi-square tests using JMP version 7.0.2 (SAS Institute Inc, Cary, NC, U.S.A.). Results were considered statistically significant for p-values < 0.05. Only statistically significant results are reported in the text.

Results

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information

Demographic data

The mean duration of pregnancy at time of enrolment was 8.9 (standard deviation [SD] ± 3.3) weeks of gestation. Age at the last menstrual period ranged from 15.3 to 43.5 (mean 29.5 ± 5.0) years. The epilepsy syndrome was classified as idiopathic generalized in 1,497 (39.3%), localization-related in 1,793 (47.1%), and undetermined in 516 (13.6%) pregnancies.

Overall seizure control

Information on seizure control was available in 3,784 of the 3,806 pregnancies; 2,521 (66.6%) were free from seizures during the entire pregnancy, with 1,263 (33.4%) having seizures, of which 687 (18.2%) were exclusively non-GTCS and 576 (15.2%) GTCS (with or without other seizure types).

Among the 728 pregnancies exposed to VPA, 75.0% were completely free from seizures, compared with 67.3% of those exposed to CBZ (n = 914), 73.4% of those exposed to PB (n = 157), and 58.2% of those exposed to LTG (n = 722). The proportion of pregnancies without seizures was significantly lower for the LTG cohort compared with the cohorts exposed to each of the other three AEDs (p < 0.0001). GTCS also occurred more often in LTG-exposed pregnancies (21.1%) than in pregnancies exposed to CBZ (12.6%), PB (14.0%), and VPA (11.5%) (p < 0.0001, for each comparison).

Further details on seizure control classified by type of treatment (AED and dose category at conception) are given in Table 1. Pregnancies exposed to the highest dose categories of CBZ and LTG were the least likely to be free from seizures (41.9% and 41.2%, respectively). Of 1,491 pregnancies occurring in 1,356 women with idiopathic generalized epilepsies and for which there was information on seizure control, 1,096 (73.6%) were seizure-free. This compared with seizure freedom in 1,063 (59.5%) of 1,786 pregnancies occurring in 1,607 women with localization-related epilepsies (p < 0.0001).

Table 1. Seizure control during pregnancy and delivery by type of pharmacologic treatment
TreatmentAllNo seizures during pregnancySeizures during pregnancy and delivery (including cases with status epilepticus)
Type of AED and dose (mg/day) at conceptionn%n%Generalized tonic–clonic seizures (with or without other seizure)Any seizure type excluding generalized tonic–clonicTotalp-Value
n%pn%n%
  1. ap < 0.0001 versus LTG ≥ 300; bp < 0.01 versus LTG < 300; cp < 0.001 versus CBZ ≥ 1,000; dp < 0.0001 versus CBZ ≥ 1,000; ep < 0.05 versus VPA < 700; fp < 0.01 versus VPA ≥ 1,500; gp < 0.001 versus VPA < 700; hp < 0.05 versus PB ≥ 150; ip < 0.0001 versus VPA ≥ 1,500; jp < 0.0001 versus VPA ≥ 700 < 1,500; kp < 0.0001 versus VPA < 700; lp < 0.001 versus PB ≥ 150; mp < 0.001 versus PB < 150; np < 0.0001 versus LTG < 300; op < 0.05 versus VPA ≥ 700 < 1,500; pp < 0.05 versus VPA ≥ 1,500.

CBZ < 4001483.910973.6149.5a, b, c2516.93926.4a, d
CBZ ≥ 400 < 1,0001,01526.872271.111711.5e, a, b, c17617.329328.9a, d
CBZ ≥ 1,0001965.28342.34120.9f, g, h7236.711357.7 i–n
LTG < 30081121.454567.214417.8f, k, a12215.026632.8o, k, l, h, a
LTG ≥ 30042911.317741.311827.5p, j, g, m13431.225258.7i, j, k, m
PB < 1501654.412676.42012.1 1911.53923.6 
PB > 150491.33163.31020.4 e 816.31836.7 e
VPA < 70042411.233077.84410.4 5011.89422.2 p
VPA ≥ 700 < 1,50045412.033573.85311.7 6614.511926.2 
VPA ≥ 1,500932.56367.71516.1 1516.13032.3 
All3,784100.02,52166.657615.2 68718.11,26333.4 

Changes in seizure frequency

Seizure control during the second and third trimesters was compared with that during the first trimester. Information on changes in seizure frequency was available for 3,735 pregnancies. Seizure frequency was unchanged in 2,634 cases (70.5%), of whom 2,521 (95.7%) were seizure-free during the entire pregnancy. Of the remaining 1,037 pregnancies, 448 (12.0%) had a reduction in seizure frequency in the second or third trimester (or both), and 589 (15.8%) deteriorated. Of those who deteriorated, 189 (32%) had an increase in seizures during the second trimester, 229 (39%) in the third, and 171 (29%) in the second as well as the third compared to the first trimester. In 64 pregnancies (1.7%), seizure frequency category changed in opposite directions (increase or decrease, or vice versa) in the second and the third trimesters compared with the first trimester.

Worsening seizure control in the second and the third trimesters compared with the first trimester was more common in pregnancies exposed to LTG (19.9%) than in those exposed to CBZ (14.6%, p < 0.001), PB (11.7%, p < 0.01), or VPA (13.2%, p < 0.0001).

Seizures occurred during delivery in 2.6% of pregnancies exposed to CBZ and to LTG, in 1.9% of those exposed to PB, and in 1.4% of those exposed to VPA.

Change in treatment

The AED dose was increased from the first to the third trimester in 26.0% of pregnancies (990/3,806). Another AED was added in 98 pregnancies (including 41 in which the dose was not increased). An increase in dose and/or addition of another AED between the first and the third trimesters occurred in 16.7% of pregnancies exposed initially to CBZ monotherapy, compared to 47.7% of those exposed to LTG, 29.3% of those exposed to PB, and 20.5% of those exposed to VPA (p < 0.0001). Treatment changes by trimester for different AEDs and dose categories are summarized in Table 2. The mean dose increase from the first to the third trimester was 5% for CBZ, 26% for LTG, 11% for PB, and 6% for VPA. Adding a second AED was more common among LTG pregnancies (58/1,251 4.6%, p < 0.0001). AEDs most frequently added were VPA (n = 22), clobazam (n = 10), levetiracetam (n = 9), and clonazepam (n = 8).

Table 2. Increase in AED dose or addition of another AED, by treatment and dose categories
TreatmentTotalPregnancies with increase in AED dose or AED added in second trimesterPregnancies with increase in AED dose or AED added in third trimesterPregnancies with higher doses in third trimester compared to first
Type of AED and dose (mg/day) at conception Other AED addedDose ncreasedAED added and/or dose increasedOther AED addedDose increasedAED added and/or dose increasedOther AED addedDose increasedAED added and/or dose increasedp-Values
nnnn%nnn%nnn%
  1. ap < 0.0001 versus LTG < 300; bp < 0.0001 versus LTG ≥ 300; cp < 0.05 versus PB < 150; dp < 0.0001 versus PB < 150; ep < 0.05 versus VPA < 700; fp < 0.001 versus VPA ≥ 700 < 1,500; gp < 0.001 versus LTG < 300; hp < 0.001 versus PB < 150; ip < 0.05 and versus VPA ≥ 700 < 15.

CBZ < 4001480151510.11192013.51303120.9 a–c
CBZ ≥ 400 < 1,0001,020659656.4511712212.01115116215.9a, b, d–f
CBZ ≥ 1,0001986172311.65182311.611243517.7a, b
LTG < 3008181215716920.71426928334.62632334942.7 b
LTG ≥ 3004331611413030.01618920547.33221624857.3 
PB < 1501663141710.21404124.74495331.9g, b
PB ≥ 1504914510.209918.4191020.4g, b
VPA < 700424233358.32676916.34869021.2a, b, h
VPA ≥ 700 < 1,5004575444910.70656514.25949921.7 a-c
VPA ≥ 1,500931788.6281010.8381111.8a, b, h, e, i
Total3,8065246451613.64680184722.3989901,08828.6 

An increase in drug dose or addition of another drug was significantly more common in pregnancies with seizures during the first trimester. GTCS were reported in 14.8% of pregnancies in which the dose was increased or another AED was added, compared with 4.6% of pregnancies not associated with such treatment changes. The corresponding values for all seizure types combined (first trimester) were 35.4% and 15.3%, respectively (p < 0.0001). However, increased AED load was also common in pregnancies without seizures if women entered pregnancy on monotherapy with lamotrigine (35% having higher dose in third vs. first trimester) or phenobarbital (27.4%) (Table 3).

Table 3. Increase in AED dose or addition of another AED by type of treatment
Treatment Type of AED at conceptionTotal number of pregnancies assessed (seizure-free)Pregnancies with increase in AED load in second trimester compared to first trimesterPregnancies with increase in AED load in third trimester compared to second trimesterPregnancies with higher doses in third trimester compared to first
Other AED addedDose increasedAED added and/or dose increasedOther AED addedDose increasedAED added and/or dose increasedOther AED addedDose increasedAED added and/or dose increasedp-Values
nnnn%nnn%nnn%
  1. ap < 0.0001 versus LTG; bp < 0.0001 versus PB; cp < 0.001 versus VPA.

Carbamazepine914125262.8359626.8476808.8 a–c
Lamotrigine722211511716.2718319026.3924425335.0 
Phenobarbital157011117.00383824.20434327.4 
Valproic acid728247496.71767710.6310310614.6a, b
Total2,52151982038.11135636713.81646648219.1 

Status epilepticus

There were 21 cases of status epilepticus, of which 10 were convulsive. These cases were evenly distributed over the three trimesters. One case of convulsive status epilepticus in the third trimester ended in perinatal death, although it was not in proximity to the episode of status epilepticus. Three offspring born to three women who developed status epilepticus during pregnancy were diagnosed with major congenital malformations: one had high grade stenosis of the duodenum (mother on CBZ, convulsive status in third trimester); one had spina bifida (mother on PB, nonconvulsive status in the third trimester); and one had a cardiac malformation (mother on CBZ, convulsive status in the first trimester). There were no maternal fatalities.

Discussion

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information

Preliminary information on seizure control and treatment changes in 1,956 women followed prospectively in the EURAP registry who were exposed to any type of treatment was reported in 2006 (The EURAP Study, 2006). That report included 1,026 of the 3,806 pregnancies analyzed in the present study, which is based on a more homogenous cohort of pregnancies exposed to the four most frequently used monotherapies, organized by dose taken at the time of enrollment. Hence, 930 pregnancies from the 2006 report did not meet the inclusion criteria for the present analysis. An added value of the present study is that the analyzed seizure outcomes and treatment changes refer to pregnancies for which the teratogenic outcome has been reported (Tomson et al., 2011). The majority (66.5%) of these pregnancies remained completely free from seizures, a proportion slightly higher than that (58.3%) found in the 2006 study (The EURAP Study, 2006). The difference between the current and the earlier finding could be because the latest analysis excluded women on polytherapy, who are known to be less likely to exhibit complete seizure control (The EURAP Study, 2006). The seizure freedom rate was also higher in women with idiopathic generalized epilepsies (73.6%) than in those with localization-related epilepsy (59.5%), in agreement with previous findings (Thomas et al., 2012). Fewer pregnancies exposed to the highest dose category of CBZ (41.9%) or LTG (41.2%) were free from seizures, an observation that probably reflects a greater severity of epilepsy in women who received higher AED doses at conception (Table 1). In almost one third of the pregnancies, drug dose was increased or a second AED was added to the initial monotherapy. These changes in treatment schedule were more common in pregnancies associated with seizures, suggesting that they could have been prompted by poor seizure control. However, the AED load was also increased in 19.1% of pregnancies without seizures, significantly more often with LTG and PB than with CBZ or VPA (Table 3). This suggests that some treating physicians were aware of the effects of pregnancy on serum concentrations of these AEDs and increased the dose to prevent breakthrough seizures.

Compared with pregnancies exposed to other monotherapies, fewer pregnancies exposed to LTG were free from GTCS, or from seizures in general. Worsening in seizure control after the first trimester was also more common among LTG pregnancies, and could explain the higher proportion of pregnancies with dose increments or addition of another AED among LTG-treated women (Table 2). This finding, which is in line with earlier observations from our group (The EURAP Study, 2006) and from other investigators (Vajda et al., 2006; Pennell et al., 2008) could be explained at least in part by the marked fall in serum LTG concentration that is often observed during pregnancy (Öhman et al., 2008; Pennell et al., 2008). The fact that increases in doses and/or number of AEDs were more common in pregnancies with seizures may suggest that treatment changes in many cases were reactive to seizures, rather than being made proactively to prevent seizure deterioration. In this respect, it is of interest that increases in dose or number of AEDs were recorded in no >50% of LTG-exposed pregnancies, and that the mean LTG dose was only 26% higher in the third trimester compared with the first trimester. This dose increment is less than what would be expected to be necessary to maintain stable serum LTG concentrations, considering that LTG clearance increases by 200–300% in late pregnancy compared with the pre-pregnant state (Öhman et al., 2008; Pennell et al., 2008; Tomson et al., 2013). The EURAP protocol does not include provisions for collection of information on serum AED concentrations, or the physicians' reasons for making treatment changes. Nevertheless, our data suggest that there might be scope for a more proactive approach in adjusting LTG dose, a strategy that has been claimed to reduce the risk of deterioration in seizure control (Sabers & Petrenaite, 2009).

Status epilepticus was reported in 0.6% of all pregnancies, and convulsive status in 0.3%. None of the episodes of status epilepticus were associated with maternal mortality, and the only fetal mortality occurred perinatally and was not temporally related to the status. These data confirm our previous observations (The EURAP Study, 2006) and are in contrast with earlier estimates, which were probably affected by reporting bias, suggesting high rates of maternal and fetal mortality in status epilepticus during pregnancy (Teramo & Hiilesmaa, 1982).

Strengths of the EURAP registry include its prospective design, strict inclusion and exclusion criteria, close and regular follow-ups, and relatively large size of the investigated cohort. However, there are also important limitations. First, EURAP is not a population-based study, and it is unclear to what extent findings can be generalized. However, although the possibility of selection bias is acknowledged, all data reported in this article refer to women on monotherapy, which is the prevailing treatment strategy in epilepsy (Morrow et al., 2006; Harden et al., 2009; Veiby et al., 2009; Hernandez-Diaz et al., 2012), and to different dose levels, presumably representing different levels of severity of the seizure disorder. Second, the primary objective of EURAP is to compare teratogenic outcomes, not to assess seizure control or treatment changes. Hence, the registry does not collect data on seizure control prior to pregnancy for comparison, and seizures are grouped into broad categories, GTCS and others, rather than being classified according to International League Against Epilepsy (ILAE) criteria. Nevertheless, most of the reporting physicians participating in EURAP are experienced neurologists or epileptologists, which presumably adds to the quality of seizure counts and seizure and epilepsy classification. Another limitation is inherent to the observational study design. Because women were not randomized to the different AEDs or AED doses, treatment choices were presumably dictated by individual characteristics and needs. This assumption is supported by the observation that seizure control tended to be worse at higher doses rather than the opposite. Finally, as mentioned above, no information is available on serum drug levels or the reasons for making treatment changes, which remain open to speculation.

Despite the above limitations, the present findings on seizure control and treatment changes, combined with those previously reported for malformation risks (Tomson et al., 2011), provide useful information for physicians who are managing women with epilepsy who are of childbearing potential. We have shown that the risk of malformations increases with AED dose at the time of conception (Tomson et al., 2011); that many women enter pregnancy at low doses; that many can maintain seizure control throughout pregnancy, although frequent dose adjustments may be required, depending on the AED used; that the risk of status epilepticus is low and in most cases apparently without serious consequences for the pregnant woman and the fetus; that monotherapy can be maintained throughout pregnancy in most and that addition of a second AED was deemed necessary in only 2.6% of pregnancies. A recent report from the North American AED Pregnancy Registry suggested that AEDs associated with a higher frequency of seizures during pregnancy tend to be associated with a lower risk of fetal malformations (Hernandez-Diaz et al., 2012). This is consistent with our findings concerning seizure control with LTG and VPA, and illustrates the challenge in balancing efficacy against teratogenic risks. Although it is important to aim for the lowest effective AED dose at conception and during early pregnancy, our data suggest that more consideration should be given to dose adjustments as pregnancy progresses in order to optimize the outcome.

Acknowledgments

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information

EURAP has received financial support from the following pharmaceutical companies: Bial, Eisai, GlaxoSmithKline, Janssen-Cilag, Novartis, Pfizer, Sanofi-Aventis, and UCB.

Disclosures

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information

Dina Battino received honoraria for giving a lecture from UCB Pharma. John Craig received grants to undertake research and honoraria for giving lectures and funding to attend scientific meetings from UCB Pharma, Sanofi-Synthelabo, GlaxoSmithKline (GSK), Janssen-Cilag, Pfizer, and Eisai. Emilio Perucca received speaker's or consultancy fees and/or research grants from Eisai, GSK, Lundbeck, Medichem, Sun Pharma, Supernus, and UCB Pharma. Anne Sabers served as a paid consultant for Eisai Denmark, UCB Nordic, and GSK and has received travel support from Eisai Denmark and UCB Nordic. Torbjörn Tomson received research grants from GSK and UCB and has received speaker's or consultancy fees from GSK, UCB, Eisai, Sun Pharma, and Bial. Erminio Bonizzoni, Dick Lindhout, and Frank Vajda have no relevant conflicts of interest to report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

References

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information
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Supporting Information

  1. Top of page
  2. Summary
  3. Patients and Methods
  4. Results
  5. Discussion
  6. Acknowledgments
  7. Disclosures
  8. References
  9. Supporting Information
FilenameFormatSizeDescription
epi12302-sup-0001-Appendix1.docWord document75KAppendix S1. EURAP Study group.

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