Introduction {#s1}
============

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system which particularly affects young women. The male to female ratio ranges between 1∶2--3 [@pone.0099106-Pugliatti1], [@pone.0099106-Koutsouraki1] and, while incidence seems to increase in general [@pone.0099106-Kotzamani1], [@pone.0099106-Orton1], it seems to increase even stronger in women [@pone.0099106-Trojano1]. First symptoms typically arise between the third and fifth decade of life which overlaps with the period of reproduction and family planning. Assuming a prevalence in Europe of 70--80/100.000 during the third and fourth decade [@pone.0099106-Pugliatti1], there are estimated to be 250.000 female MS patients of fertile age in Europe. Hence, there is a great need of patients for counseling about inheritance risk, sexual dysfunctions, influence of MS on a pregnancy, birth and lactation, but also vice versa about the effect of pregnancy on the MS course.

In the past, especially during the first half of 20th century, female patients were often discouraged from becoming mother as pregnancy was considered to be a risk in MS [@pone.0099106-Schapira1]. Although some studies may suggest that MS increases the risk of adverse pregnancy outcomes [@pone.0099106-Chen1], [@pone.0099106-Dahl1], the majority of studies could show that risk of complications during pregnancy and birth outcome is the same as in healthy women [@pone.0099106-Finkelsztejn1], [@pone.0099106-VanderKop1]. Many patients in our outpatient department and in MS internet forums report that they received the advice to deliver by caesarean section although current studies show that it is not necessarily preferable to vaginal delivery in MS patients [@pone.0099106-Jalkanen1], [@pone.0099106-Mueller1]. Patients report to be frequently advised against peridural anesthesia, although it is well documented that peridural anaesthesia does not increase post partum relapse rate and can be used in MS patients too [@pone.0099106-Confavreux1]. The problem of sexual dysfunction seems to be often underestimated as either patients do not report these symptoms or physicians do not routinely ask for them [@pone.0099106-Calabr1]. Briefly summarized, increasing data regarding MS and pregnancy has become available in the literature during the last years [@pone.0099106-Borisow1]. However, it is not known to what extent these findings are transferred into today's clinical routine.

The uncertainties among patients and attending physicians also apply to handling of MS pharmacotherapy. Within the last years pregnancy registries could show that exposure to interferon beta (IFN-β) and glatiramer acetate (GA) during conception and even during pregnancy seems to be relatively safe [@pone.0099106-SandbergWollheim1], [@pone.0099106-WeberSchoendorfer1]. However, it is commonly agreed to discontinue IFN- β or GA treatment when pregnancy is detected. Limited data concerning pregnancy is available for the monoclonal antibody natalizumab and the sphingosine receptor modulator fingolimod [@pone.0099106-Hoevenaren1], [@pone.0099106-Hellwig1]. Mitoxantrone is known for teratogenic effects, and its withdrawal is recommended in female as well as in male patients at least six months before pregnancy. Until now, there are no reliable data whether it is favorable to start immunomodulatory therapy (IMT) directly after delivery instead of nursing or to postpone IMT in favor of breastfeeding [@pone.0099106-Hellwig2], [@pone.0099106-Portaccio1].

Taken together, MS patients that plan to conceive or are already pregnant have currently unmet needs in terms of guidance. As obstetricians are usually not experienced in MS counseling and, vice versa, neurologists have only little knowledge regarding obstetrics, pregnant MS patients may have difficulties to get competent advice.

This study surveys neurologists as main source of information for pregnant MS patients regarding delivery, course of the disease and medication during pregnancy, child birth and lactation.

Methods {#s2}
=======

Prior to conducting our study we approached the institutional review board of the Charité -- Universitätsmedizin Berlin and received approval for waiver of ethics committee vote.

We collected demographic and general data of the participants (e.g. age, sex, year of completing residency and number of treated MS patients). In Germany it is possible to pass board certification only in neurology or in both neurology and psychiatry; therefore we also asked for the individual specialization.

After a brought review of literature, we created a questionnaire containing 16 multiple choice questions about pregnancy related topics in MS. The questions were chosen among the issues that were brought up most often by patients in our outpatient department and that are topic of discussion in current literature [@pone.0099106-Borisow1]. These questions were designed as multiple choice items with single correct answer and "I don't know" option; the language of the questionnaire was German. The questionnaire is available as supplement.

To evaluate the comprehensibility and time needed to complete the questionnaire, questions and possible answers of the survey were at first discussed and reviewed by neurologists and obstetricians not participating in the study. Approximately 15 minutes were needed to fill in the questionnaire.

For further analysis, the 16 questions were assigned to one of three categories.

1.  family planning before conception

2.  pregnancy and delivery

3.  period after delivery.

Category 1 contains questions 1--5, 15 and 16 which deal with inheritance risk, frequency of sexual dysfunction, assisted reproduction technique, handling of immunomodulatory therapy during time of contemplating pregnancy, and influence of pregnancy on the long term course of MS.

Questions 6--11 address relapse rates during pregnancy, pregnancy associated complications, treatment of relapses during pregnancy, assisted delivery, peridural anaesthesia, and birth outcome in MS patients; they are summed up in category 2.

Category 3 encloses the questions 12--14 which deal with relapse rates after delivery, breast feeding, and immunomodulatory therapy during lactation.

The questionnaire was mailed to all neurologists in outpatient care in Berlin, registered at the Association of Statutory Health Insurance Physicians (Kassenärztliche Vereinigung). Physicians that treat mainly psychiatric patients (n = 101) were excluded from the study. One month later a reminder was sent. Participants received an expense allowance to the amount of 30 Euro. Anonymity was assured by using two envelopes: informed consent, accounting documents and the first envelope containing the completed questionnaire were placed inside a second envelope. In our institution the first envelope was stored separately from the other documents; therefore a personal allocation to specific persons was not possible.

Statistical analysis was performed by using SPSS Statistics version 19. To compare percentages, Kruskal-Wallis-test and Mann-Whitney-U-test were used for independent samples. Wilcoxon signed rank-test was used to compare related samples. Our study was an exploratory analysis, no power calculation had previously been performed, and not more than three groups were compared. Therefore no correction for multiple comparisons was performed.

Results {#s3}
=======

Demographic Characteristics {#s3a}
---------------------------

Out of 248 neurologists, 56 sent back the completed questionnaire (response rate 23%). Mean age of respondents (±SD) was 52 (±8.8) years. They passed board certification as a specialist in neurology on average 17 (±8.8) years ago and were in private practice for 11 (±9.2) years on average. 21 (37%) treat less than 10 MS patients per quarter, 24 (43%) attend 10--100 patients and 11 (20%) treat more than 100 MS patients per quarter. A summary of demographic data is presented in [Table 1](#pone-0099106-t001){ref-type="table"}.

10.1371/journal.pone.0099106.t001

###### Demographic characteristics.

![](pone.0099106.t001){#pone-0099106-t001-1}

  ------------------------------------------------------------------- ------------------------ ----------
  Gender                                                                        male            33 (59%)
                                                                               female           23 (41%)
  Age                                                                        \<50 years         24 (43%)
                                                                             ≥50 years          30 (54%)
                                                                           not specified         2 (3%)
  Board certification                                                        neurology          24 (43%)
                                                                       neurology & psychiatry   32 (57%)
  Period of board certification                                              \<15 years         24 (43%)
                                                                             ≥15 years          31 (55%)
                                                                           not specified         1 (2%)
  Private practice                                                           \<10 years         29 (52%)
                                                                             ≥10 years          26 (46%)
                                                                           not specified         1 (2%)
  Treated MS patients per quarter                                               \<10            21 (37%)
                                                                              10--100           24 (43%)
                                                                               \>100            11 (20%)
  Counseling of female patients concerning pregnancy related topics         extensively         23 (41%)
                                                                        to a certain degree     28 (50%)
                                                                             not at all          5 (9%)
  Counseling of male patients concerning pregnancy related topics           extensively         14 (25%)
                                                                        to a certain degree     35 (62%)
                                                                             not at all         7 (13%)
  Relevance of pregnancy aspects in MS                                     very relevant        18 (32%)
                                                                        moderately relevant     25 (45%)
                                                                          little relevant       9 (16%)
                                                                            not relevant         3 (5%)
                                                                           not specified         1 (2%)
  ------------------------------------------------------------------- ------------------------ ----------

Survey Results {#s3b}
--------------

About half (54%) of all questions were answered correctly. Among those who indicated to counsel MS patients about pregnancy related topics extensively or to a certain degree, the rate of correct answers was 59%.

The question which was most frequently answered correctly refers to MS relapse rate during pregnancy. 47 (84%) of the participants knew that relapse rate decreases during the course of pregnancy [@pone.0099106-Confavreux1]. 42 (75%) were aware that the rate of pregnancy related complications in MS patients is the same as in healthy women. With 28 (50%) wrong answers the question about frequency of sexual dysfunctions in MS patients was the question most often answered incorrectly. Topics in which most of the participants were aware of their lack of knowledge refer to assisted delivery and artificial fertilization. 52% and 47%, respectively, answered these questions with "I don't know". [Table 2](#pone-0099106-t002){ref-type="table"} summarizes the survey results.

10.1371/journal.pone.0099106.t002

###### Survey results.

![](pone.0099106.t002){#pone-0099106-t002-2}

                                                    correct    incorrect   I don't know   missing
  ------------------------------------------------ ---------- ----------- -------------- ---------
  Inheritance risk                                  31 (56%)   13 (23%)      9 (16%)      3 (5%)
  Frequency of sexual dysfunctions                  14 (25%)   28 (50%)      13 (23%)     1 (2%)
  IMT before conception (female patients)           28 (50%)   19 (34%)      6 (11%)      3 (5%)
  IMT before conception (male patients)             36 (64%)    8 (14%)      11 (20%)     1 (2%)
  Escalation therapy before conception              14 (25%)    6 (11%)      11 (20%)     8 (14%)
  Relapse rate during pregnancy                     47 (84%)    3 (5%)        5 (9%)      1 (2%)
  Complications during pregnancy                    42 (75%)    7 (13%)       5 (9%)      2 (3%)
  Relapse treatment during pregnancy                26 (46%)   18 (32%)      11 (20%)     1 (2%)
  Assisted delivery                                 15 (27%)   11 (19%)      29 (52%)     1 (2%)
  Peridural anaesthesie                             41 (73%)    4 (7%)       10 (18%)     1 (2%)
  Pregnancy outcome                                 35 (63%)    9 (16%)      10 (18%)     2 (3%)
  Post partum relapse rate                          37 (66%)    8 (14%)      8 (14%)      3 (5%)
  Breast feeding                                    17 (31%)   27 (48%)      9 (16%)      3 (5%)
  IMT post partum                                   33 (59%)    8 (14%)      7 (13%)      8 (14%)
  Influence of pregnancies on longterm MS course    35 (63%)    3 (5%)       14 (25%)     4 (7%)
  Assisted reproductive technique                   12 (21%)   14 (25%)      26 (47%)     4 (7%)

IMT: immunomodulatory therapy.

After assigning the 16 questions to the three categories mentioned above, we found the most correct answers (68%) within category 2, which refers to the period of pregnancy and questions about delivery. The questions about topics before the beginning of pregnancy (category 1) were answered at least correctly (55%) and mostly with "I don't know" (18%).

[Table 3](#pone-0099106-t003){ref-type="table"} summarizes the results of the statistical analysis. We compared the percentages of correct and "I don't know" answers for age, sex, board certification, duration in private practice, number of treated MS patients, and the assumed relevance of the topic pregnancy in MS. Moreover, we evaluated the degree of counseling referring to time and content of counseling.

1.  *Influence of gender, age and board certification on survey results.* Related to gender, age and the kind of board certification there were no differences in correct and "I don't know" answers to all questions and to the questions of the various groups.

2.  *Influence of period of board certification and duration in private practice on survey results.* If we compare neurologists who passed their exam within the last 15 years to those who are specialized in neurology more than 15 years we found no significant differences in correct and "I don't know" answers to all questions and to the questions of the various categories. Moreover, there were no differences between physicians in private practice over 10 years compared to neurologists less than 10 years in private practice.

3.  *Association between number of treated MS patients and survey results.* The percentage of correct answers to all 16 questions (p = 0.001) and to the questions of category 1 (p\<0.001) was significantly associated with the number of treated MS patients. Moreover, the rate of questions answered with "I don't know" decreases with rising numbers of attended patients for all questions (p = 0.001) and for the questions of the various categories (p\<0.001; p = 0.001 and p = 0.01, respectively; [Figure 1](#pone-0099106-g001){ref-type="fig"}).

4.  *Association between degree of counseling of female patients and survey results.* Significant correlations were found between the degree of counseling and the number of correct answers to all 16 questions (p\<0.001) and to questions of the three categories (p\<0.001, p = 0.001 and p = 0.004, respectively). Participants that rarely advise patients about pregnancy topics significantly more often answered "I don't know" to all questions and to questions of the single categories (p\<0.001).

5.  *Association between degree of counseling of male patients and survey results.* The percentage of correct answers to all 16 questions (p\<0.001) and to the questions of the three categories (p\<0.001, p = 0.003 and p = 0.03) significantly correlated with the degree of counseling. With rising degree of counseling the rate of questions answered with "I don't know" decreased for all questions (p = 0.001) and for the questions of the three categories (p = 0.001, p = 0.001 and p\<0.001, respectively).

6.  *Influence of assumed relevance of pregnancy in MS on survey results.* Physicians that consider pregnancy in MS to be a relevant topic in their practice more frequently answered correctly to all questions (p = 0.002) and to questions of category 1 (p = 0.002) and 2 (p = 0.006). Low assumed relevance is associated with more "I don't know" answers related to all of the 16 questions (p = 0.001) and to questions of category 1 (p = 0.001), category 2 (p = 0.004) and category 3 (p = 0.014).

![Percentage of correct and I don't know-answers in relation to the number of treated MS patients per quarter: Kruskal-Wallis-test.](pone.0099106.g001){#pone-0099106-g001}

10.1371/journal.pone.0099106.t003

###### Statistical analysis.

![](pone.0099106.t003){#pone-0099106-t003-3}

                                                                                                                              Correct answers (%)   I Don't know (%)                                                                              
  ----------------------------------------------------------------------------------------------- -------------------------- --------------------- ------------------ ------------- ------------- --------------- --------------- --------------- ---------------
  Sex                                                                                                        male                     55                   54              58            51             21              21              23              22
                                                                                                            female                    58                   47              69            63             21              28              20               9
                                                                                                          *p-value*                 *0.87*               *0.27*          *0.12*        *0.17*         *0.26*           *0.1*          *0.62*          *0.23*
  Board certification                                                                                     neurology                   61                   55              65            64             19              22              19              10
                                                                                                    neurology & psychiatry            53                   48              60            49             23              25              23              22
                                                                                                          *p-value*                 *0.27*               *0.31*          *0.67*        *0.83*         *0.86*          *0.74*          *0.97*          *0.08*
  Period of board certification                                                                          *\<15 years*                *56*                 *47*            *63*          *62*           *22*            *25*            *23*            *13*
                                                                                                         ≥*15 years*                 *58*                 *55*            *64*          *53*           *20*            *23*            *20*            *17*
                                                                                                          *p-value*                 *0.47*               *0.43*          *0.69*        *0.26*         *0.35*           *0.5*          *0.42*          *0.45*
  Period in private practice                                                                              \<10 years                  57                   51              63            59             23              26              23              17
                                                                                                          ≥10 years                   56                   51              62            52             20              22              20              16
                                                                                                          *p-value*                  *0.9*               *0.9*           *0.97*         *0.4*         *0.15*          *0.22*          *0.19*          *0.63*
  Treated MS patients per quarter[\*](#nt102){ref-type="table-fn"}                                           \<10                     42                   33              51            47             41              45              40              33
                                                                                                           10--100                    59                   52              66            60             14              16              14               9
                                                                                                            \>100                     76                   80              76            65              3               3               5               0
                                                                                                          *p-value*               ***0.001***        ***\<0.001***       *0.08*        *0.35*      ***\<0.001***   ***\<0.001***    ***0.001***     ***0.01***
  Counseling of female patients about pregnancy related topics[\*](#nt102){ref-type="table-fn"}          extensively                  69                   68              75            57              8              10               7               4
                                                                                                     to a certain degree              53                   42              59            64             24              27              24              14
                                                                                                          not at all                  11                   14              13             0             84              79              83              100
                                                                                                          *p-value*              ***\<0.001***       ***\<0.001***     ***0.001***   ***0.004***   ***\<0.001***   ***\<0.001***   ***\<0.001***   ***\<0.001***
  Counseling of male patients about pregnancy related topics [\*](#nt102){ref-type="table-fn"}           extensively                  71                   73              73            63              8               9               8               3
                                                                                                     to a certain degree              57                   48              66            60             18              22              18              10
                                                                                                          not at all                  18                   18              19            17             73              69              72              83
                                                                                                          *p-value*              ***\<0.001***       ***\<0.001***     ***0.003***   ***0.03***     ***0.001***     ***0.001***     ***0.001***    ***\<0.001***
  Relevance of pregnancy aspects in MS                                                             very/moderately relevant           62                   57              69            59             15              17              15              10
                                                                                                     little/not relevant              36                   28              41            46             46              50              46              38
                                                                                                          *p-value*               ***0.002***         ***0.002***      ***0.006***     *0.26*       ***0.001***     ***0.001***     ***0.004***     ***0.014***

\*Kruskal-Wallis-test; for further analysis Man-Whitney-U-test was used.

Discussion {#s4}
==========

The intention of the study was to investigate neurologists' expertise in MS and pregnancy. Overall, respondents answered about half of our questions correctly. Only seven out of 56 (13%) participants indicated not to counsel male and/or female MS patients about pregnancy and sending them to specialized outpatient centers, to a gynecologist, general practitioner or other neurologists. The remaining 49 (87%) physicians reported to counsel MS patients at least to a certain extent. Erroneous knowledge or knowledge gaps revealed by our survey are particularly concerning as they might influence the treatment of patients: for example, 27% of the participants would treat a MS relapse with high dose methylprednisolone (MP) throughout pregnancy. Although administration of MP is not strictly contraindicated during pregnancy, one should be aware that steroids are weak teratogens with higher risks for oral clefts (OR 3.35) [@pone.0099106-ParkWyllie1], miscarriage (12 vs. 7%) [@pone.0099106-Gur1], and preterm birth (27 vs. 11%) [@pone.0099106-Gur1] after exposition during the first trimester [@pone.0099106-ParkWyllie1]--[@pone.0099106-Ferrero1]. Hence, a strict risk-benefit-assessment is required during the first three months of pregnancy. In contrast, 10% are erroneously convinced that MP is contraindicated throughout the entire pregnancy, although during second and third trimester the use of steroids does not seem to have adverse effects on the fetus [@pone.0099106-Ferrero1].

Handling with IFN-β and GA in the context of pregnancy is controversially discussed. According to IFN-β manufacturers' information, starting of IFN-β therapy during pregnancy is contraindicated. Likewise, it is common practice to discontinue IFN-β or GA treatment when a pregnancy is detected. On the other hand, the manufacturers indicate that in highly active MS IFN-β discontinuation during pregnancy should be critically weighted up against the risk of severe relapses and there are several reports showing no detrimental effects when IFN-β and GA were continued during pregnancy [@pone.0099106-Hellwig3], [@pone.0099106-DungDung1]. This view, however, conflicts with Lu et al. [@pone.0099106-Lu1], who in general recommend discontinuation of DMT when a pregnancy is planned. This recommendation is based on one single study where birth weight and length were reduced on average by 114 g and 1.1 cm, respectively [@pone.0099106-Amato1]. However, unlike mitoxantrone, no precise interval between withdrawal of IFN-β and begin of unprotected sexual intercourse is defined in women planning to conceive. On the contrary, some authors warn of leaving patients untreated while waiting for conception [@pone.0099106-Charles1].

Prevalence of sexual dysfunction is underestimated by many physicians. 50% of respondents think that only 10 or 40% of MS patients were affected by symptoms like reduced libido, erectile dysfunction or disturbances of ejaculation. However, recent studies showed that up to 70% of MS patients suffer from sexual dysfunctions [@pone.0099106-Zorzon1], [@pone.0099106-Celik1]. Moreover, 20% respectively 8% of respondents erroneously think that a vaginal delivery mode or a peridural anesthesia is responsible for higher relapse rate after delivery. That is a cause of concern as thereby unnecessarily a primary caesarian section may be recommended or patients unnecessarily avoid peridural anesthesia. The questions most often answered with "I don't know" refer to assisted delivery and artificial fertilization which reflects the necessity of close cooperation with obstetricians. Overall, a fifth (21%) of all questions were answered with "I don't know".

Most knowledge gaps concern questions of category 1 dealing with family planning before conception. This is a cause of concern as incorrect advice at this time may have devastating consequences such as abstaining from having children at all, or abortion or congenital malformations due to certain medications. The percentage of correct answers significantly increases when more than 100 MS patients were treated per quarter (≙ 400 MS patients per year).

Until now, the only study which investigated neurologists' treatment regimes about gender specific topics in MS was performed by Coyle et al [@pone.0099106-Coyle1]. In that study, which was reported in 2004, up to 79% of respondents recommended discontinuing IMT prior to planned conception, whereas in our study only 27% counsel in this way. In our study 50% gave advice for discontinuing IMT only after conception, compared to 20% in the other study. These differences probably reflect the changes in treatment strategies due to the increase of knowledge over the last ten years. Further questions in the study by Coyle et al. [@pone.0099106-Coyle1] refer to contraception, menstrual irregularities, hormone replacement therapy, and breastfeeding. Other relevant topics such as treatment of relapses during pregnancy and lactation, mode of delivery, or risks of assisted reproductive technique were not discussed. Another limitation of that study is that only female neurologists were included. The surveyed cohort was less homogenous than ours, as the interviewed physicians worked as well in private practice as in academic and MS centers in the USA and Canada. In our study only physicians in private practice in Berlin were surveyed.

Our study has a number of limitations as well. As response rate was only 23% a non-response bias cannot be ruled out. However, previous questionnaire studies among physicians showed only few differences between responders and non-responders [@pone.0099106-McFarlane1]--[@pone.0099106-Kellerman1] suggesting that nonresponse bias may not be as crucial as in surveys of the general population. Since only city-based physicians in private practice were included it is impossible to estimate to what degree our results are representative of other regions or countries. Berlin is Germany's largest city, and supposedly, the overall offer for education is higher than in rural areas. Therefore it cannot be ruled out that our survey performed in rural areas might have resulted in a lower proportion of correct answers. Although our findings are not applicable to rural areas, it is possible that our results even overestimate physicians' expertise in general. Moreover, compared to neurologists in private practice, hospital-based physicians and neurologists in other institutions may differ in their expertise about pregnancy aspects in MS. To address these issues, a survey of neurologists outside Berlin as well as of physicians in academic centers and the comparison to neurologists in private practice might be the objective of further studies.

One fifth of the participants in our study do not consider pregnancy to be a relevant topic in their practice. We assume that those physicians who answered the questionnaire are in general more interested in the topic than non-responders. Thus, it is possible that expertise in general may be lower than determined in our study. Likewise, we cannot rule out that respondents looked up the relevant information which could also result in overestimation of expertise.

To sum up, our results provide some insights into the state of knowledge among neurologists in private practice in Berlin, Germany. MS patients cannot take for granted to receive correct advice concerning pregnancy related topics. Level of expertise rises with the number of attended MS patients and assumed relevance of the topic. Therefore MS patients should seek advice from physicians attending a large number of MS patients. Many uncertainties regarding assisted delivery and artificial fertilization reveals the importance of close cooperation with attending obstetricians.

Supporting Information {#s5}
======================

###### 

Multiple sclerosis (MS), family planning and pregnancy.

(DOC)

###### 

Click here for additional data file.

We thank Klaus-Dieter Wernecke, Sostana Statistics GmbH, Charité Universitätsmedizin Berlin, Berlin, Germany and Gerda Siebert, Institute of Biometrics Charité Universitätsmedizin Berlin, Berlin, Germany for performing statistical analysis.

[^1]: **Competing Interests:**Friedemann Paul is a PLOS ONE Editorial Board member. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. The other authors have declared that no competing interests exist.

[^2]: Conceived and designed the experiments: NB SO JD. Performed the experiments: NB SO. Analyzed the data: NB DP FF. Contributed reagents/materials/analysis tools: DP FF FP. Wrote the paper: NB FP JD.
