Time to Pregnancy in Multiple Sclerosis: A Case-Control Study

Special Article - Multiple Sclerosis

Austin J Clin Neurol 2017; 4(6): 1123.

Time to Pregnancy in Multiple Sclerosis: A Case-Control Study

Cuello JP¹*, Romero Delgado F¹, Lozano Ros A¹, Salgado Camara P¹, Garcia Dominguez JM¹, Higueras Y¹, Goicochea Briceño H¹, Garcia-Tizon Larroca S², De Leon-Luis J², Martinez Gines ML¹

¹Department of Neurology, Hospital General Universitario Gregorio Marañón, Spain

²Department of Gynecology, Hospital General Universitario Gregorio Marañón, Spain

*Corresponding author: Cuello Juan Pablo, Department of Neurology, Juan Pablo, Hospital General Universitario Gregorio Marañón, Calle Doctor Esquerdo 47, Madrid, CP 28007, Spain

Received: July 14, 2017; Accepted: August 17, 2017; Published: September 05, 2017


Multiple sclerosis (MS) is the most common degenerative neurologic disorder in young adults, with a female predominance. A couple’s fertility is inherently uncertain. Time to Pregnancy (TTP) refers to the number of menstrual cycles exposed to unprotected intercourse until conception. In normal couples, the cumulative pregnancy rate after 6 months is near 75%. With increasing TTP, there is an important decline in conception rate per cycle. In MS, TTP can be used to a better birth planning regarding pharmacotherapy.

Methods: Case-control, longitudinal study. Pregnancies between 2007- 2016 was included. Demographical data and clinical characteristics of MS patients were analyzed by medical records and patients interview.

Results: 54MS patients and 64 controls were included consecutively. No differences in demographical data were found, except for a higher proportion of primiparous in the control group. We found no differences in TTP between groups. The majority of pregnancies occur during the first 6 months (75%).

Discussion: None of the DMT is approved during pregnancy, and some need a mandatory washout period, to avoid fetal harm. The washout period entails the risk of MS reactivation. We found no significant difference in TTP between MS patients and controls, occurring the majority of the pregnancies during the first six months. These results further suggest that there is no direct impact of MS on fecundity when comparing to healthy age-matched women. In MS patients, knowing the usual TTP could be important, because there is an increased risk of relapse in those patients where the DMT were withdrawn.

Keywords: Multiple sclerosis; Pregnancy; Time to pregnancy; DMT; Washout period


Multiple sclerosis (MS) is the most common degenerative neurologic disorder in young adults, with at least 2.5 million individuals affected worldwide. The disease shows a female predominance that now approximates 3 to 1. Nowadays, pharmacotherapy is probably one of the most important issues regarding pregnancy in MS [1]. Fecundity refers to the biological ability to give birth. It is estimated for a population by the Time to Pregnancy (TTP), which refers to the number of menstrual cycles exposed to unprotected intercourse until conception. In normal couples, the fecundity, or the chance to achieve a pregnancy within one cycle, is 20% [2,3]. While the process of attempted conception over time can be modeled as occurring in continuous time, it has been proposed to model the process as one that occurs over successive discrete menstrual cycles [4]. This is because most of the pregnancies occur within the first six menstrual cycles. In fact, in normal fertile couples, the cumulative pregnancy rate after 6 months ranges from 75 to 90% [2,5,6]. A TTP of 12 months or more is often used as a measure of sub fecundity [7]. TTP estimations are important to find suitable thresholds to determine the prevalence of subfertility. These thresholds are used as the major indicator for timing routine infertility investigations and eventually starting treatment [5]. In MS, TTP can be used to a better birth planning regarding pharmacotherapy. Nowadays there are distinct approved disease-modifying therapies (DMT) for relapsing forms of MS, which encompass many different mechanisms of action. None of the DMTs are approved for use in women who are actively trying to become pregnant and most of them are not recommended for use in patients who are pregnant or trying to become pregnant. In addition, none of the DMTs are approved during lactation. The use of DMT before pregnancy is now common in many MS patients, and it has been suggested that its use might affect postpartum relapses incidence [8,9]. A study, using the MS Base global registry, reported that prior DMT use, any time in the 2 years before pregnancy, resulted in a 45% decreased risk for postpartum relapse [10]. Our aim is to analyze TTP in an MS cohort and to compare their results with healthy age-matched controls. Knowing the usual TTP in MS could help us planning an appropriate personalized strategy, which may include an adequate DMT washout period to minimize the risk of a relapse rebound and to avoid iatrogenic harm.

Material and Methods

We conducted a retrospective case-control, longitudinal study. Patients with diagnosis of MS admitted at the Hospital General Universitario Gregorio Marañón of Madrid, Spain, who have had a pregnancy between2007 to 2016, have been included [11]. MS diagnosis was based on the McDonald criteria and the 2010 revisions to these criteria, depending on the date of diagnosis [12]. All patients were evaluated at our MS clinic once pregnancy was confirmed. Neurological assessments were conducted every 3 months during pregnancy and at 3 months after delivery. During this period, patients were evaluated for the appearance of any worsening in their neurological status, suggestive of relapse or disease progression. Besides, they were instructed to report any symptoms that could arise in between the scheduled visits. The appearance, reappearance or worsening of focal neurological signs lasting more than 24 hours in the absence of fever was regarded as a relapse. Demographical data and clinical characteristics of MS patients were collected from their medical files, and gathered the following data: maternal age at conception, clinical form of MS, disease progression in years, annualized relapse rate (ARR)2 years prior conception, the degree of disability according to the Kurtz ke EDSS, and history of pharmacological treatment [13]. All neurologists with Neurostatus e-Test certification performed the neurological examination on each visit [14]. Reproductive history and potential confounders were also analyzed by medical records or using self-questionnaires that were completed during the outpatient appointment and included the number of prior pregnancies, prior live births and if the pregnancy was planned. Time to Pregnancy was assessed by a retrospective recall. The control group was randomly selected from among all pregnant women attended at our institution during the study period. All participants were attended by the hospital’s gynecology department and received the standard prenatal and postnatal care. All patients were informed and approved to participate in this study prior inclusion. Each patient signed an informed consent form for participation in the study. Our hospital ethical committee approved the realization of this study. Continuous variables were expressed as either means ± SD or means and ranges. Normal distribution was assessed with the Kolmogorov-Smirnov test. To compare means between 2 groups, we used parametric (t-test) and non-parametric tests (Mann-Whitney U test), depending on whether or not data was normally distributed and on the total number of patients of each group. TTP was recorded as months, and its distribution was described as the cumulative proportion of pregnancies occurring up to a given waiting time. Statistical analysis was conducted using SPSS version 21.0 and statistical significance was set at p <0.05.


Fifty-four women with MS were included consecutively and 64 controls. Demographical data and reproductive history of the MS patients and the controls group are shown in (Table 1). No differences in the general demographical data were found between both groups, except for the proportion of primiparous, being higher in the control group (p 0.02), which might reflect that the MS patients prefer to start earlier their reproductive life planning. The clinical characteristics of the MS group are shown in (Table 1 and 2). Twenty seven (50%) MS patients were treated with DMT prior pregnancy, most of them with Interferon Beta formulations. Eight (14.8%) patients were treated with subcutaneous Interferon Beta-1a, 6 (11%) with intramuscular Interferon Beta-1a, 5 (9%) with Interferon Beta-1b, 6 (11%) with Glatiramer Acetate, 1(2%) with Fingolimod and 1 (2%) with Natalizumab. Mean time on DMT was of 20 months (range 2-130 months). All MS patients who had a planned pregnancy underwent a controlled wash out strategy, depending on which DMT they were on. They were instructed to wait at least 1 menstrual cycle until start conception in all DMT cases, except the patient on Fingolimod, who completed a wash out period of 2 cycles. After the treatment withdrawn, the mean delay until having a positive pregnancy test was of 3 months (range 1-24 months). Nine (16%) MS patients presented an unplanned pregnancy during DMT treatment, being 3 (5%) patient sunder Glatiramer acetate, 2 (4%) on subcutaneous Interferon Beta- 1a, 2 (4%) on intramuscular Interferon Beta-1a, 1 (2%) on Interferon Beta-1b and 1 (2%) on Natalizumab. No serious adverse effects were reported in any of their 9 cases. Their pregnancies developed without complications, deliveries were normal and newborns were healthy. After analyzing the TTP in MS patients and the control groups with the Kolmogorov-Smirnov test, we found that the parameters have a not normally distribution, so we used the Mann-Whitney U test for comparing them. We found no differences in TTP between both groups. The majority of pregnancies occur during the first 6 months (70-75%), as it is shown by the cumulative distribution of TTP (Table 3).