A Real-World Prospective Multiple Sclerosis Pregnancy Registry in the United States: PREG-MS.

Background and Objectives Multiple sclerosis (MS) affects more than 1 million people in the United States, including reproductive-age women. There has been a paucity of prospective, pregnancy registries based on MS disease rather than medication exposures. A prospective MS pregnancy registry (PREG-MS) was established in 2017 as a prospective, single-cohort, real-world MS pregnancy registry in New England States of the United States, with goals to evaluate (1) course of MS and disease-modifying therapies (DMT) use during conception attempts and in the peripartum period, (2) pregnancy outcomes in women with MS (WwMS), and (3) longer-term developmental outcomes in offspring of WwMS.

Between 2017 and 2020, PREG-MS recruited from 11 preselected academic and community MS centers and followed WwMS and their children from conception attempts and any pregnancy trimester, up to 3 years of postpartum. Comprehensive neurologic, obstetric, and pediatric development information was collected through telephone interviews and medical records.

One hundred forty-six patients were enrolled between 2017 and 2020; there were 122 pregnancies from 135 participants, and 105 infants were born on study. 24.6% pregnancies were unplanned; 14.1% had an infertility diagnosis. Assisted reproductive technologies were used by 12.6%. 54% of pregnancies were designated as “high-risk”, and ∼40% had peripartum obstetrical complications with 17% adverse pregnancy outcomes. Mean baseline Expanded Disability Status Scale was 1.09 ± 0.84. ∼85% were treated with DMTs up to the time of conception. 19.7% had 1 or more relapses within prepregnancy year, correlating with increased duration of conception attempts (p < 0.0001). 12% had intrapartum, and 24.5% had postpartum relapses. Any fertility treatments predicted intrapartum relapses independent of DMT status (OR 5.18, 95% CI 1.58–17.02, p = 0.007). 33.6% were exposed to DMTs in pregnancy. Intrapartum relapses (p = 0.008) and high-risk pregnancy (p = 0.036) were associated with postpartum exacerbations.

Our real-world, prospective, nondisabled MS pregnancy cohort had a sizable proportion of participants with clinical disease activity in the prepartum and intrapartum period, despite high-DMT utilization prepartum. A greater-than-expected number of participants were considered to have high-risk pregnancies and reported peripartum complications. The use of any fertility treatments was independently predictive of intrapartum relapses, supporting hormonal-immune interactions as disease modulators in MS. Larger prospective, longitudinal registries are needed to confirm our findings. Trial Registration Information Clinical trial registration number: NCT03368157.

Multiple sclerosis (MS) is a chronic demyelinating inflammatory autoimmune disease of the CNS. In the United States, approximately 1 million people are affected with a 3:1 female-to-male predominance.1 Peak disease onset is at approximately 30 years of age, and up to 33% of women become pregnant after the diagnosis.2-4 A landmark paper established a reduction of the relapse rate (RR) during pregnancy followed by RR increase 3–6-month postpartum.5 Investigations into long-term effects of childbearing on MS outcomes do not show any negative effect and may suggest a possible correlation with delayed disability progression.6-9 Many disease-modifying therapies (DMTs) have worldwide pregnancy registries that aim to understand possible risks and adverse pregnancy and pediatric outcomes in cases of pregnancy exposures to specific DMTs.10-15 However, in the United States, there has been a paucity of prospective, longitudinal registries that collect obstetric, neurologic, and pediatric outcomes for women based on a disease state MS rather than medication exposures. It remains important to prospectively evaluate the MS, pregnancy, and pediatric outcomes considering the complexities of current MS treatment landscapes and a reported increase in pregnancy rates among patients with MS over the past decade.16 This real-world prospective MS pregnancy registry (PREG-MS) was conceptualized to fulfill this unmet need for high-quality, prospective information. PREG-MS was established in 2017 with goals to prospectively (1) evaluate the course of MS and DMT use during conception attempts and in the peripartum period, (2) identify predictors of peripartum relapses, (3) assess pregnancy outcomes in women with MS (WwMS), (4) document the timing of resumption of DMT postpartum, and (5) determine the longer-term developmental outcomes in offspring of WwMS.

PREG-MS Study Design PREG-MS followed WwMS and their children from active conception attempts (ACAs) and any stage of pregnancy up to 3 years of postpartum. In this article, the study population (WwMS) specifically refers to the participants who self-reported biological female sex. Transgender men who were biologically capable of pregnancy were not included in this cohort because none were referred to the study. Patients were recruited from 11 preselected academic and community MS centers throughout the 5 New England states of the United States. Women with confirmed MS diagnosis by McDonald criteria who were either pregnant or involved in ACA were referred to join the registry by their primary neurologists.17 Patients were contacted by either the principal investigator (Houtchens) or the research assistant to explain the study protocol and obtain informed consent. Investigators collected information on demographics, social status, diet and habits, MS-specific variables, medication exposures, comorbidities, fertility, pregnancy and postpartum outcomes, and information related to pediatric health and development for up to 3 years of follow-up. All data were collected through structured telephone interviews and were validated with medical records. Telephone interviews were conducted every 3 months during ACA and at each pregnancy trimester, on delivery, and in the postpartum period. Pediatric information was collected at 2 weeks of postpartum and at 2, 4, 6, 9, 12, 18, 24, and 36 months of postpartum, corresponding to routine pediatric “well-visits” (Table 1). Data have been organized and stored in Research Electronic Data Capture, a clinical and translational research database software.18 Data management was performed through LabArchives, a web-based Health Insurance Portability and Accountability Act compliant application. Table 1. | Intake interview | 3 mo preg | 6 mo preg | 9 mo preg | 2 mo postpartum | 4 mo postpartum | 6 mo postpartum | 9 mo postpartum | 12 mo postpartum | 18 mo postpartum | 24 mo postpartum | 36 mo postpartum | | | Demographics | X | X | X | X | X | X | X | X | X | X | X | X | | Personal medical/surgical history | X | X | X | X | X | X | X | X | X | X | X | X | | Neurologic disease history | X | X | X | X | X | X | X | X | X | X | X | X | | Reproductive history | X | X | X | X | X | X | X | X | X | X | X | X | | Medical treatments | X | X | X | X | X | X | X | X | X | X | X | X | | Hospital admission record | X | X | X | X | X | X | X | X | X | X | X | X | | Medical family history | X | ||||||||||| | Diet | X | X | X | X | X | X | X | X | X | X | X | X | | Current pregnancy | X | X | X | X | |||||||| | Pregnancy and delivery | X | ||||||||||| | Pediatric birth record | X | ||||||||||| | Pediatric hospital admission record | X | X | X | X | X | X | X | X | |||| | Pediatric developmental milestones | X | X | X | X | X | X | X | X | Abbreviation: preg = pregnancy. This table illustrates the timeframe, and the key data categories collected throughout the study period. Standard Protocol Approvals, Registrations, and Patient Consents The registry was approved by the Institutional Review Board (IRB) at the Brigham and Women's Hospital (BWH) and by each referral site. Participants consented to the study before the intake interview as per the IRB protocol and signed medical release forms to obtain medical records from neurologists, obstetricians, and pediatricians throughout the study. The study was registered on the clinicaltrials.gov portal (Clinical trial registration number: NCT03368157). Study Participants Patient recruitment began in early 2017; this analysis reflects data capture through October 2020. Further data collection was hindered by the COVID-19 pandemic. Women with a diagnosis of MS according to the McDonald criteria who were either pregnant or actively planning to become pregnant, and who received neurologic care at one of the eleven selected centers, were eligible to enroll in the study. Women who were unable to give the informed consent or pediatric assent due to severe cognitive impairment were excluded from the PREG-MS study. Neurologic Measures Participants' antepartum, peripartum, and postpartum MS course was recorded, including age at disease onset, disease duration, dates of clinical visits, MRI results, MS relapses, Expanded Disability Status Scale (EDSS), and prior and ongoing DMTs, including DMT washout periods (time between DMT cessation and conception), DMT exposure (treatment received after confirmed conception), and length of pregnancy DMT exposure (time between conception and cessation of DMT) (Table 2).19 This information was confirmed with the treating neurologists and through a medical record review. EDSS scores were calculated based on a neurologic record review by the study principal investigator or were taken directly from the medical records based on assessment of the treating neurologist, when available.19 Relapses were adjudicated through patient's reports and confirmatory neurologic records from the treating neurologist. MRI outcomes were assessed through radiology MRI reports. Table 2. | Mean age, y | 33.5 ± 4.27 | | Mean age at disease onset, y | 25.0 ± 6.89 | | Mean disease duration, y | 7.64 ± 5.13 | | Mean baseline EDSS score, (range 0—3.5) | 1.09 ± 0.84 | | Baseline brain MRI, n (%) | | | No new lesions | 102 (76.6) | | New T1 gadolinium-enhancing lesions | 15 (11.1) | | New T2 lesions | 13 (9.2) | | Not administered | 5 (3.6) | | Baseline cervical spine MRI, n (%) | | | No new lesions | 74 (54.8) | | New T1 gadolinium-enhancing lesions | 1 (0.7) | | New T2 lesions | 9 (6.7) | | Not administered | 51 (37.8) | | Relapses during ACA, n (%) | 9 (6.7) | | aRelapses in the year preceding pregnancy, n (%) | 24 (17.8) | | Months 9–12 | 7 (29.2) | | Months 6–9 | 4 (16.7) | | Months 3–9 | 5 (20.8) | | Months 1–3 | 8 (33.3) | | DMT before pregnancy, n (%) | | | No treatment | 14 (10.4) | | Glatiramer acetate | 26 (19.3) | | Interferon b-1a | 7 (5.2) | | Dimethyl fumarate | 26 (19.3) | | Fingolimod | 11 (8.1) | | Alemtuzumab | 4 (3.0) | | Natalizumab | 19 (17.8) | | Ocrelizumab | 17 (12.6) | | Rituximab | 9 (6.7) | | Pegylated interferon b-1a | 2 (1.5) | | aPregnancy exposed to DMT (n = 41), n (%) | | | Glatiramer acetate | 14 (34.1) | | Dimethyl fumarate | 8 (19.5) | | Fingolimod | 2 (4.9) | | Pegylated interferon b-1a | 1 (2.4) | | Natalizumab | 7 (17.1) | | Ocrelizumab | 7 (17.1) | | Rituximab | 2 (4.9) | | aMean treatment washout period (n = 62), wk | 61.2 ± 78.0 | | aMean treatment exposure period (n = 38), wk | 8.88 ± 9.46 | | aMean pregnancy EDSS (range 0–3.5) | 0.98 ± 0.80 | | aRelapses during pregnancy | 15 (12.3) | | First trimester | 4 (26.7) | | Second trimester | 5 (33.3) | | Third trimester | 6 (40.0) | | bMean postpartum EDSS (range 0–6) | 1.08 ± 1.12 | | bPostpartum brain MRI | | | No new lesions | 65 (63.7) | | New T1 gadolinium-enhancing lesions | 8 (7.8) | | New T2 lesions | 12 (11.8) | | Not administered | 17 (16.7) | | bPostpartum cervical spine MRI | | | No new lesions | 61 (59.8) | | New T2 lesions | 3 (3.9) | | Not administered | 38 (37.3) | | bPostpartum relapses, n (%) | 25 (24.5) | | Months 1–3 | 8 (32.0) | | Months 3–6 | 4 (16.0) | | Months 6–9 | 6 (24.0) | | Months 9–12 | 1 (4.0) | | Months 12–24 | 6 (16.0) | | bDMT postpartum, n (%) | | | No treatment | 32 (31.4) | | Glatiramer acetate | 12 (11.8) | | Interferon b-1a | 3 (2.9) | | Pegylated interferon b-1a | 2 (2.0) | | Dimethyl fumarate | 13 (12.7) | | Fingolimod | 6 (5.9) | | Teriflunomide | 1 (1.0) | | Alemtuzumab | 1 (1.0) | | Natalizumab | 8 (7.8) | | Ocrelizumab | 20 (19.6) | | Rituximab | 4 (3.9) | Abbreviations: ACAs = active conception attempts; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; MS = multiple sclerosis. Values are mean ± SD when appropriate. This table presents the baseline demographics and the baseline MS characteristics of the participants enrolled in the registry. The data are categorized into demographic details and clinical, imaging, and treatment disease characteristics relevant to the study population. For participants who are pregnant or in the postpartum phase at the time of analysis (n = 122). For participants who gave birth at the time of analysis (n = 102). Obstetric Measures Participants' reproductive history was noted at the time of the intake interview. For ongoing pregnancy, duration of ACAs, use of assisted reproductive technologies (ARTs) and fertility treatments, routine pregnancy care and related testing, and any complications were recorded. Postpartum interviews were conducted 2 weeks after delivery, and information (date of birth, type of labor and delivery, use of anesthesia, birth presentation, and birth complications) was recorded (Table 3). This information was also validated with the obstetrics medical records. Table 3. | Parity, nullipara, n (%) | 55 (40.7) | | Age at menarche, y | 12.94 ± 1.70 | | Advanced maternal age, n (%) | 57 (42.2) | | Active conception attempts, mo (range 0–38) | 3.86 ± 6.29 | | Cause of infertility (n = 19), n (%) | | | Unknown | 5 (26.3) | | Advanced maternal age | 2 (10.5) | | Endometriosis | 6 (31.6) | | Polycystic ovarian syndrome (PCOS) | 4 (21.1) | | Other (Infertility due to male factor) | 1 (5.3) | | Oligomenorrhea | 1 (5.3) | | Assisted reproductive technology (n = 17), n (%) | | | In vitro fertilization | 12 (70.6) | | Intrauterine insemination | 4 (23.5) | | Intracytoplasmic sperm injection (ICSI) | 1 (5.9) | | Received no routine obstetrical care throughout pregnancy (%) | 3/122 (2.45) | | Delivery information, (n = 102) | | | Single birth, n (%) | 99 (97.1) | | Gestational age at delivery, wk | 38.9 ± 2.52 | | Type of labor and delivery | | | Spontaneous labor and vaginal delivery, n (%) | 41 (40.2) | | Induction of vaginal delivery, n (%) | 27 (26.5) | | Reasons for induction of vaginal delivery | | | Postdates | 7 (25.9) | | Gestational hypertension | 3 (11.1) | | Oligohydramnios | 2 (7.4) | | Intrauterine growth restriction | 1 (3.7) | | Preeclampsia | 1 (3.7) | | Premature rupture of placental membrane | 2 (7.4) | | Presumed chronic abruption of placental membrane | 1 (3.7) | | Start of DMT | 1 (3.7) | | Unknown reasons | 7 (25.9) | | Presumed fetal macrosomia | 1 (3.7) | | Fetal distress | 1 (3.7) | | Planned caesarean delivery (CD), n (%) | 22 (21.6) | | Reasons for scheduled CD | | | Fetal distress | 5 (22.7) | | Repeat of CD | 4 (18.2) | | Maternal request | 3 (13.6) | | Placenta previa | 3 (13.6) | | Multiple gestation | 1 (4.5) | | Myomectomy surgical history | 3 (13.6) | | Unknown reasons | 2 (9.1) | | Uterine fibroids | 1 (4.5) | | Presumed fetal macrosomia | 1 (4.5) | | Induction of labor (IOL) and caesarean delivery (CD), n (%) | 6 (5.9) | | Reasons for IOL and CD | | | Postdates and fetal destress | 3 (50.0) | | Possible MS relapse and failure to progress | 1 (16.7) | | Preeclampsia | 1 (16.7) | | Unknown reasons | 1 (16.7) | | Spontaneous labor and caesarean delivery, n (%) | 6 (5.9) | | Reason for spontaneous labor and CD | | | Fetal position | 5 (83.3) | | Failure to progress | 1 (16.7) | | Delivery anesthesia, n (%) | | | No anesthesia | 18 (17.6) | | Epidural anesthesia | 57 (55.9) | | Spinal anesthesia | 23 (22.5) | | General anesthesia | 2 (2.0) | | Pudendal anesthesia | 2 (2.0) | | Normal birth presentation, n (%) | 68 (66.7) | | Instrumental delivery, n (%) | 3 (2.9) | | Sex of infant, female, n (%) | 47 (44.8) | | APGAR score at 1 min (range 2–9) | 8.25 ± 0.96 | | APGAR score at 5 min (range 5–10) | 8.80 ± 0.56 | | Infant birth weight, lbs | 7.22 ± 1.52 | | Infant birth length, inches | 19.97 ± 3.99 | | Infant birth head circumference, inches | 13.82 ± 3.84 | Abbreviations: APGAR = appearance, pulse, grimace, activity, and respiration; DMT = disease-modifying therapy; MS = multiple sclerosis. This table presents data on the obstetrical measures of the study population, encompassing the categories of fertility and assisted reproduction, pregnancy and delivery outcome, obstetrical anesthesia, and immediate neonatal outcomes. Pediatric Measures Infants' anthropometric measurements (weight, length, and head circumference); appearance, pulse, grimace, activity, and respiration (APGAR) scores; intercurrent illnesses; and feeding habits were recorded from birth to 3 years of age and verified with the pediatric records. In addition, following the Center for Disease Control and Prevention Child Development milestone standards, developmental outcomes were evaluated prospectively with the mothers during the interviews.20 Statistical Analysis Descriptive statistics (mean, SD, and percentages) were adopted to describe the cohort. The effects of maternal neurologic and obstetrical measures on the duration of conception attempts were assessed using the independent sample t test for categorical variables and Pearson correlation for continuous variables. An analysis of variance (ANOVA) was performed to compare women with and without an intrapartum relapse in maternal age at conception, length of conception attempts, age at disease onset, disease duration at conception, DMT washout length, and length of DMT exposure. Additional ANOVA using the same variables was performed to compare women with and without a postpartum relapse. If a significant difference was found between groups, the analysis of covariance was adopted to adjust for the type of DMT used before conception. The correlation between the types of DMTs used before conception and the occurrences of intrapartum and postpartum relapses were evaluated with the Fisher exact test because of the small sample size of each group with unique DMTs. Furthermore, we looked for predictors of intrapartum and postpartum relapses. Multivariate logistic regression models were constructed to identify the probability of the outcome. Statistical analyses were performed with SPSS V. 27 (IMB SPSS, 2020), and p values <0.05 were considered statistically significant. Data Availability Anonymized data not published within this article will be made available by request from any qualified investigator.

By October 2020, 225 participants were referred to the study; 146 patients were reachable, agreed to participate, signed informed consent, and have been actively enrolled in the study; validated health information had been collected for 135 women. 105 babies were born during the study period (Figure 1). Further recruitment became difficult because of the COVID-19 pandemic. 33.5% and 13.6% of the participants did not answer questions about their racial and ethnic background, respectively. Of the remaining participants who responded to these questions, 5% self-identified as Black, 2% self-identified as Pacific Islander, and 7.2% were of mixed race. 15% of the participants self-identified as Hispanic or Latino. Obstetric Outcomes Fertility and Prepartum Conception attempts lasted 3.86 ± 6.29 months resulting in 122 pregnancies from 135 participants. Thirty of 122 (24.6%) pregnancies were unplanned. Nineteen (14.1%) women had an infertility diagnosis (Table 3) at the time of study enrollment, and 57 (42.2%) women were in advanced maternal age (AMA) (defined as ≥ 35 years at delivery). There was an expected correlation between these 2 variables (p = 0.047). Fifty-one of 57 (89.5%) women in the AMA category successfully conceived at the time of analysis. ART were used by 17 (12.6%) women (Table 3). Duration of conception attempts was lengthened by an infertility diagnosis (p = 0.001) but not increased by age (p = 0.993) or AMA designation (p = 0.646). Twelve of 57 (21.1%) women in the AMA category and 7/78 (9.0%) women younger than 35 had an infertility diagnosis. Pregnancy and Delivery At the time of analysis, 122 women either were pregnant or had given birth to 99 singletons, 2 monoamniotic monochorionic twins, 2 monozygotic twins, and 2 sets of monochorionic diamniotic twins. Average gestational age at delivery was 38.9 ± 2.52 weeks, 41 women (40.2%) had spontaneous vaginal deliveries (SVDs), 27 women (26.5%) had induction of vaginal deliveries, 22 participants (21.6%) had planned cesarean deliveries (CDs), and 12 participants (11.8%) had unscheduled CDs for obstetrical indications while laboring for expected SVD (Table 3). Eighteen women (17.6%) did not receive anesthesia during labor, while 84 women (82.4%) received some form of obstetrical anesthesia (Table 3). APGAR scores for the newborns were 8.25 ± 0.96 at 1 minute and 8.80 ± 0.56 at 5 minutes (Table 3). Fifty-one of 122 (41.0%) mild obstetric complications were reported (Table 4), with 9/51 (17.6%) resultant adverse pregnancy outcomes. One case of intrauterine growth restriction (IUGR) was explained by a diagnosis of Alazami syndrome (AS) in this infant by 12 months of age. Seven women (6.9%) delivered prematurely (Table 4) at 24.5 weeks, 27 weeks, and 33 weeks (4 women) due to primary obstetrical reasons. At the time of analysis, infants born at 24.5 weeks and 27 weeks were 24 months of age showed mild developmental gross motor function delays. There were no other developmental delays. One participant diagnosed with polyhydramnios delivered a healthy infant who later died of sudden infant death syndrome (SIDS) at 6 weeks of age. None of the complications were believed to relate to maternal neurologic disease. Table 4. | Complications | Number of cases (%) | Adverse pregnancy outcomes | | Gestational diabetes | 6 (4.9) | — | | Gestational hypertension | 5 (4.1) | — | | Gestational thrombocytopenia | 1 (0.8) | — | | Infections | 7 (5.7) | — | | Iron-deficiency anemia | 4 (3.3) | — | | Preterm labor | 6 (4.9) | Premature delivery (n = 6) | | Intrauterine growth restriction | 2 (1.6) | Infant diagnosed with Alazami syndrome by 12 mo of age (n = 1) | | Oligohydramnios | 2 (1.6) | — | | Placenta previa | 10 (8.2) | — | | Preeclampsia | 4 (3.3) | — | | Preterm premature rupture of membrane | 1 (0.8) | Intertwined fetal parts of monoamniotic-monochorionic twins and preterm delivery (n = 1) | | Polyhydramnios | 1 (0.8) | Infant died of SIDS (n = 1) | | Uterine fibroids | 1 (0.8) | — | | Velamentous cord insertion | 1 (0.8) | — | Abbreviation: SIDS = sudden infant death syndrome. Higher-than-expected rates of obstetrical complications and adverse pregnancy outcomes were not observed in PREG-MS cohort. Postpartum Eighty-two of 102 participants (80.4%) breastfed their infant for 5.32 ± 4.81 months. Exclusive breastfeeding status was not assessed. Fifty-seven of 82 participants (69.5%) ceased breastfeeding to restart MS treatment (50.9%), as a lifestyle choice (26.3%), due to unrelated medical or social reasons (15.9%), or for work-related reasons (7.0%). Neurologic Outcomes Prepartum Our cohort included 135 women with a baseline EDSS score of 1.09 ± 0.84, an average disease duration of 7.64 ± 5.13 years at the time of conception, and 115/135 (85.8%) were treated with DMTs before attempting ACA or pregnancy (Table 2). For women who had not conceived at the time of analysis, 1/13 (7.7%) reported having a relapse in the ACA phase. For participants who were pregnant or had delivered at the time of analysis, 24/122 (19.7%) had a relapse within the year preceding pregnancy. Of these, 8 women (33.3%) had a relapse while actively trying to conceive, and 14 women (66.7%) had a relapse within the 12 months preceding conception while not reporting ACAs. Of the 9 participants who had a relapse while actively trying to conceive, 5/9 (56%) received steroid treatment. For women who became pregnant, increased duration of conception attempts was predicted by having a relapse in the ACA phase (p < 0.0001) but was not lengthened by having a relapse in the year preceding conception (p = 0.071), by the timing of discontinuation of DMTs (p = 0.885), or by disease duration (p = 0.947). Intrapartum Thirty-four of 122 participants (27.9%) had early pregnancy (4.91 ± 2.51 weeks) DMT exposure to various pharmaceuticals. Four participants (3.3%) had ongoing glatiramer acetate (GA) exposure through the second and third pregnancy trimesters, and 3 participants had ongoing exposure to ocrelizumab exposure through 16–22 weeks' gestation (Table 2). Of the 41 DMT exposed pregnancies as defined by Food and Drug Administration product labels, 70.7% were unplanned pregnancies. Nine of the 41 pregnancies exposed to DMTs were considered high-risk by obstetrics team because of the DMT exposure. One infant with maternal exposure to fingolimod for the first 8 weeks of pregnancy was born with ventricular septal defect (VSD) that resolved spontaneously by 2 months of age. There was 1 case of IUGR in early-term GA exposure. In addition, obstetrics teams marked 22/122 pregnancies (18.0%) as “high-risk” exclusively because of known MS diagnosis, although DMT treatment was discontinued before conception. Eleven (9.0%) DMT-exposed pregnancies and 24 (19.7%) nonexposed to DMT pregnancies were designated “high-risk” for nonneurologic indications. There was no correlation between “high-risk” pregnancy designation and increased obstetrical complications (p > 0.05). Fifteen study participants (12.3%) had intrapartum relapses ranging from mild to severe as reported by participants and confirmed through the medical records. Eleven participants had sensory relapses, and 4 participants had optic neuritis. 26.7% of relapses occurred in the first trimester, 40.0% occurred in the second trimester, and 33.3% occurred in the third trimester. Relapses lasted for 3.83 ± 2.59 weeks. Eleven of 15 (73.3%) women received intravenous methylprednisolone 1 g for 1–5 days, 1 woman was treated with high-dose oral prednisone, and 1 woman was treated with glatiramer acetate. Six of 15 (40.0%) women who had an intrapartum relapse conceived through fertility therapies. For the entire cohort, women with (12.3%) and without intrapartum relapses did not differ based on age at conception, age at disease onset, disease duration, baseline EDSS, and length of ACA (p > 0.2). However, women who experienced an intrapartum relapse had a shorter DMT washout period (p = 0.001). After adjusting for the types of DMTs used before conception, only fingolimod preconception exposure correlated with the intrapartum relapses (p = 0.030). Following adjustment for maternal neurologic measures, the multivariate logistic regression model illustrated that the use of fertility therapies was predictive of intrapartum relapses (OR 5.18, 95% CI 1.58–17.02, p = 0.007) (Table 5). Individual types of DMTs were not predictive of intrapartum relapses (p = 0.993), most likely due to the small sample size once DMTs were categorized. Table 5. | Variable | Odds ratio | 95% CI | p Value | | Age at conception | 0.61 | 0.10–3.86 | 0.599 | | Age at disease onset | 1.05 | 0.96–1.14 | 0.311 | | Disease duration | 0.97 | 0.87–1.07 | 0.524 | | Baseline EDSS | 0.99 | 0.49–1.97 | 0.967 | | DMT washout period | 0.98 | 0.96–1.00 | 0.110 | | Relapse within 1 y before conception | 0.69 | 0.12–4.07 | 0.683 | | Use of fertility treatment | 5.18 | 1.58–17.02 | 0.007a | Abbreviations: DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale. The use of (any) fertility treatment was significantly correlated with intrapartum relapses in this cohort. Postpartum Participants received routine neurologic follow-up care at 13.8 ± 14.0 weeks of postpartum, and mean EDSS scores were rated at 1.08 ± 1.12 (Table 2). There was no difference between prepregnancy and postpartum mean EDSS (Table 2). Twenty-five of 102 (24.5%) women had a relapse in the postpartum period. Women with and without postpartum relapses were not different based on the age at conception, age at disease onset, disease duration, baseline EDSS, DMT washout period, or length of ACA (p > 0.4). A multivariate logistic regression model was used to evaluate for predictors of postpartum relapses after adjusting for maternal disease variables (Table 6). The model demonstrated that the occurrence of an intrapartum relapse (OR 4.71, 95% CI 1.50–14.78, p = 0.008) and designation of high-risk pregnancy due to MS diagnosis (OR 2.77, 95% CI 1.03–2.38, p = 0.036) were predictive of postpartum relapse. Postpartum EDSS scores were higher for women who experienced a postpartum relapse (p = 0.025). Table 6. | Variable | Odds ratio | 95% CI | p Value | | Age at conception | 0.99 | 0.88–1.11 | 0.803 | | Age at disease onset | 1.03 | 0.96–1.11 | 0.386 | | Disease duration | 0.98 | 0.89–1.07 | 0.613 | | Baseline EDSS | 1.38 | 0.86–2.22 | 0.186 | | DMT washout period | 1.00 | 1.00–1.01 | 0.763 | | DMT exposure during pregnancy | 0.66 | 0.26–1.72 | 0.397 | | Relapse within 1 y before conception | 1.48 | 0.53 | 0.416 | | Relapse while ACA | 2.49 | 0.52–11.97 | 0.255 | | Pregnancy EDSS | 1.60 | 0.84–2.76 | 0.084 | | Intrapartum relapse | 4.71 | 1.50–14.78 | 0.008a | | ACA duration | 1.03 | 0.92–1.17 | 0.607 | | Infertility Dx | 2.5 | 0.72–8.73 | 0.151 | | Use of fertility Tx | 3.60 | 0.95–13.68 | 0.060 | | High-risk pregnancy | 1.33 | 0.52–3.39 | 0.546 | | High-risk pregnancy due to MS | 2.77 | 1.03–2.38 | 0.036a | | Pregnancy complications | 0.95 | 0.38–2.34 | 0.907 | | Labor | 1.05 | 0.43–2.59 | 0.914 | | Delivery | 0.55 | 0.20–1.55 | 0.258 | | Epidural anesthesia | 1.97 | 0.76–5.10 | 0.164 | | Breastfeeding duration | 1.07 | 0.98–1.17 | 0.135 | Abbreviations: ACA = active conception attempt; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; MS = multiple sclerosis. Having an intrapartum relapse and a “high-risk pregnancy due to MS” designation by obstetrical providers was significantly correlated with postpartum relapses in this cohort. MRI studies were performed at 14.2 ± 12.1 weeks after delivery. Eight participants (7.8%) had new T1 gadolinium-enhancing lesions, 12 participants (11.8%) had new T2 lesions on a brain MRI, 3 participants had new T2 cervical spine MRI lesions, compared with prepregnancy MRI (Table 2). Only the occurrence of relapse during pregnancy was predictive of new brain and c-spine lesions (OR 5.21, 95% CI 1.50–18.10, p = 0.009). New cervical lesions also correlated with the use of any fertility treatments (p = 0.007). Seventy of 102 participants (68.6%) had restarted DMT by 23.7 ± 28.2 weeks after delivery. Sixty-four of 102 participants (62.7%) had restarted therapy within a year after delivery. Twenty-three women switched to a different DMT in the postpartum phase. At the time of analysis, 77 of 102 participants who breastfed (35.2%) deferred DMT use to breastfeed their infant. Pediatric outcomes were previously reported elsewhere (Figure 2).20

PREG-MS cohort had minimal MS-related neurologic disability, yet a substantial number of patients suffered a relapse in the peripartum period (17.8% prepartum, 12.3% intrapartum, and 24.5% postpartum) (Table 2). In the past 2 decades, few studies have prospectively reported prepartum, intrapartum, and postpartum RRs.5,21-25 Historically, the reported peripartum RR has been shown to be even higher than in PREG-MS, but earlier studies reflected largely untreated cohorts. Despite the differences in study designs, and between the cohorts, the fundamental relationship between the RR and pregnancy remains similar and suggests a reduction of relapses during pregnancy, and an increase in the postpartum phase. In contrast to antecedent information, the lower RRs in the PREG-MS cohort could be explained by an overall decrease in annual exacerbations in the new treatment era. 85.8% of the PREG-MS cohort followed a therapy course known to effectively reduce relapses.26-28 The relationship between relapses occurring in the ACA phase and the effect they have on the time to successful conception has not yet been elucidated. In our cohort, the presence of any clinical relapse in the ACA phase correlated significantly with increased time to conception, irrespective of the need for steroid therapy. This was observed independent of the timing of DMT discontinuation before attempting conception. Methylprednisolone, most commonly used for MS relapse treatment, is not known to have a significant effect on fertility, but there is a general paucity of data on this subject.29 It is likely that factors other than direct fertility effects contributed to increased time to conception in patients with prepartum MS exacerbations. Aside from possible relapse-related neurologic dysfunction, there are known negative effects of MS exacerbations on quality of life and mental health status of patients with MS. A study comparing participants with a recent relapse with those in remission illustrates a significant postrelapse deterioration in patient-reported outcomes across multiple domains, including vitality, social functioning, and emotional well-being.30 It seems likely that the emotional effect and associated reduction in quality of life from relapses could affect conception attempts through multiple mechanisms, resulting in increased time to conception. Previous studies suggested a possible correlation between the use of ARTs and MS disease activity. Gonadotropin-releasing hormone (GnRH) agonists used in in vitro fertilization infertility protocols have been linked to an increase in relapses 3 months after treatment, if no pregnancy ensued.31,32 Others reported an association between the failed fertility protocols using either GnRH agonists or antagonists and an increase in subsequent relapse risk.33 A recent retrospective multicenter study did not find an association between ART use and relapses in patients with MS during, or after pregnancy.34 We observed that conception through ART was predictive of intrapartum relapses and new MRI lesions in the postpartum period. Many previous observations reporting on the relationship between ART protocols and RR suffered from a small sample size and, often, retrospective nature of the analysis; thus, a change in RR in pregnancy, and beyond, after ART had been difficult to ascertain prospectively.31-33 Investigators have partially attributed the association between use of ART and increased RR to the stress of fertility protocols.33 Stressful events, in general, have been reportedly associated with increased RR.35 The stress and unpredictability of undergoing fertility treatments regardless of fertility outcome could in part explain an increase in disease activity. Relapses may also be triggered by the sudden decrease in estrogen levels occurring after the failure of ART, or delivery in with physiologic pregnancies. However, the mechanism underlying our observation of increased intrapartum RR after ART, independent of DMT, is not well understood. Caution should be exercised in interpreting these findings, due to a small number of study participants who used the ART, and WwMS should not be discouraged from using fertility therapies to achieve pregnancy. Furthermore, a wide-spread use of monoclonal B-cell depleting treatments throughout peripartum period, more prevalent since the conclusion of this study, is likely to increase the safety of ART in WwMS. This finding should be further investigated with large-scale, prospective studies. Twenty-nine women had an unplanned pregnancy that resulted in DMT-exposed pregnancies and shorter-than-recommended washout times, associated with intrapartum relapses (p = 0.001). As consistently reported by other investigators, preconception fingolimod treatment cessation correlated with intrapartum relapses (p = 0.03) in our cohort. A small number of participants on natalizumab likely explain why an increase in RR posttreatment-withdrawal was not observed in our study. Postpartum RR in our sample was 24.5%, similar to previously reported.5 Historically, disease stability prepartum, DMT use, and breastfeeding status were known correlates of the postpartum relapse risk. We identify 2 additional predictors of postpartum relapses: intrapartum relapses and designation of high-risk pregnancies due to maternal neurologic disability. These factors could be used to help select the optimal timing of DMT reinitiation postpartum. For participants who conceived successfully, 76.2% were pregnant within 3 months, similar to the general population (68% rate of conception in 3 months).36 Nine significant adverse peripartum pediatric events (7.4%) were identified in our cohort, including AS and SIDS. AS is a novel form of primordial dwarfism characterized by a mutation in LARP7.37 There is no definitive link between maternal MS diagnosis and either AS or SIDS.38,39 This rate of peripartum pediatric adverse events is similar to the general population. Up to 50% of pregnancies in the United States are unplanned.40 Treatment discontinuation for some DMTs, including interferon b-1a, glatiramer acetate, and dimethyl fumarate, is usually advised at the time of pregnancy confirmation, while specific washout guidelines are recommended for other DMTs before conception attempts.40 Currently, the medication labels recommend to discontinue fingolimod 2 months prior, natalizumab 3 months prior, alemtuzumab 4 months prior, and ocrelizumab and rituximab 6 months before conception.41-43 However, the standards of practice for prepartum DMT discontinuations vary between MS providers, and unintended pregnancies can further change the early pregnancy DMT exposures.44 In our cohort, 33.6% participants did not discontinue DMTs as per the labels and had either first trimester or full-pregnancy exposure to DMTs. There was no increase in maternal or infant postpartum complications specifically related to these exposures. Patients with MS are known to display a 70% higher rate of IUGR compared with healthy women.43 However, only 1 patient with GA exposure throughout pregnancy had an IURG, unlikely related to such exposure.10,44-47 A recent analysis reported no definite increased risk of major congenital malformations in infants born after fingolimod exposure in comparison with healthy women.48 However, it is known that fingolimod interacts with the receptors involved in vascular formation during embryogenesis, and cardiac abnormalities have been seen in preclinical studies in rats and in previously reported human cases.44,49,50 One infant with exposure to fingolimod had a transient VSD in our cohort. Historically, maternal MS did not seem to be associated with adverse pregnancy or delivery outcomes.16,49,50 A recent study reviewed medical insurance claims for more than 2,000 MS pregnancies and compared the outcomes with age-matched healthy women. A higher-than-expected rates of preterm labor, infections, anemia and acquired coagulation disorders, cardiovascular disease, neurologic complications, acquired damage to the fetus, and congenital hereditary fetal malformations were observed in MS cohort.51 This observation will require further confirmation through larger prospective MS pregnancy registries. PREG-MS cohort has shown generally favorable outcomes, although ∼40% of observed pregnancies had (generally, mild) peripartum obstetrical complications, consistent with retrospective claim-based report. An earlier study has shown that MS mothers are 1 to 4.85 times more likely to have operative deliveries including the use of forceps, vacuum extractor, or CD.52 At the time of analysis, 3 participants' delivery required forceps and 34 participants (33.3%) had CDs (Table 3). Our cohort has a similar rate of CDs when compared with the general US population (33.3% vs 31.9%).52 General pediatric outcomes of the cohort were reported separately.20 Our study has several important limitations: a sizeable proportion of women initially referred to the study, were lost to follow-up, did not return our calls, or declined to participate. Recruitment to the study had to be halted prematurely with the onset of COVID-19 pandemic. Therefore, the overall number of study participants was smaller than initially anticipated. It is possible that the results of the study would have been different if all participants who were referred to the study, completed all study timepoints, and if the study were able to be continued for additional time, as initially planned. Twenty-three of 225 prospectively referred participants suffered a miscarriage and were not enrolled in the study (Figure 1). This group of participants was not independently analyzed, introducing a potential selection bias to the cohort, and this is another important study limitation (Figure 1). The study, while comprehensive and up to date, does not take into consideration the rapidly changing therapeutic MS landscape, as initial recruitment started in 2017, and before the wider use of B-cell depleting agents in reproductive-age WwMS. Since the conclusion of this study, the use of monoclonal antibody therapies, especially B-cell depleting therapies, has greatly increased, and many neurologists resume these DMTs soon after delivery, in addition reducing the risk of postpartum exacerbations. Furthermore, recruitment, timely follow-up, and analysis efforts were interrupted by the COVID-19 pandemic, and continuous recruitment into the cohort could have also change the results. Although this cohort reflects the uniformity of the geographic region (the Northeast United States), participants were recruited from different clinics and providers, possibly resulting in nonuniform practice patterns by neurologists and obstetricians, which also has the potential to skew the results. In addition, racial and ethnic minorities were underrepresented in our cohort, and a significant number of participants did not respond to questions about their racial and ethnic background, limiting our ability to analyze race-specific and ethnicity-specific pregnancy outcomes. Our results might, therefore, not be reflective of racial and ethnic pregnancy outcome disparities, well documented in the general population, and among WwMS, and this is a significant limitation of our work. Furthermore, the higher mean age at pregnancy in this registry than the mean age of pregnancy in the United States (27 years), and the high rate of prenatal care may reflect a regional bias, which may have also contributed to the positive pregnancy outcomes in this cohort. PREG-MS adds to a body of literature on prospective, longitudinal real-world investigations of pregnancy outcomes in patients with MS. At the time of analysis, no signal for unexpected adverse pregnancy outcomes related to MS has been identified. However, our data set brings to light several important observations. There is a high percentage of early DMT exposed pregnancies and unplanned pregnancies among patients with MS, underscoring the need for reproductive counseling with patients with MS at every visit. We showed an association between clinical MS relapse in the preconception phase and an increased in time to conception, irrespective of exposures to DMT and steroids. We also identified a significant association between the use of any form of fertility therapy and intrapartum MS relapse, irrespective of DMT, although this finding should be viewed with caution. Results from our study contribute to the growing literature on the use of fertility therapies and the associated relapse risks. PREG-MS cohort will continue to report the real-world outcomes in pregnant WwMS and their offspring and will expand to include participants with myelin oligodendrocyte glycoprotein antibody disease, and neuromyelitis optica spectrum disorders. Similar efforts are underway in Canada, Europe, and elsewhere in the United States. With the development of this and similar registries, we hope to understand the reciprocal effects of pregnancy and neurodemyelinating diseases, as well as pediatric outcomes in the new treatment era. TAKE-HOME POINTS → PREG-MS is a prospective, longitudinal pregnancy registry of WwMS in the Northeastern United States. → ∼85% of all participants remained on disease-modifying therapy up until the time of conception. → 25% of participants in the cohort had unplanned pregnancies, which is lower than the ∼50% unplanned pregnancies in the general population. → The risk of prepartum relapses highly correlated with increased duration of conception attempts. → Postpartum relapses were highly correlated with intrapartum exacerbations and a high-risk pregnancy designation by obstetrical providers. → There was no signal for unexpected adverse pediatric or maternal pregnancy outcomes in this cohort. Appendix. Authors | Name | Location | Contribution | | Maria K. Houtchens | Brigham MS Center, Harvard Medical School; | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data | | Maria Claudia Manieri | Georgia State University | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data | | Tatenda Dawn Mahlanza | Brigham and Women's Hospital | Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data | | Jeta Pol-Patil | Brigham and Women's Hospital | Major role in the acquisition of data | | Eric C. Klawiter | Massachusetts General Hospital, Harvard Medical School | Major role in the acquisition of data | | Andrew J. Solomon | University of Vermont | Major role in the acquisition of data | | Ellen Lathi | Elliot Lewis MS Center, Wellesley, MA | Major role in the acquisition of data | | Joshua Katz | Elliot Lewis MS Center, Wellesley, MA | Major role in the acquisition of data | | Carolina Ionete | University of Massachusetts | Major role in the acquisition of data | | Idanis Berrios Morales | University of Massachusetts | Major role in the acquisition of data | | Christopher Severson | Brigham and Women's Hospital | Major role in the acquisition of data | | Jonathan Zurawski | Brigham and Women's Hospital | Major role in the acquisition of data | | James M. Stankiewicz | Novartis pharmaceuticals | Major role in the acquisition of data | | Ann Cabot | Concord Hospital | Major role in the acquisition of data | | Adele Dessa Sadovnick | University of British Columbia | Drafting/revision of the manuscript for content, including medical writing for content; study concept or design | Study Funding Unrestricted Investigator-initiated grant from Sanofi Genzyme; Philanthropic donation by Michele LeMay Foundation. Disclosure Disclosures will be provided separately, by each contributing author. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp.

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