Intravenous immunoglobulin treatment in multiple sclerosis: A prospective, rater‐blinded analysis of relapse rates during pregnancy and the postnatal period

Summary

Background

Multiple sclerosis (MS) affects predominantly young women. Currently available disease‐modifying drugs have neither been approved during pregnancy nor nursing.

Aims

Evaluating the effect of treatment with intravenous immunoglobulin (IVIg) in MS patients with desire to have a baby.

Methods

In all, 70 MS patients were either treated with IVIg before conception, during first trimester of pregnancy and 12 months postnatal (group I, n = 38) or started IVIg after delivery for 12 months (group II, n = 23) or were untreated (group III, n = 9). Relapse rates and disease progression were analyzed.

Results

Pre‐gestational relapse rates differed between groups. Lowest relapse rates were observed during late pregnancy, followed by an elevated relapse rate after delivery compared to the pre‐pregnancy year and the first trimester. Only in group I, the postnatal relapse rate did not exceed the relapse rate before conception. IVIg treatment did not influence disease progression after delivery.

Conclusions

In MS patients, IVIg treatment during and/or after delivery is an option to reduce the incidence of relapses during pregnancy and the postnatal period. Surprisingly, untreated patients becoming pregnant showed an increase in the relapse rate in the first trimester compared with the pre‐gestational period. How alterations of hormone status during pregnancy affect disease activity in MS has to be further investigated.

1. INTRODUCTION

Multiple sclerosis (MS) is the most common disease in young adults leading to disability. Immune‐mediated processes seem to be the underlying cause. Immunomodulatory and immunosuppressive therapeutic agents (disease‐modifying drugs (DMD)) have shown positive effects on disease activity. Worldwide, there are about 2.5 million patients suffering from MS. Relapsing‐remitting MS (RRMS) is most frequently reported in patients. More women than men are affected by MS, with a female‐to‐male ratio of about 3:1.1, 2, 3 Consequently, pregnancy and breastfeeding are important issues for a large number of patients. Immunomodulators may cause birth defects in infants, when administered during pregnancy.4 Conception under treatment with interferon‐beta (IFN‐beta) or glatiramer acetate does not seem to bear increased risks for the unborn.5, 6 However, DMD administration is usually stopped when pregnancy is confirmed.7 The only available therapeutic agent available during pregnancy is glatiramer acetate, which is no longer contraindicated during pregnancy since December 2016.8

Pregnancy is typically a stabilizing period in the clinical course of MS. During the third trimester, the MS relapse rate can be 70% lower when compared with the time before pregnancy, but aggravation of the disease is commonly seen after delivery.9, 10, 11, 12, 13 The reasons for this are not understood in detail. Recent evidence shows that the glucocorticoid receptor in T cells mediates protection from autoimmunity in pregnancy via progesterone.14 Facing the aggravation of the disease after childbearing, there is a need for sufficient treatment during the breastfeeding period. None of the available agents should be given unconditionally during the nursing period. Therapeutic agents show only low concentrations in breast milk, but may be stored in the newborn.10 Due to missing safety data and known fetal risks of immunomodulatory or immunosuppressive drugs, these licensed drugs should be avoided or are hitherto contraindicated during gestation, or lactation.15, 16, 17, 18 Therapeutic options should be chosen with regard to the risks and harms to the unborn and the infant.

Intravenous immunoglobulin (IVIg), which has shown beneficial effects in a variety of autoimmune diseases,19 seems to be a treatment option that can be used unhesitatingly during pregnancy and lactation. No safety concerns are known for the fetus or the newborn.15, 16, 20 Several clinical studies performed to evaluate the effects of IVIg on the disease course and relapse rate in MS patients suggest efficaciousness.21, 22 Positive results during puerperium have been reported in small trials23, 24 as well as in prospective randomized trials.25, 26 Still, large placebo‐controlled phase III trials are missing. Consequently, approval for IVIg treatment of MS during breastfeeding is still pending.

2. OBJECTIVES

The aim of this study was to evaluate relapse rates and disease progression under treatment with IVIg during pregnancy and the postnatal period compared to untreated MS patients in a real‐life scenario.

3. METHODS

For this single‐center study (University of Rostock, Rostock Germany), 103 women with RRMS following the revised McDonald criteria have been included (Table 1) between 2005 and 2015. We followed 70 pregnancies for at least 12 months after delivery. In addition, a historic control group of untreated pregnant MS patients was introduced due to the low number of untreated pregnant women in our cohort.9 All patients were informed about treatment options and potential side effects during pregnancy and lactation. The study was performed in accordance with the Declaration of Helsinki and approved by the local ethics board.

Table 1.

Demographic data, EDSS over time, and previous treatment

	Group I IVIg treatment pre‐gestation and postpartum (n = 38)	Group II postpartum IVIg (n = 23)	Group III no treatment (n = 9)	Group IV IVIg pre‐gestation (n = 33)
Age at gestation [years]mean and SD	29 ± 4.8	28 ± 4.9	27 ± 4.9
Disease duration at gestation [years] mean and SD	4.0 ± 2.9	2.4 ± 2.8	3.9 ± 4.5
Relapsing‐remitting MS % (n)	100 (38)	100 (23)	100 (9)	100 (33)
EDSS 3 months before conception mean and SD	1.3 ± 1.3	1.3 ± 1.2	1.2 ± 1.0
EDSS 3 months after conception mean and SD	1.5 ± 1.2	1.5 ± 1.3	1.4 ± 1.0
EDSS 1 month after deliverymean and SD	1.7 ± 1.3	1.4 ± 1.0	1.6 ± 1.0
Previous treatment% (n)
None	45 (17)	39 (9)	56 (5)	45 (15)
IFN‐beta	37 (14)	57 (13)	22 (2)	45 (15)
Glatiramer acetate	11 (4)	4 (1)	‐	3 (1)
Natalizumab	3 (1)	‐	11 (1)	3 (1)
Other	5 (2)	‐	11 (1)	3 (1)

Group I: IVIg treatment before gestation, during the first trimester of pregnancy and during the postpartum period. Group II: IVIg treatment after delivery only. Group III: no treatment during pregnancy and lactation.

3.1. Treatment

Decision for treatment with IVIg was made depending on disease activity, that is, relapse rate prior to pregnancy in each patient, and it was the sole responsibility of the treating physician and the individual patients. Safety aspects and the needs for adequate treatment were taken into account. IVIg treatment was performed at a standard dose of 0.4 g/kg body weight/day. Administration details differed as follows.

Group I (n = 38) patients were treated with IVIg before gestation, during the first trimester of pregnancy and during the postpartum period: Treatment was initiated by infusions over 5 consecutive days, followed by single booster doses every 4 weeks until the second trimester of pregnancy. Immediately after delivery, IVIg treatment was restarted, again with infusions for 5 consecutive days, followed by additional single booster doses once every 4 weeks during lactation.

Group II (n = 23) patients were treated with IVIg for 5 consecutive days within the first week after delivery with additional single booster doses every 4 weeks during lactation. No infusions or other disease‐modifying treatments were given during pregnancy.

Group III (n = 9) patients were untreated during pregnancy and lactation.

Group IV (n = 33) patients were treated with IVIg due to the desire to have a baby but did not become pregnant.

Group V (n = 227) historic control group of pregnant MS patients without treatment.9

During the follow‐up period of 1 year after delivery none of the patients received DMD other than IVIgs (Group I and II).

3.2. Parameters

Annualized relapse rates (ARR) were analyzed per woman and year before, during, and after pregnancy. ARR were compared between the patient groups.

Relative relapse rate (RRR) per woman. RRR was calculated by comparing the relapse rates (ARR) before, during, and after pregnancy with the relapse rate before conception for each of our groups I‐III and for the historic group V of untreated pregnant MS patients9 (Figure 1). The annualized relapse rates (ARR) of the enrolled patients before conception was set to 100%. Relative relapse rates (RRR) were calculated based on ARR.

Figure 1.

Relative relapse rates (index relative to pre‐gestational annualized relapse rate) before, during, and after pregnancy. Solid lines: IVIg treatment, dashed lines: no IVIg treatment. Group I: IVIg treatment before gestation, during the first trimester of pregnancy and during the postpartum period. Group II: IVIg treatment after delivery only. Group III: no treatment during pregnancy and lactation. Group IV: IVIg treatment because desire to have a baby but did not conceive pregnancy. Confavreux et al. = Group V: (n = 227) historic control group of pregnant MS patients without treatment. For more detailed definition of groups, see chapter Methods

Expanded Disability Status Scale (EDSS)27 was used to assess neurological disability every 3 months. Progression was defined as a sustained increase in the EDSS of 1.0 over a 3‐month period for patients with baseline EDSS ≤ 5.0, none of the enrolled patients had a baseline EDSS > 5.0.

3.3. Statistics

Statistics were performed with SPSS. The data were checked for normal distribution. Pair‐wise comparisons between the patient groups were performed by two‐tailed t‐tests. In comparison with the historical group, we used one‐sample two‐tailed t‐tests. The significance level was set at ≤0.05.

4. RESULTS

Baseline data of the various patient groups are shown in Table 1. Age at conception was similar between the treatment groups. Mean disease duration was between 2.4 and 4.0 years, and was shortest for group II (2.4 ± 2.8). All patients suffered from RRMS. Group IV patients (no pregnancy) did not differ in terms of age from group I‐III (mean age at baseline was 27 ± 5.3 years), but showed the longest disease duration (5 ± 4.0 years). The proportion of patients with immunomodulatory treatment prior to gestation or wish of pregnancy was highest for group II (61%), followed by group I (56%) and group IV (54%), and lowest for group III (44%). IFN‐beta treatment was the most common treatment option in all groups. EDSS 3 months prior to conception was comparable between the groups (see Table 1). The mean baseline EDSS in group IV was slightly higher than those of the other patients (1.4 ± 0.8). Three months after conception, the mean EDSS increased from 1.3 ± 1.3 to 1.5 ± 1.2 (group I), from 1.3 ± 1.2 to from 1.5 ± 1.3 (group II), and from 1.2 ± 1.0 to 1.4 ± 1.0 (group III). EDSS 1 month after delivery was highest for group I, with a further increase to 1.7 ± 1.3, followed by group III with an increase to 1.6 ± 1.0, and lowest for group II, with a decrease to 1.4 ± 1.0. Group I patients received approximately 22 months of IVIg treatment (21.7 ± 26.3 mean and SD) before gestation.

The ARR the year before gestation was significantly higher for group I (0.84) compared to group II (0.30; P = 0.019) and non‐significantly higher compared to group III (0.33; P = 0.105). Pregnancy led to reduced disease activity, with decreasing ARRs toward delivery in all groups; nevertheless, patients in group II (0.52) and group III (0.90) showed an increase in ARR during the first trimester being even higher than before gestation. In the first 3 months after delivery, ARR increased and reached a peak for all three groups, with a significant increase compared to the third trimester for patients in groups I and II (see Tables 2 and 3). Over the follow‐up period (months 4‐12 after pregnancy), relapse rates decreased again and were lowest for group I compared to groups II and III (Table 2).

Table 2.

Annualized relapse rates per group over time

Time points	Year before IVIg treatment	Year before conception	Trimester 1	Trimester 2	Trimester 3	Month 0‐3 postpartum	Month 4‐6 postpartum	Month 7‐9 postpartum	Month 10‐12 postpartum
Group I	0.76	0.84	0.63	0.53	0.32	0.84	0.42	0.21	0.21
Group II		0.30	0.52	0.35	0.35	0.70	0.55	0.00	0.38
Group III		0.33	0.89	0.00	0.00	0.89	0.44	0.44	0.44
Group V		0.7	0.5	0.6	0.2	1.2	0.9	0.9	0.6
Analysis 1
Group I vs. Group V		0.329	0.586	0.742	0.518	0.190	0.023	<0.001 a	0.012
Group II vs Group V		0.021	0.940	0.305	0.545	0.133	0.250	<0.001a	0.414
Group III vs Group V		0.059	0.527	<0.001a	<0.001a	0.611	0.335	0.335	0.735
Analysis 2
Group I vs Group II		0.019	0.774	0.603	0.914	0.733	0.723	0.282	0.541
Group I vs Group III		0.105	0.653	0.259	0.395	0.940	0.960	0.529	0.529

All data of analyses 1 and 2 are raw p values not corrected for multiple testing assuming equal variances. Analysis 1: one‐sample two‐tailed t‐test. Analysis 2: two‐tailed t‐test for two independent samples. Group I: IVIg treatment before gestation, during the first trimester of pregnancy and during the postpartum period. Group II: IVIg treatment after delivery only. Group III: no treatment during pregnancy and lactation. Group IV: IVIg treatment because desire to have a baby but no confirmed pregnancy. Group V: (n = 227) historic control group of pregnant MS patients without treatment. For definition of groups, see chapter Methods. Bold values are statistically significant.

^ano relapse occurred in this group during the time interval.

Table 3.

Comparison between different periods of time (two‐tailed paired t‐test p values)

Time points	Trimester 1 vs month 0‐3 postpartum	Trimester 1 vs trimester 3	Trimester 3 vs month 0‐3 postpartum
Group I	0.600	0.324	0.058
Group II	0.665	0.665	0.328
Group I + II	0.496	0.289	0.034
Group III	1.000	0.169	0.169

Group I: IVIg treatment before gestation, during the first trimester of pregnancy and during the postpartum period. Group II: IVIg treatment after delivery only. Group III: no treatment during pregnancy and lactation. Bold value is statistically significant.

Figure 1 shows the RRR for the various treatment groups and in comparison to the historical cohort of Confavreux et al9 Patients with IVIg treatment during pregnancy (group I) had the lowest RRR during pregnancy, with rates being comparable to the historical patient group V. Only in group I patients, the ARR in the first 3 months after delivery did not exceed the ARR in the year before pregnancy (Table 2, Figure 1). During the first months after delivery, all groups in our study showed lower ARRs than the historical group V. The lowest postpartum ARRs were observed in the IVIg‐treated groups I and II.

Annualized relapse rates in Group IV patients, who did not become pregnant during IVIg treatment, decreased from 1 year before (0.61) to 1 year after (0.45) the start of IVIg treatment.

5. DISCUSSION

Data on pregnancy in MS patients are limited, and a lot of knowledge is based on a European study published by Confavreux et al, who presented the natural course of disease during pregnancy in 227 cases.9 Pregnancy is a stabilizing factor for MS course, and whether treatment is necessary is dependent on prior disease activity and on balancing the risks and benefits (ARRs differed tremendously between the groups in our study). Pregnancy and medical treatment is a sensitive issue. Randomized trials are not feasible due to ethical issues. Our study aims to increase knowledge of treatment of patients with a desire to have a baby, and pregnant patients by analyzing relapse rates. RRR were introduced to compare disease activity in the various treatment groups. Due to the low number of untreated patients, a historical patient group (untreated) was introduced to assess differences in RRR between the historical group and our treated patients. However, the early postpartum period is associated with an increased ARR. Treatment opportunities are often limited by the mothers' wish of breastfeeding. IVIg might be a useful and safe alternative for these patients.20 We investigated the ARR of IVIg‐treated RRMS patients during pregnancy and after delivery in a real‐world scenario. Thus, our study aimed to expand the knowledge on a safe and beneficial treatment of MS patients during pregnancy and nursing.

The results suggest positive effects of IVIg treatment on ARR during pregnancy and lactation. Treated patients (group I) showed higher relapse rates (ARR) before gestation compared to patients without treatment, suggesting influence of disease activity on the likelihood of IVIg treatment. Although ARR prior to gestation was significantly higher for treated patients than for untreated ones, ARR during pregnancy was similar for all groups toward delivery. The reduction of disease activity during second and third trimesters of pregnancy and its increase in the postpartum period is consistent with previous reports.4

During the first 3 months after delivery, all patient groups showed an increase in ARR compared to the last trimester of pregnancy, with a significant increase for treated patients in groups I and II (P = 0.034). Group I patients had high ARRs prior to gestation, thus those patients were recognized as active patients by the treating physicians. However, whereas the postnatal ARR for groups II and III was higher than the ARR before gestation and during the first trimester of pregnancy, postnatal ARR of group I did not exceed the ARR before gestation. ARR for treated patients during lactation (group I and II) was lower during the year after delivery than for non‐treated ones (group III). Positive effects of IVIg treatment hence are to be discussed.

Interestingly, the historical group presented by Confavreux et al9 showed a very similar pattern of disease activity during pregnancy and nursing to those of group I patients. After delivery, the ARR observed in their study was considerably higher than those of our patients. Consequently, the option of IVIg treatment should be discussed after delivery if patients wish to breastfeed their children.

We could not find a significant difference considering the ARR after delivery when comparing the different treatment regimens of group I and group II (see Table 2). Comparing the first trimester of pregnancy with the first 3 months after delivery for each group (Table 3), we observed less pronounced changes in relapse rates than for the patients of the historical control group.9 Considering groups I and II, this might represent a therapeutic effect of IVIg treatment immediately after delivery. For group III, due to the small number of untreated patients, we could not show statistical significance for the increase in relapse rate after delivery as previously demonstrated.9 In contrary to published studies,10 we noted that untreated patients during first trimester of pregnancy faced an increased ARR compared with the pre‐gestational period, whereas a decreased ARR was only seen for group I patients (treatment during pregnancy and nursing) who had the highest ARR before gestation (see Figure 1).

The decrease in ARR from 1 year before to 1 year after the start of IVIG treatment in group IV suggests beneficial effects of IVIg treatment independent of pregnancy.

Interestingly, for all groups, EDSS scores increased during the first trimester compared to the period before pregnancy (see Table 1). Reasons for this are unclear, and there is a need for confirmation (interrater EDSS variability and statistical reasons cannot be ruled out). No sustained effects on disease progression were shown in follow‐up EDSS assessments up to 1 year after delivery, pregnancy and IVIg treatment (see Table 1), longer follow‐up periods might be necessary. Moreover, no serious adverse events were reported under IVIg treatment. Due to a low infusion rate, no complaints of known adverse events of IVIg treatment, for example, headache and rashes, were reported. No significant effects on the relapse rate were seen between patients who switched from other DMDs to IVIg treatment and patients who initiated IVIg treatment without pretreatment (0.66 vs 0.69).

Besides pregnancy, also the nursing period is a highly sensitive topic for women, with several benefits for the mother. Among others, decreased gynecological postpartal problems, decreased risk of breast and ovarian cancer, and a decreased risk of hip fractures and osteoporosis in the postmenopausal period have been shown.28 Additionally, mothers with MS might benefit from reduced postpartum relapse rates 29, 32 and disability.30 Recent epidemiological and biological findings of breastfeeding effects over the last decade indicate protection against child infections and malocclusion, increases in intelligence, and probable reductions in overweight and diabetes.28 The intensified mother‐child contact promotes maternal responsiveness, healthy neurodevelopment and a lower likelihood to develop allergies or autoimmune disease like MS during life.28, 31, 33, 34

There are several limitations of our study. First, a randomized‐controlled trial is not feasible due to ethical reasons. Thus, administration of IVIg was based on the physicians' and patients' decision and independent from the present study. Second, due to the small number of untreated patients during pregnancy and nursing, we introduced a historical control group. However, this introduction is associated with some concerns, and indeed the historical cohort of Confavreux et al showed higher ARR than our patients.9 Reasons for this reduction in ARR might be manifold. Decreasing ARRs have been observed over the last decades in large trials. One explanation might be that with the improvement of diagnosis and treatment of MS, more “benign” patients might be included.35, 36, 37 Most of our patients have been on treatment prior to gestation, and this number further increases in the future. Although ARRs were higher in the historical group, disease activity showed similar patterns during pregnancy and nursing compared with our patients.

6. CONCLUSION

Although recent data suggest that treatment with glatiramer‐acetate or interferons do not lead to an increased rate of spontaneous abortion, stillbirth or congenital birth defects,5, 6, 38, 39 usage of them during the first trimester of pregnancy cannot be recommended explicitly, and a major part of patients is untreated during this time period. We do believe that our study throws up important questions. Most interestingly, we observed an increased disease activity during the first months of pregnancy that has not been described hitherto. Reasons for these changes in disease activity are not elucidated. None of the females had undergone in vitro fertilization prior to pregnancy. However, following the results of our study, treatment during the first trimester of pregnancy seems to be of importance, which is to be discussed with patients.

Although some of the approved DMDs might be safe during pregnancy, patients and clinicians are usually reserved in prescribing those medications during pregnancy and/or lactation period. IVIg might be an alternative for patients who need treatment. Additionally, IVIg so far seems to be the only possibility to enable sufficient breastfeeding periods of 6 months40 with the potential to prevent relapses in the postpartum period of women with MS. Data on the utilization of IVIg in pregnancy are still limited; nevertheless, IVIg treatment is a safe treatment option during the gestational period and lactation, and should be considered during and after pregnancy in case of active disease.

CONFLICT OF INTERESTS

AW received travel expense compensation and fees for speaking, consulting, serving on advisory boards and conducting clinical trials from Alexion, Bayer Healthcare, Biogen, Genzyme, Merck Serono, Novartis, Octapharma, Roche, Sanofi and Teva with the approval of the director of the University of Rostock Medical School. PSR received speaking fees, travel funds, and research support from Biogen, Genzyme, Novartis, Roche, Shire, Teva. MH received speaking fees and travel funds from Bayer HealthCare, Biogen, Novartis, and Teva. UKZ received speaker honorary from Bayer Pharma AG, Novartis Pharma AG, Teva Pharma AG, Biogen IDEC, Merck Serono GmbH, Sanofi‐Aventis GmbH.

AUTHOR CONTRIBUTIONS

AW and UKZ designed the research; AW performed data extraction; AW and PSR performed the literature search; and MH and AW performed statistical analysis. All authors analyzed the data; AW and PSR wrote the paper. UKZ and MH reviewed and provided comments on the manuscript.

Winkelmann A, Rommer PS, Hecker M, Zettl UK. Intravenous immunoglobulin treatment in multiple sclerosis: A prospective, rater‐blinded analysis of relapse rates during pregnancy and the postnatal period. CNS Neurosci Ther. 2019;25:78–85. 10.1111/cns.12985