. 2024 Jan 11;13(2):283–322. doi: 10.1007/s40120-023-00565-7

Table 2.

Key studies of pregnancy outcomes after interferon exposure

Study and timing	Design and population	Outcomes
Amato et al. [97]	Cohort study Study groups: Patients • 87 women (88 pregnancies) who discontinued IFN-β < 4 weeks before conception (exposed) • 311 women (318 pregnancies) who discontinued IFN-β ≥ 4 weeks before conception or who were never treated (not exposed)	• IFN-β exposure was not related to spontaneous abortion (OR 1.08, 95% CI 0.4 to 2.9, p = 0.88) • IFN-β exposure was associated with lower baby weight (β = − 113.8, 95% CI − 114.1 to − 113.5, p < 0.0001) and length (beta = − 1.102, 95% CI − 1.366 to − 0.839, p < 0.0001) • IFN-β exposure was not associated with an increased risk of birth weight < 2500 g) (OR 1.14, 95% CI 0.41 to 3.15, p = 0.803)
Boskovic et al., 2005 [92]	Longitudinal, cohort study with two control groups Study groups: women who were • Exposed to IFN (to be detrimental 12 women with 21 pregnancies) • Healthy comparative group (18 women with 20 pregnancies)	• The study group was exposed to IFN-β-1a (Avonex®, Rebif®) or IFN-β-1b (Betaseron®) • Mean birth weight was decreased in the exposed group vs healthy controls (3189 ± 416 g with IFN vs 3783 ± 412 g in controls; p = 0.002) • Women exposed to IFN-β had a higher rate of miscarriages and stillbirths vs healthy controls (39.1% vs 5%, respectively; p = 0.03)
Fragoso, et al., 2013 [93]	Retrospective chart review Mothers with MS (n = 180) • 95 unexposed during pregnancy • 85 exposed to DMTs for ≥ 2 weeks during pregnancy	Of mothers exposed to DMTs, 39 were exposed to GLAT, 39 to IFN-β (19 IFN-β-1a at 30 µg/week [Avonex®], 10 to IFN-β-1b at 10–250 µg on alternate days [Betaseron®], and 10 to IFN-β-1a at 22 or 44 µg tiw [Rebif®]) • There were also 3 exposures to methylprednisolone, 2 exposures to immunoglobulin, 1 exposure to azathioprine, and 1 exposure to rituximab The authors noted • No pattern of drug-related adverse events or complications in the children whose mothers were exposed to DMTs • No specific long-term adverse events observed in the offspring of women with MS who were exposed to drugs during pregnancy
Hellwig et al., 2010 [94]	Nationwide questionnaire and patients within the authors’ outpatient clinic Children of • MS-fathers with DMT (n = 40) • MS-mothers without DMT (n = 75) • MS-mothers treated with IFN-β at the time of conception (n = 75) • Healthy mothers (n = 75)	Of pregnancies that were fathered by patients with MS receiving DMTs (32 paternities of 46 pregnancies), the fathers were treated with • 15 IFN-β-1a im • 7 IFN-β-1b sc • 12 under glatiramer acetate • 5 IFN-β-1a im 22 μg • 3 IFN-β-1a im 44 μg • 2 natalizumab • 1 methotrexate • 1 combination of • Azathioprine and IFN-β-1b sc Mean birth weight of newborns from MS fathers treated with DMTs was not significantly reduced vs those from healthy mothers Mean birth weight of newborns of MS mothers was significantly reduced vs MS-fathers whether or not the MS-mothers were treated with IFN-β No statistical difference was observed in birth weight of IFN-β-exposed vs untreated MS-mothers
Hellwig et al., 2012 [95]	Observational, partially retrospective Pregnant women with MS • 78 pregnancies exposed to IFN-β (n = 15 IFN-β-1b, n = 63 IFN-β-1a) • 41 pregnancies exposed to GLAT • 216 non-DMT-exposed pregnancies	No differences were observed between groups regarding • Birth weight (IFN-β-exposed mothers, 3260 ± 606 g; GLAT-exposed mothers, 3295 ± 688 g; and non–DMT-exposed mothers, 3383 ± 544 g) • Newborn body length (IFN-β-exposed mothers, 51.0 ± 2.3 cm; GLAT-exposed mothers, 51.5 ± 2.7 cm; and non-DMT-exposed mothers 51.4 ± 2.6 cm) • Gestational age (IFN-β-exposed mothers, 38.9 ± 2.4 gw; GLAT-exposed mothers, 39.2 ± 1.7 gw; and non-DMT-exposed mothers, 39.1 ± 2.3 gw) An increased risk for abnormalities in neonates was not observed for DMT-exposed mothers
Korjagina et al., 2021 [96]	Register-based cohort study 2115 pregnancies • Exposed only to IFN-β (n = 718) • Unexposed to any DMTs (n = 1397)	Serious adverse pregnancy outcomes occurred in • 4.3% (95% CI 1.9–8.3) of pregnancies exposed only to IFN-β 6 months before or during pregnancy • 2.7% (95% CI 1.2–5.0) of unexposed pregnancies The prevalence of serious and other adverse pregnancy outcomes was not significantly different between the exposed and unexposed groups

Study and timing

Design and population

Outcomes

Amato et al. [97]

Cohort study

Study groups: Patients

• 87 women (88 pregnancies) who discontinued IFN-β < 4 weeks before conception (exposed)

• 311 women (318 pregnancies) who discontinued IFN-β ≥ 4 weeks before conception or who were never treated (not exposed)

• IFN-β exposure was not related to spontaneous abortion (OR 1.08, 95% CI 0.4 to 2.9, p = 0.88)

• IFN-β exposure was associated with lower baby weight (β = − 113.8, 95% CI − 114.1 to − 113.5, p < 0.0001) and length (beta = − 1.102, 95% CI − 1.366 to − 0.839, p < 0.0001)

• IFN-β exposure was not associated with an increased risk of birth weight < 2500 g) (OR 1.14, 95% CI 0.41 to 3.15, p = 0.803)

Boskovic et al., 2005 [92]

Longitudinal, cohort study with two control groups

Study groups: women who were

• Exposed to IFN (to be detrimental 12 women with 21 pregnancies)

• Healthy comparative group (18 women with 20 pregnancies)

• The study group was exposed to IFN-β-1a (Avonex®, Rebif®) or IFN-β-1b (Betaseron®)

• Mean birth weight was decreased in the exposed group vs healthy controls (3189 ± 416 g with IFN vs 3783 ± 412 g in controls; p = 0.002)

• Women exposed to IFN-β had a higher rate of miscarriages and stillbirths vs healthy controls (39.1% vs 5%, respectively; p = 0.03)

Fragoso, et al., 2013 [93]

Retrospective chart review

Mothers with MS (n = 180)

• 95 unexposed during pregnancy

• 85 exposed to DMTs for ≥ 2 weeks during pregnancy

Of mothers exposed to DMTs, 39 were exposed to GLAT, 39 to IFN-β (19 IFN-β-1a at 30 µg/week [Avonex®], 10 to IFN-β-1b at 10–250 µg on alternate days [Betaseron®], and 10 to IFN-β-1a at 22 or 44 µg tiw [Rebif®])

• There were also 3 exposures to methylprednisolone, 2 exposures to immunoglobulin, 1 exposure to azathioprine, and 1 exposure to rituximab

The authors noted

• No pattern of drug-related adverse events or complications in the children whose mothers were exposed to DMTs

• No specific long-term adverse events observed in the offspring of women with MS who were exposed to drugs during pregnancy

Hellwig et al., 2010 [94]

Nationwide questionnaire and patients within the authors’ outpatient clinic

Children of

• MS-fathers with DMT (n = 40)

• MS-mothers without DMT (n = 75)

• MS-mothers treated with IFN-β at the time of conception (n = 75)

• Healthy mothers (n = 75)

Of pregnancies that were fathered by patients with MS receiving DMTs (32 paternities of 46 pregnancies), the fathers were treated with

• 15 IFN-β-1a im

• 7 IFN-β-1b sc

• 12 under glatiramer acetate

• 5 IFN-β-1a im 22 μg

• 3 IFN-β-1a im 44 μg

• 2 natalizumab

• 1 methotrexate

• 1 combination of

• Azathioprine and IFN-β-1b sc

Mean birth weight of newborns from MS fathers treated with DMTs was not significantly reduced vs those from healthy mothers

Mean birth weight of newborns of MS mothers was significantly reduced vs MS-fathers whether or not the MS-mothers were treated with IFN-β

No statistical difference was observed in birth weight of IFN-β-exposed vs untreated MS-mothers

Hellwig et al., 2012 [95]

Observational, partially retrospective

Pregnant women with MS

• 78 pregnancies exposed to IFN-β (n = 15 IFN-β-1b, n = 63 IFN-β-1a)

• 41 pregnancies exposed to GLAT

• 216 non-DMT-exposed pregnancies

No differences were observed between groups regarding

• Birth weight (IFN-β-exposed mothers, 3260 ± 606 g; GLAT-exposed mothers, 3295 ± 688 g; and non–DMT-exposed mothers, 3383 ± 544 g)

• Newborn body length (IFN-β-exposed mothers, 51.0 ± 2.3 cm; GLAT-exposed mothers, 51.5 ± 2.7 cm; and non-DMT-exposed mothers 51.4 ± 2.6 cm)

• Gestational age (IFN-β-exposed mothers, 38.9 ± 2.4 gw; GLAT-exposed mothers, 39.2 ± 1.7 gw; and non-DMT-exposed mothers, 39.1 ± 2.3 gw)

An increased risk for abnormalities in neonates was not observed for DMT-exposed mothers

Korjagina et al., 2021 [96]

2115 pregnancies

• Exposed only to IFN-β (n = 718)

• Unexposed to any DMTs (n = 1397)

Serious adverse pregnancy outcomes occurred in

• 4.3% (95% CI 1.9–8.3) of pregnancies exposed only to IFN-β 6 months before or during pregnancy

• 2.7% (95% CI 1.2–5.0) of unexposed pregnancies

The prevalence of serious and other adverse pregnancy outcomes was not significantly different between the exposed and unexposed groups

DMT disease-modifying therapy, GLAT glatiramer acetate, IFN interferon