Pregnancy and Breastfeeding in MS

Pregnancy. 1

Effect of MS on pregnancy. 1

Effect of pregnancy on MS. 1

Breastfeeding. 1

IVF/Assisted reproductive therapy. 1

MS medications – evidence in pregnancy and breastfeeding. 1

Effect of treatment on Relapse. 1

Pregnancy

• 20-30%of women diagnosed with MS will have a child after the diagnosis

Effect of MS on pregnancy

• No effect on ability to conceive

• No increase in foetal abnormalities or obstetric complication (some reports have suggested some increased complications but have not been substantiated)

• Should not influence method of delivery or anaesthesia used

Genetic Risk to Child

• Risk in general population is 0.13%, risk if parent has MS is 2-2.5%

• Risk is higher for infants born in ‘spring’ (peak November) and lowest for ‘autumn’ (peak April).

Effect of pregnancy on MS

• PRIMS study

• Relapse rates fall by 70% in third trimester

• Relapse rates rebound during the first 3 months post-partum to 70% above prepregnancy level

o Risk factors include – high prepregnancy relapse rate, relapse during pregnancy and higher disability level prior to pregnancy

• Some studies have suggested that more pregnancies is linked to better long term prognosis in RRMS (this was not the case in PPMS)

• Method of delivery and type of anaesthetic did not affect relapse rate (in Italian study on this question)

Month	Relapse rate
12 months pre-pregnancy	0.7
First trimester	0.5
Second trimester	0.6
Third trimester	0.2
First 3 months post-partum	1.2
Second 3 months	0.9
Third 3 months	0.9
Forth 3 months	0.6

NEJM 1998 – PRIMS study

NEJM 1998 – PRIMS study

Effect of multiple pregnancies MS in long term

Group	Median time to EDSS 6 (years) (of those who reached this EDSS)	Estimated median time to EDSS 6 (years) - (for whole group)	Estimated difference relative to group one (years)
Never had children	8	15
Children prior to MS	10	13	No significant difference
Children after diagnosis of MS	21	23	8
Children before and after MS	21	22	7

JNNP 2010 81:38

Breastfeeding

• No clear evidence that breastfeeding affects relapse rate

o Multiple studies have shown opposing effects

o A meta-analysis suggested an overall slight benefit of breast feeding

o Further analysis suggested that only exclusive breast feeding for at least 2 months was required to show a benefit

o Another study (Hellwig et al. 2012) also concluded exclusive breastfeeding decreased relapse rate vs non-exclusive or no breastfeeding (0.68vs1.5vs1.68).

o (Hellwig et al 2015 JAMA Neurol) – 201 women, 60% exclusively breastfed for 2 months, 20% did partial breastfeeding, 20% did no breast feeding.

- MS treatments were in general restarted much earlier in non-breastfeeding group.

- Despite this there were less relapses in the exclusively breastfed group (38% vs 25%) in the first 6 months

- By the end of the year the relapse rates were similar again (as breast-feeding women stopped)

• Use of disease modifying treatment

o Formal recommendation is not to, however some agents are probably quite safe

o Use of IVIG as an interim measure was trialled (GAMPP study) with suggestion of a positive effect

IVF/Assisted reproductive therapy

• The use of GnRH agonists increased risk of relapse for 3 months following treatment

• GnRH agonists not frequently used in Australia

MS medications – evidence in pregnancy and breastfeeding

Drug and Pregnancy Category	Evidence for pregnancy recommendations	Recommendations	Breast Feeding	Advice
Interferons D (FDA-C)	A large macromolecule with no significant passage across the placenta Animal models show increased abortions but not teratogenicity Avonex registry – 500 women worldwide – No adverse effects Rebif registry – 425 women – No adverse effects Systematic review (2012) – 761 pregnancies – lower mean birth weight, shorter mean length and increased preterm birth. No association with low birth weight (<2500g), congenital anomaly or spontaneous abortion. PI- If the patient becomes pregnant or plans to become pregnant while taking interferon beta-1b, she should be informed of the potential hazards and it should be recommended that she discontinue therapy (Avonex adds: unless the potential benefit justifies the potential risk to the foetus)	British guidelines: - Safe to use at least until conception Washout - Nil	The levels of interferon beta-1a in breastmilk are minuscule. In addition, because interferon is poorly absorbed orally, it is not likely to reach the bloodstream of the infant. Six women on Avonex - Milk samples from both breasts were collected after pumping with an electric breast pump at 8 times after a dose at baseline and at 7 other times during the first 72 hours after a dose. About half of the samples had undetectable (<20 ng/L) amounts of drug. The highest concentrations were found at 1 or 4 hours after the dose in all women. The highest concentration found was 171 ng/L in one woman. Using this value, the authors estimated that the maximum weight-adjusted dosage that an infant would receive is 0.006% of the maternal dose. PI – Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue breastfeeding or Interferon therapy TG- Caution, insufficient data (Large molecular weight proteins/polypeptides are unlikely to transfer into milk. In the absence of specific information, adverse effects in the infant are unlikely) AMH - Should be safe (interferons are not absorbed by the oral route).	Likely safe
Copaxone Aust - B1 (FDA-B)	A large macromolecule with no significant passage across the placenta Animal studies – no ill effects Systematic review of 97 cases – no association with obstetric complications or congenital abnormalities. Post marketing surveillance (Conference abstract 2003) 345 pregnancies 215 known outcomes 43 spontaneous abortions (20%) 9 elective abortions 1 ectopic pregnancy 155 live births 6 congenital anomalies (3.9% of live births) 90% had minimal/first trimester only exposure PI - Because animal reproduction studies are not always predictive of human response, Copaxone should be used during pregnancy only if clearly needed.	British guidelines: - Safe to use at least until conception Washout - Nil	Undergoes rapid degradation to amino acids that cannot be detected in the plasma, urine or faeces – unlikely to transfer intact into breast milk (but has not been measured). Data on approximately 30 women breast feeding – no adverse effects. PI - caution should be exercised when Copaxone is administered to women who are breastfeeding TG - avoid, insufficient data AMH – No human data	Likely safe
Fingolimod Aust - D (FDA –C)	Penetrates the CNS Animal models – increased malformations and growth retardation. Exposure in clinical trials – 66 pregnancies – 5 congenital abnormalities (7.6%) – higher than would be expected. (219 exposed pregnancies, 5 malformations – CNS drugs 2014 28:89)	British guidelines: - Avoid in pregnancy - 2 month washout - State that no increased risk has been noted?? Washout – 2 months	No outcomes data at all. Excreted in the breast milk of rats PI – Should not breastfeed. TG – Avoid, insufficient data AMH - No human data; avoid breastfeeding.	Avoid
Dimethyl Fumarate Aust - B1 (FDA-C)	Animal data – at very high doses – reduced foetal weight and delayed ossification. Effects not evident at lower doses. Registry – 3463 women exposed (as of March 2018, Biogen communication, not published) – no association with birth defects has been seen. Clinical trials – 60 exposed women, 29 live births, none with defects. 13 elective terminations 2 with abnormalities detected (felt unrelated to DMF)	British guidelines: - Avoid in pregnancy - No specific washout time advised Washout: No formal recommendation Drug is out of system by 24 hours in most patients.	10 exposed infants – no major adverse effects noted (as of March 2018, biogen communication) Unknown if excreted in breast milk. PI - A risk to the newborn/ infant cannot be excluded. A decision must be made whether to discontinue breastfeeding or to discontinue Tecfidera treatment. The benefit of breastfeeding for the child and the benefit of treatment for the woman should be taken into account. TG – No entry AMH - No data; avoid breastfeeding	Appears to be lower risk of harm, however due to lack of data should avoid
Teriflunomide Aust - X (FDA-X)	Does not penetrate the CNS Animal data – high rate of congenital abnormalities in rats and rabbits. Limited human data to date with leflunomide and teriflunomide (7 pregnancies) has not detected any abnormalities. (59 exposed pregnancies – high elective abortion rate, no major abnormalities - CNS drugs 2014 28:89)	British guidelines: - Avoid in pregnancy – high risk Washout: 24 months Accelerated washout: Advised not to conceive for 6 weeks after drug concentration has been reduced to 0.02mg/L	Passes into breast milk in animal studies (up to 23% of the dose). No outcomes data for leflunomide or teriflunomide. Avoid PI – Avoid TG – No entry AMH - Avoid	Avoid
Natalizumab Aust - C FDA - C	Probably crosses placenta Alpha-4 integrin receptors are expressed on embryonic tissue Animal studies at high doses– decreased guinea pig pup survival. Haematological abnormalities in primates. Registry of 362 women exposed during pregnancy – no adverse associations. Systemic review of 35 pregnancies – no adverse associations. 9 women with severe disease treated throughout pregnancy – reversible, mild-moderate haematological abnormalities in 8 newborns. My conclusion: Probably safe	British guidelines: - No evidence of significant harm in pregnancy - Weigh up risk of rebound vs unknown harms - May cause haematological issues if given in 3^rd trimester. Therefore last dose should be <34 weeks gestation - Consider 8 weekly dosing to avoid exposure. Washout: If desire to avoid exposure, wait 1-3 months	Large protein molecule hence, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. No data on levels or outcomes. PI - the potential for serious adverse reactions is unknown, a decision should be made whether to discontinue breastfeeding or Tysabri therapy. TG - Caution, insufficient data (Large molecular weight proteins/polypeptides are unlikely to transfer into milk. In the absence of specific information, adverse effects in the infant are unlikely) AMH - Detected in breast milk; unlikely to be absorbed by child, however, manufacturer does not recommend breastfeeding during treatment.	Probably safe Caution, in newborn/preterm – consider delaying first dose after pregnancy to 8 weeks post partum.
Alemtuzumab Aust – B3 FDA - C	139 pregnancies to date 2015 No signal to increased abortion/malformation etc.	British guidelines: - Avoid in pregnancy - Antibodies are very low at 1 month, however 4 month wait is official advice.	Large protein molecule hence, the amount in milk is likely to be very low and absorption is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Theoretical small risk of immune depletion in infant. No data on levels or outcomes.	Avoid breastfeeding (if alemtuzumab has been given in last 4 months)
Ocrelizumab Aust – C US - NA	As of March 2019 – 118 exposed in utero, 31 live births, 27 health babies, 4 preterm. Various other small case series with a variety of indications – no clear signal of increased risk. One case of a pregnancy with exposure in third trimester where infant had/has prolonged B-cell depletion once born.	British guidelines: - Avoid in pregnancy - UK advises 12 month washout Washout: Aust/US guidelines 6 months (Although drug is likely completely out of the system by 3 months) Late pregnancy exposure possibly more of a concern.	Cases of minor B-cell reduction in breastfeeding infants, but probably coincidental.	Avoid breastfeeding (if ocrelizumab has been given in last 6 months – although probably safe after 1-3 months)
Cladribine Aust - D FDA - D	Teratogenic/lethal effects in some animal studies. No human data	British guidelines: - Avoid pregnancy for 6 months after last dose - Men should avoid pregnancy for 6 months as well	No data	Avoid breastfeeding until 1 week after the last dose.
Mitoxantrone D	Adverse outcomes have been demonstrated in aminal studies and human cases. Avoid pregnancy for 6 months after treatment.			Avoid
Steroids – Methylprednisolone and prednisolone. A FDA - No official category (Category C suggested)	Increased rate of cleft palate and lower birth weight if used in the first trimester. Used in many women in second and third trimester without any adverse effects.		Low levels are excreted in breast milk. Advised to avoid breast feeding for 3-4hours after a large intravenous dose to decrease exposure. No adverse effects have been reported. No adverse effects on ability to lactate have been substantiated. TG - caution with high pulse doses AMH – Nil advice

Effect of treatment on Relapse

Fragoso, Boggild et al. Effects of long-term exposure to DMD during pregnancy in MS. Clin Neurol and Neurosurg. 2013

• International database

• Compared women exposed (by definition to >8weeks, median 18weeks of treatment) to controls

• 37 GA

• 17 Interferon Beta

• IFN babies slightly smaller, otherwise no other significant differences (some of these women were probably included in previous meta-analysis).

• EDSS 45 months post pregnancy showed average increased EDSS in all groups

o Controls EDDS went from 1.39 to ~2.2.

• Probably a slightly lower post pregnancy EDDS in treated groups (however multiple confounding factors)

Hellwig et al. MS and pregnancy, experience from a nationwide database in Germany 2012.

• Treatment used in patient with worse disease (hence confounding results)

• However relapse rate post pregnancy was lower than pre-pregnancy in treated groups and higher post-pregnancy in non-treated groups.

• Defect rate:

o IFN 3/78 (3.8%)

o GA 2/41 (4.9%)

o No treatment 7/216 (3.2%)

•