Comment: Primum non-Nocere

The manuscript of Edward E. Winger, MD and Jane

L. Reed, BS Treatment with tumor necrosis factor (TNF)

inhibitors and intravenous immunoglobulin (IVIG)

improves live birth rates in women with recurrent sponta-

neous abortion (RSA) provides the views of the Alan

Beer Reproductive centres. This manuscript is wel-

comed because it deals with IVIG, not lymphocyte

allo-immunization as a technique for treatment of

recurrent pregnancy loss. It is, nevertheless, note-

worthy that the present study reports a 54% concep-

tion rate and only 19% for heparin alone, which are

lower rates than many other reports, which some-

times are very high: see for example the 81.5%

(Enoxaparin) and 84% live birth rates in the recent

randomized study of the group of Carp.1 However, it

must be mentioned that many of the most successful

open (see for example,2) or randomized studies often

associate heparin with aspirin, and that this is also

often reserved for women with anti-phospholipid

antibody syndrome3 which is not the case here.

Despite the success rates reported when using

IVIG instead of allo-immunization, there are still

important concerns about the treatment reported.

These do not concern IVIG as much as anti-TNFatherapy. One must note that for IVIG treatment as

well as for anti-TNFa drugs, several patients appar-

ently refused the offered therapy because of safety

concerns.

While this reflects a certain level of information,

concerns are still pending about what is justly

termed ‘a more aggressive TNFa therapy protocol’

using either EnbrelA� or HumiraA�, with either Ada-

limumab at 40 mg being injected by subcutaneous

injection every 1–2 weeks or Etanercept 25 mg

injected by subcutaneous injection every 48 hr

(which is indeed both costly and, as mentioned in

the text, a more aggressive approach). Importantly,

an increased incidence of lymphomas in patients

with rheumatoid arthritis treated with anti-TNFaagents has been suggested in4 – even if not 100%

proven.5

One wonders to what extent the women were

fully informed about such risks. Peculiarly important

in that context is the fact that pregnancy itself is

known to slightly increase the incidence of many

cancers albeit recent studies indicate that it might in

fact have a slight protective effect on some lym-

phoma and Hodgkin disease.6–9 The combined effects

of pregnancy condition and anti-TNF treatments are

not known since no such study devoted to this

aspect exists yet, for very good reasons indeed,

namely the aforementioned risks of the drug alone.

Concerning the effects of anti-TNF therapy per se

on lymphoma incidence, the authors state that, this

increased incidence is believed to be related to the

increased incidence in the underlying conditions,

quoting the study of Rychly and DiPiro.10

It is also true that no gross teratogenic effects have

been observed in the rats. The same applies to the

mother for lymphoma incidence. Yet, for both drugs,

the FDA sites states that ‘because animal reproduc-

tion and developmental studies are not always

predictive of human response, HUMIRA’ – or others

– ‘should be used during pregnancy only if clearly

needed’.

The Hippocratic principle primum non-nocere and

the principle of precaution should have been

applied. Especially, when Dr Beer co-signed a paper

where the heparin ⁄ aspirin combination which is

innocuous to the foetus, yielded a 90.9% success

rate.2 This indeed again was an open study, but we

are well above the combination IVIG ⁄ heparin ⁄anti-TNF reported in this issue by Winger and

Reed.

Gerard Chaouat

U 782, Inserm, Hopital A Beclere Pavillon Jean

Dalsace Maternite, Clamart, France

E-mail: gerard_chaouat@wanadoo.fr

doi:10.1111/j.1600-0897.2008.00628.x

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CHAOUAT

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Journal compilation ª 2008 Blackwell Munksgaard