The following is copied and pasted from the Feb 10th issue of MedScape Week in Review. It
primarily talks about RA and mentions Crohn's disease but does elude to
all inflammatory diseases. Its a bit complicated, even after reading it
several times, I could still use a translation!
QUOTE
Anti-TNF Therapy and Pregnancy Outcomes in Women With Inflammatory Arthritis
Posted 02/04/2009
Evelyne Vinet, MD; Christian Pineau, MD; Caroline Gordon, MD; Ann E. Clarke, MD, MSc; Sasha Bernatsky, MD, PhD
Author Information
Information from Industry
Assess clinically focused product information on Medscape.
Click Here for Product Infosites – Information from Industry.
Abstract and Introduction
Abstract
Women suffering from inflammatory arthritis may experience a change in
disease activity during and after pregnancy. Although the majority will
improve, some women may need to continue therapy throughout pregnancy
and/or in the lactation period. Since certain disease-modifying
antirheumatic drugs have proven to be human teratogens, treatment is
limited in these women. Anti-TNF agents fall within the US FDA category
B concerning fetal risk, indicating that no adequate and
well-controlled studies have been conducted in pregnant or lactating
women. However, in the last decade, numerous case series and case
reports of pregnancies exposed to anti-TNF therapy have accumulated in
the literature. Since these agents may constitute an important
therapeutic alternative in pregnant women facing persistent or
increased disease activity, we propose a review of the available
information on the safety of anti-TNF agents in pregnancy and lactation.
Introduction
Inflammatory arthropathies have variable disease activity during and
after pregnancy. Although many women suffering from these conditions
will improve during pregnancy, some may require continuation of
disease-modifying antirheumatic drugs (DMARDs) throughout pregnancy and
in the postpartum. In this critical period, therapeutic options are
limited since certain DMARDs, such as methotrexate and leflunomide,
have been shown to be teratogenic. Furthermore, anti-TNF agents are not
recommended during pregnancy, in the absence of well-controlled studies
of their safety. However, in recent years, mounting data on pregnancies
exposed to anti-TNF therapy have been published by different
investigators. Since pregnant patients facing persistent active disease
or disease exacerbation may require treatment with these agents, it is
crucial to review the available information on the safety of anti-TNF
therapy.
What is Known (& Unknown)
Anti-TNF agents have demonstrated efficacy in reducing disease activity
and joint damage and improving health-related quality of life in
patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA),
juvenile idiopathic arthritis (JIA) and ankylosing spondylitis (AS).[1]
Commonly used anti-TNF agents include infliximab, a chimeric monoclonal
IgG1 anti-TNF antibody, adalimumab, a human monoclonal IgG1 anti-TNF
antibody, and etanercept, a soluble TNF receptor fusion protein linked
to the Fc portion of a human IgG1.[1] These three agents fall within
the US FDA category B concerning fetal risk, which indicates, in this
case, that 'animal reproduction studies fail to demonstrate a risk to
the fetus but adequate and well-controlled studies of pregnant women
have not been conducted'.[1] Furthermore, drug manufacturers currently
recommend that anti-TNF therapy be avoided during pregnancy and
lactation. However, manufacturers' recommendations often represent
legal considerations and may be hard to strictly follow in the clinical
setting when facing difficult or refractory cases.
Moreover, a recent survey, questioning rheumatologists in the USA about
the safety of anti-TNF agents in pregnancy, showed how clinical
practice may depart from official recommendations and reflected the
paucity of human data available to date.[2] Fewer than half of the
rheumatologists surveyed agreed that pregnancy is contraindicated with
the use of these medications (38.6% for etanercept and 46.5%
infliximab). Almost half stated that they were uncertain about
pregnancy safety with the use of these agents (49.7% for etanercept and
45.4% for infliximab). Despite this uncertainty, respondents generally
recommended effective methods of contraception when prescribing these
agents to their female patients (75.4% for etanercept and 73.4% for
infliximab). However, markedly fewer were likely to review ongoing
contraception with women treated with etanercept or infliximab (41.7
and 43.8%, respectively).
In women of reproductive age suffering from inflammatory arthritis,
adequate treatment of their condition may increase their chances of
reproduction and pregnancy outcome.[1] Indeed, in the past few years,
pregnancies in women with rheumatic diseases have increased and this
may be due in part to treatment advances.[3] Although it is still
controversial if anti-TNF agents have a positive impact on fertility,
anti-TNF therapy may improve reproductive function by decreasing
disease activity and increasing functional status in patients with
inflammatory arthritis.[4] Furthermore, disease activity in
inflammatory arthropathies shows different patterns with pregnancy, and
some of these women may require more-aggressive therapy, such as
anti-TNF agents.
Inflammatory Arthritis in Pregnancy
Several rheumatic diseases exhibit a fluctuation in disease activity
during and after pregnancy. In the majority of women suffering from RA,
the disease improves during pregnancy and flares up in the postpartum
period.[5,6] Retrospective and prospective studies have shown that
66-75% of women with RA will improve during pregnancy.[6-10] Also, if
remission occurs during one pregnancy, it is likely to occur again in
future pregnancies.[11] Improvement in disease activity usually occurs
during the first and second trimesters and is due to a shift toward a
Th2-subtype immune profile, as occurs in normal pregnancy.[12] In late
pregnancy, an increase in IL-1 receptor antagonist (IL-1Ra) and soluble
TNF receptor (TNFR) serum levels correlates with low RA disease
activity.[12] Elevated levels of IL-1Ra and TNFR in the third trimester
may lead to improvement of the disease in patients with RA.
Contrary to RA, in which a Th1 immune response predominates during the
nonpregnant state, in AS, a Th2 immune response prevails.[12] While RA
improves in most pregnant women, AS demonstrates persistent activity
that seems to decrease only in late pregnancy.[12,13] Disease activity
in AS may either be unchanged, improved or worsened, each with equal
frequency.[14,15] Improvement in disease activity during pregnancy is
usually correlated with a history of peripheral arthritis.[15] A
postpartum flare is experienced by 60-90% of females affected by AS,
generally within 6 months after delivery, most often in women with
active disease at conception.[14,15]
Similar to patients with RA, patients with PsA improve or experience
disease remission in 80% of pregnancies.[15] Approximately 70% of PsA
pregnancies have a postpartum flare during the first 3 months after
delivery.[15] In addition, in JIA, quiescent disease is usually not
reactivated by pregnancy, and approximately 60% of patients with active
disease at conception ameliorate during pregnancy.[15] However, most
patients flare in the postpartum period.[15,16] In these women who may
face disease exacerbation during or after pregnancy, it is imperative
to explore the safety of anti-TNF therapy exposure in utero or during
lactation.
Role of TNF-α in Pregnancy
TNF-α is a pleiotropic cytokine released by activated macrophages,
monocytes and T lymphocytes,[17] and plays an important role in
pregnancy. As demonstrated in animal studies, TNF-α is involved in the
control of cell proliferation, pregnancy loss and the development of
peripheral lymphoid tissue.[18,19] In TNF-α-knockout mice, very poor
formation of the secondary structures of lymphoid organs, such as
germinal centers, has been observed.[20] Therefore, exposure to
anti-TNF therapy during pregnancy and at the time of immune system
development could potentially have adverse effects. Furthermore, TNF-α
promotes blastocyst implantation, endometrial vascular permeability and
uterine deciduation by inducing COX-2 gene expression in early
pregnancy.[21] Although it promotes blastocyst implantation in early
pregnancy, TNF-α may mediate recurrent spontaneous abortions at a later
stage, and higher concentrations of serum TNF-α and serum soluble
TNFR-1 have been observed in women with unexplained early spontaneous
abortions.[22] TNF-α is also involved in labour onset by inducing
uterine contractions, in conjunction with other inflammatory
cytokines.[23] TNF-α levels are elevated in the serum and in the
amniotic fluid at the time of labour onset and in adverse conditions
such as fetal growth retardation, pre-eclampsia and pathological
labor.[12,24] TNF-α levels are low in the first trimester, but increase
in the second and third trimesters, peaking at the onset of labor.[23]
However, the mechanism by which TNF-α may induce the demise of the
implanted embryo remains unclear. It has been suggested that ischemic
events within materno-fetal blood vessels trigger death of the
embryo.[25] In murine models, TNF-α is thought to upregulate a
fibrinogen-related prothrombinase, fgl2, which generates thrombin.[25]
Thrombin production through this pathway leads to compromise of the
placental circulation. The protein C anticoagulant system is the
principal inhibitor of thrombin generation. This anticoagulant system
includes protein C, protein S, activated protein C, thrombomodulin and
endothelial cell protein C receptor (EPCR).[26-28] Protein C and
thrombin have opposite roles; protein C promotes trophoblast growth and
controls excessive fibrin deposition whereas thrombin production
inhibits trophoblast growth.[29] At sites of damaged endothelium, there
is crosstalk between inflammatory and thrombogenic systems.[30] TNF-α
is known to downregulate protein C, thrombomodulin and EPCR, altering
the balance between procoagulant and anticoagulant molecules.[31]
TNF-α may also promote embryonic death by triggering an apoptotic
signal in reaction to embryonic structural defects caused by a
detrimental stimulus.[1] A study showed that pregnant mice had markedly
increased levels of natural killer (NK) cells producing TNF-α and
TGF-β2, and promoting spontaneous abortions in the presence of another
stimulus.[32] Paradoxically, TNF-α may trigger protective mechanisms if
repair of the structural defects is possible.
In addition, during pregnancy, soluble cytokine receptors, such as
TNFR, are involved in the regulation of cytokines' activities, such as
TNF-α. Soluble cytokine receptors can antagonize cytokine activity by
binding them. In healthy pregnant women, levels of soluble cytokine
receptors are increased.[33] Indeed, when compared with the levels of
nonpregnant women, TNFR has been found to increase significantly in the
second and third trimesters of pregnancy.[13]
Anti-TNF Therapy & Infertility
As TNF-α is a pleiotropic cytokine involved in pregnancy, with
potential adverse effects, some investigators have proposed a
beneficial effect of anti-TNF agents in infertility. As elevated TNF-α
levels have been shown to be associated with recurrent spontaneous
abortions, it has been hypothesized that lowering TNF-α might prevent
this complication. Indeed, it has been demonstrated that the Th2 bias
observed in women having a normal pregnancy was significantly increased
compared with women with unexplained recurrent pregnancy losses.[13]
This suggests that recurrent pregnancy losses may be associated with a
Th1 bias. Anecdotal experiences of the use of anti-TNF agents to treat
infertility have been reported in patients with inflammatory diseases,
such as Crohn's disease and psoriasis.[34]
However, the use of anti-TNF agents to treat infertility has raised
some concerns about the potential risks and benefits, as well as
appropriate attainment of informed consent in patients who may be
desperate to give birth and be more inclined to agree to risky
therapy.[4] Multiple immune therapies, such as intravenous
immunoglobulins (IVIGs) and steroids, have been used with unclear
efficacy to treat healthy, asymptomatic women who have difficulty in
conceiving and have been diagnosed as having 'subclinical
autoimmunity'.[4] Some authors are concerned by the employment of these
therapies by noninternists and/or nonreproductive endocrinologists who
manage infertility, and pinpoint the lack of recognized standards or
board certifications required for a physician to practice as a
reproductive immunologist.[4] A potential use of etanercept to treat
infertility may relate to its effect on lowering NK-cell levels;
however, it is still controversial as to whether increased levels of NK
cells cause miscarriages or prevent conception, or whether anti-TNF
agents, such as etanercept, prevent this by decreasing the levels of
these cells.[4]
Although it generates controversy, research assessing the efficacy of
anti-TNF therapy in infertile patients has been performed. A recent
study by Winger et al. retrospectively analyzed patients with a history
of recurrent spontaneous abortions (defined as more than three
miscarriages) who were treated with combinations of anticoagulants,
IVIGs and anti-TNF agents.[25] These investigators aimed to determine
if the addition of an anti-TNF agent could increase the success rates
of their standard protocol of heparin and IVIG. In total, 75
pregnancies were retrospectively evaluated. Subjects were divided into
three groups: group I were treated with heparin alone (21 patients),
group II were treated with heparin and IVIG (37 patients) and group III
were treated with heparin, IVIG and etanercept or adalimumab (17
patients). Patient groups were formed partly through self selection and
partly through differences in initial work up and history. For example,
patients with a more-difficult reproductive history, such as repeated
in vitro fertilization (IVF) failure, in addition to recurrent
miscarriages, were offered the more-aggressive anti-TNF protocol. In
group III, either adalimumab 40 mg injected subcutaneously every 1-2
weeks or etanercept 25 mg injected subcutaneously every 84 h was
administered. The anti-TNF agent was generally started 1 month before
initiating a cycle of conception and was continued until ultrasound
evidence of fetal cardiac activity. Subjects from the three groups were
relatively homogeneous for age, past miscarriages, inherited
thrombophilia and autoimmunity, except that group III had higher levels
of NK cells and positivity for antinuclear and antiphospholipid
antibodies.
Live birth rates were greater within group III and were as follows:
group I: 19% (four out of 21), group II: 54% (20 out of 37) and group
III: 71% (12 out of 17).[30] Fetal outcomes, such as gestational age
and birth weight, were similar for the three groups. A 42-year-old
woman in group II delivered a baby with Down's syndrome. No other
congenital anomaly was reported in this study. It is unclear why
patients receiving anti-TNF agents had higher rates of live births. The
authors hypothesized that the beneficial effect of the anti-TNF agent
may have been mediated by proteins of the protein C anticoagulant
system, since TNF-α is known to downregulate some of these proteins.
The impact of anti-TNF therapy on male fertility is also of interest
and several studies have investigated this issue. The effect of
anti-TNF agents on spermatozoa quantity and quality is debated. Some
studies have reported that TNF-α negatively affects spermatozoa
motility, morphology and genomic integrity.[35-37] Other studies showed
no evidence of an effect of TNF-α on sperm motility or apoptosis.[1]
Moreover, in a study performing semen analysis in ten men suffering
from Crohn's disease and treated with infliximab, a decrease in
spermatozoa motility and quantity was observed;[38] however, this study
was quite small. These studies show conflicting results and it is
therefore difficult to draw conclusions regarding the effect of
anti-TNF therapy on male reproductive function.
Safety of Anti-TNF Therapy in Animal Studies and Anti-TNF Agent Transfer Through the Placenta & Lactation
Safety of Anti-TNF Therapy in Animal Studies
Several studies assessing the safety of anti-TNF therapy have been
conducted in animal models. However, because anti-TNF antibodies do not
bind with TNF-α in species other than humans and chimpanzees,[39]
animal studies were not performed with the actual anti-TNF antibodies
used in humans Therefore, an analogous anti-TNF antibody that
selectively inhibits murine TNF-α was used to conduct reproductive,
developmental and fertility toxicology studies in mice.[39] No evidence
of anti-TNF antibody embryotoxicity or teratogenicity has been
demonstrated in animal studies. In addition, other animal studies using
a soluble TNFR combined with an IgG heavy-chain chimeric protein
reported no embryotoxicity or teratogenicity.[40]
Anti-TNF Agent Transfer Through the Placenta & Lactation
The molecular structures of anti-TNF agents, including chimeric and
human IgG1 anti-TNF antibodies, and soluble receptor fusion protein
linked to the Fc portion of human IgG1, allow minimal placental
transfer during the first trimester, but passage through the placenta
cannot be ruled out during the second and third trimesters.[41]
Although there are no published studies on the ability of engineered
molecules such as infliximab, adalimumab and etanercept to cross the
placenta, in primates, there is substantial placental transfer of
maternal IgG to the fetal circulation before birth, and the IgG1
subtype is readily transported across the placenta with the help of
immunoglobulin-binding proteins.[41] Transplacental transfer of
maternal IgG starts early during the second trimester and peaks near
term.[41] It has been observed that exogenous IVIG administered to
immunodeficient mothers crossed over to the offspring.[42] Furthermore,
it has been demonstrated that maternally derived IgG antibodies, such
as varicella and measles antibodies, can take more than a year to be
cleared by the child.[43]
Until recently, there was no evidence that engineered therapeutic
antibodies administered perinatally to pregnant women crossed the
placenta.[39,44] However, a recent study reports that a child exposed
to infliximab during pregnancy had therapeutic levels of infliximab at
6 weeks of age.[43] His mother suffered from refractory Crohn's disease
and had received five infusions of infliximab at a dosage of 10 mg/kg
during her pregnancy. Her last infusion was administered 2 weeks before
delivery and infliximab was not detected in her breast milk. The
child's serum levels of infliximab slowly declined over the next 6
months and the child's evaluation at 6 months revealed no immunologic
abnormality, including normal T- and B-cell levels, normal
immunoglobulin concentrations, and normal and protective humoral
responses to conjugated polysaccharide vaccines. This case raises some
concerns as to whether children exposed to anti-TNF therapy during
pregnancy might develop adverse events, such as drug-induced lupus,
human antichimeric antibodies (HACA), demyelinating disorders or
lymphoma.[43]
The amount of IgG1 secreted in breast milk is very small.[43] It would
be unlikely that infliximab and adalimumab would be found in breast
milk in a clinically significant quantity. The case reported by
Vasiliauskas et al. is consistent with this, and other investigators
have found absent or undetectable levels of infliximab in the breast
milk of treated patients.[1,44] However, another case report showed an
accumulation of infliximab in breast milk from a woman with RA.[45]
Even if infliximab may accumulate in breast milk, the antibody is
likely to be digested in the GI tract of the child, in theory
minimizing the risk of toxicity through breast feeding exposure.[46]
In humans, etanercept is secreted into breast milk and, until more data
are available, lactation should be discouraged during etanercept
treatment.[47] However, because etanercept is a protein, as is the case
for infliximab and adalimumab, it is likely to be digested in the GI
tract of the child and not be absorbed systemically.[46]
Case Series of Anti-TNF Therapies in Human Pregnancies
Infliximab
A large case series has been published of 96 pregnancies in women with
Crohn's and rheumatic diseases who were exposed to infliximab at
conception and/or during the first trimester.[48] They observed 68 live
births, 14 miscarriages and 18 therapeutic abortions. One child born at
24 weeks experienced intracerebral and intrapulmonary bleeding and
died. Another child developed respiratory distress and seizures. Two
children presented with congenital malformations: one had tetralogy of
Fallot and the other an intestinal malrotation. Some of these women
were concomitantly exposed to other drugs during pregnancy, such as
leflunomide, azathioprine and metronidazole, which may have played a
role in the anomalies.
The Crohn's Therapy, Resource, Evaluation and Assessment Tool (TREAT)
registry observed 66 women with Crohn's disease.[49] Of these, 36 were
exposed to infliximab. No birth defects were reported. Furthermore, the
rates of miscarriage and neonatal complications were not different
between infliximab-treated and untreated patients.
Mahadevan et al. reported on the intentional use of infliximab during
pregnancy for induction or maintenance of remission in ten women with
Crohn's disease.[44] Eight women received infliximab throughout
pregnancy, one was exposed to infliximab during the first trimester
only and one began therapy in the third trimester. All ten pregnancies
ended in live births. There were no congenital malformations. There
were three premature births, one low-birth-weight child and one child
who developed respiratory distress.
Tursi described a woman with Crohn's disease treated with infliximab
for induction and maintenance of remission throughout pregnancy. The
patient gave birth to a healthy child at 36 weeks of gestation. No
adverse events were reported.[50] Two other cases of women with Crohn's
disease exposed to infliximab during the first trimester of pregnancy
resulted in healthy live births.[51,52] A miscarriage in a woman
exposed to infliximab and methotrexate was also reported.[53]
Etanercept
A large study assessed pregnancy outcomes in 417 pregnant women with RA
exposed to anti-TNF agents.[54] Etanercept was the agent used in 81% of
cases. Of the 417 pregnancies, 387 normal deliveries were observed.
There were 25 miscarriages, five therapeutic abortions and nine preterm
births. The rates of these events were comparable to general population
figures.[55] No malformations or neonatal deaths were reported.
The Organization of Teratology Information Services (OTIS) collected
information on 33 pregnant RA patients who were exposed to etanercept
(29) or infliximab (four), without concomitant methotrexate therapy,
during the first trimester.[56] These patients were compared with 77
patients with RA who were treated with various agents, including DMARDs
but not with anti-TNF agents, with 50 healthy controls. Preterm
delivery was more frequent in patients on anti-TNF agents (28.0% for
etanercept) and in the RA control group (23.5%), compared with the
healthy subjects (4.3%). This difference was most likely due to the
underlying disease. Spontaneous abortions occurred with both etanercept
(three) and infliximab (one). A trisomy 18 chromosomal abnormality,
ending in spontaneous abortion, was observed in one etanercept-exposed
pregnancy. No difference in the rate of congenital malformations was
observed between the three groups.
The British Society of Rheumatology Biologics Register reported 22
pregnancies in women with rheumatic diseases who were exposed to
anti-TNF therapy at the time of conception (16 etanercept, three
infliximab and three adalimumab).[57] Nine of these women were on
concomitant methotrexate therapy and two were receiving leflunomide.
All patients stopped their therapy during the first trimester, except
two patients on etanercept who continued treatment throughout
pregnancy. This resulted in six first-trimester miscarriages (three in
patients also receiving methotrexate and one receiving leflunomide at
conception), three elective abortions and 13 live births (one born
preterm and one with low birthweight). The two patients exposed to
etanercept throughout pregnancy had a Caesarian section (one secondary
to fetal distress). No birth defects were observed. One patient treated
with adalimumab, which was discontinued during the first trimester,
reported recurrent cystitis during pregnancy.
The Spanish registry BIOBADASER observed 14 pregnancies in women with
inflammatory arthritis exposed to anti-TNF agents (eight etanercept,
four infliximab and two adalimumab).[58,59] They reported seven live
births with no complications in four subjects treated with etanercept
and three treated with infliximab. In addition, they reported three
therapeutic abortions (two etanercept and one adalimumab) and one
spontaneous abortion (infliximab), while three pregnancies had no
available outcome. No congenital malformations were reported.
In a study using questionnaires administered to rheumatologists,
Chakravarty et al. reported 15 pregnancies in women with rheumatic
diseases exposed to etanercept and two exposed to infliximab.[2] One
pregnancy, in a patient treated with both etanercept and methotrexate,
resulted in a miscarriage. The six pregnancies with known outcomes in
women exposed to etanercept (without methotrexate) resulted in normal
deliveries. Of the two pregnancies exposed to infliximab, one resulted
in a full-term healthy baby, while the outcome of the other pregnancy
was not stated. No congenital malformations were reported.
In a recently published review article, Skomsvoll et al. reported six
pregnancies in five women treated with etanercept during the first
trimester.[1] These pregnancies resulted in two miscarriages and four
full-term healthy babies. Furthermore, five pregnancies in women
suffering from RA and JIA were documented by Koskvik et al., and ended
in three live births and two miscarriages.[60]
Roux et al. observed a group of 442 patients treated with anti-TNF
agents, in which three women with RA unexpectedly became pregnant.[24]
One women treated with etanercept opted for a therapeutic abortion,
despite a normal ultrasound and satisfactory fetal evolution. One
patient with adalimumab exposure delivered a healthy baby at 32 weeks
gestational age. One patient with etanercept exposure delivered a baby
who suffered from a neonatal urinary infection and adrenal congenital
hyperplasia of probable hereditary origin.
In addition, normal deliveries and live births have been reported in
women with RA exposed to etanercept during the first trimester and
throughout pregnancy.[61,62]
Carter et al. recently described a woman with PsA who received
etanercept 50 mg subcutaneously twice weekly throughout her
pregnancy.[63] This patient gave birth to a child with tracheal
atresia, tracheoesophageal fistula, oesophageal atresia, unperforata
anus, hypospadias, T12 vertebral anomaly, spina bifida occulta and
patent foramina ovale. These manifestations were consistent with VATER
association (V: vertebrae anomalies; A: anal anomalies; T: tracheal
problems; E: esophageal problems; R: radius or renal defects) without
renal or limb abnormalities.
Adalimumab
Fewer data on adalimumab exposure during pregnancy are available, since
this agent was introduced to the market only relatively recently. In a
study of 61 pregnant women with inflammatory arthropathies, four were
exposed to adalimumab.[64] No maternal or fetal adverse outcomes were
reported.
Furthermore, a woman with refractory Crohn's disease was treated with
adalimumab throughout pregnancy. Her pregnancy was uncomplicated and
she delivered a healthy child with no congenital malformations.[65]
In addition, Coburn et al. described a pregnant woman with refractory
Crohn's disease who received adalimumab induction and maintenance
therapy during the second and third trimesters of pregnancy. This
resulted in a normal delivery and no fetal adverse outcomes were
reported.[66]
Expert Commentary
Current available data do not seem to support a large excess risk of
adverse pregnancy and/or fetal outcomes in women exposed to anti-TNF
therapy at some point during pregnancy. However, evidence is limited by
the relatively small number of published case series and case reports,
differences in the type and dosage of anti-TNF agents, possible use of
concomitant teratogenic drugs (e.g., methotrexate and leflunomide) and
the timing of exposure during pregnancy. Indeed, most of the data
relate to exposures during the first trimester and few patients have
been exposed throughout pregnancy or in the second or third trimester.
Furthermore, no long-term follow-up studies are available at this time.
As therapeutic levels of anti-TNF agents have been observed in a child
exposed to one of these agents late in pregnancy,[43] more information
is needed regarding adverse outcomes during infancy. In addition, some
adverse effects of in utero drug exposure might be observed decades
later in the offspring, as was the case for in utero exposure to
diethylstilbestrol (DES) and clear cell adenocarcinoma (CCA) of the
vagina and cervix,[67] highlighting the importance of long-term
follow-up studies.
Few authors have reported congenital malformations after exposure to
anti-TNF therapy. However, a recent unpublished report, which analyzed
FDA data on adverse events following the use of anti-TNF agents since
they became commercially available until 2005, revealed 41 cases of
children with congenital anomalies born to mothers taking these drugs
during pregnancy.[68] Nonetheless, no information on the total number
of women exposed to these agents during pregnancy could be provided, so
an incidence measure could not be estimated. Furthermore, in one study,
the overall number of reported malformations was not increased in women
exposed to anti-TNF therapy compared with general population
figures,[52] and no causal relationship has been proven.
Considering this uncertainty, it is clear that each woman requiring
disease-modifying drugs during her pregnancy must be evaluated
individually. In cases without a therapeutic alternative, anti-TNF
therapy has been used in the first trimester of pregnancy. However,
during the late second or third trimester, more caution is advised
since placental transfer, with therapeutic levels in the newborn, has
been documented. Furthermore, in women requiring disease control during
the period of attempted conception, which can be prolonged, anti-TNF
agents are probably one of the best therapeutic options when compared
with other DMARDs, such as methotrexate and leflunomide, which must be
stopped several months prior to conception. Finally, the toxicity of
anti-TNF therapy exposure during lactation is theoretically negligible
since these agents are likely to be digested in the GI tract of the
infant. However, in all situations, it is imperative to provide
appropriate information to the patient and family (including admission
of what remains unknown), so that the potential risks and benefits can
be weighed.
Five-year View
With the emergence of postmarketing surveillance of anti-TNF agents,
more prospective data collection is expected over the next 5 years.
This will allow for assessment of the adverse events after in utero
exposure to anti-TNF agents, compared with the general population or
other women with inflammatory arthritis not treated with anti-TNF
agents. Furthermore, studies linking data from drug and birth
registries are underway.[1]
END QUOTE
I think this is what it says.
The TNFs help women become pregnant, they aren't sure if its the actual TNFs interacting with various molecules or the fact that women who feel better, have more sex thus getting pregnant.
Though they won't know for 20-30 years, using TNFs in the first trimester is fine causing no problems. It is the late second trimester and third trimester where they recommend stopping the TNF if the woman can tolerate the disease level. No indications of birth problems but a couple babies had Remicade in their bloodstream 4 weeks after birth.
Also it is not passing in the breast milk, and the one TNF where it is, appears to be theoretically negligible because it will go through the digestive system.
The mothers who had problem births were taking MTX and Arava during their pregnancy.
Please correct me if I am wrong.Yeah, thats pretty much what I got too. I also thought I read into that woman with repeated, unexplained miscarriages like me, may benefit from treatment with TNF before pregnancy because it helps reduce the overall inflammation or something reducing the miscarriage rate???
I didn't really feel "sick" until after the second miscarriage but there are many signs that point to the probability of me having sarcoidosis since my late teens. I lost 5 babies in all, one was too early to test but the other 4 where all chromosomally healthy and no explanation has ever been found so not sure if I'm reading what I want into the article or not?
I'm on remicade but because of my history of blood clots can't use any hormonal birth control and I couldn't tolerant a diaghram. I feel that I am still to sick to really have a baby but I also admit to not ALWAYS practicing safe sex. I'm 38 and have pretty much accepted the fact I will never have a child but if some miracle happens, than it was definitely met to be. Its just really hard finding good info on the drugs we take and pregnancy.
Wow, thanks for posting! I will have to remember to read carefully later!
Copyright ArthritisInsight.com