Risk-benefit balance assessment of colchicine use during pregnancy

Horta-Baas, Gabriel
doi:10.1016/j.medcle.2016.12.055
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    "titulo" => "Risk-benefit balance assessment of colchicine use during pregnancy"
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">I have read the article published by Alijotas-Reig et al&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">1</span></a>&#44; in which colchicine was excluded because of its poor current use&#46; However&#44; in our days this drug continues to demonstrate its utility in the clinic&#44; and may be necessary in pregnancy in the familial Mediterranean fever &#40;FMF&#41;&#44; Beh&#231;et&#39;s disease &#40;BD&#41; and gout&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Colchicine has been routinely prescribed off-label &#40;OL&#41; for many years&#46; Its use for the treatment of arthritis dates back about 3000 years in ancient Greece and since the 19th century it was available for use in tablets for the treatment of gout&#46; However&#44; it was not until 2009 when it was approved by the <span class="elsevierStyleItalic">Food and Drug Administration</span> &#40;FDA&#41; for the treatment of gout and FMF&#46; Its use in pregnancy and BD remains OL&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Although colchicine is considered teratogenic in animals&#44; in most experiments with doses 30&#8211;50 times higher than those used in humans&#44; not all studies demonstrate this effect&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> It has embryotoxic effects in rabbits and cows&#44; but not in monkeys&#44; and in mice the effects are contradictory&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Furthermore&#44; it is not clear whether the teratogenic effect was due to the inhibition of mitosis or other pharmacological action&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> In humans&#44; transplacental passage was demonstrated by the presence of colchicine in umbilical cord blood in a healthy newborn &#40;NB&#41; of a 23-year-old woman with FMF who took 1<span class="elsevierStyleHsp" style=""></span>mg&#47;day of colchicine throughout pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Because of this and the potential risk of causing chromosomal abnormalities&#44; regulatory agencies consider its use contraindicated during pregnancy&#46; The FDA considers it a class C drug and should only be used if the benefit justifies the risk to the fetus&#46; For its part&#44; the Spanish Agency of Medicines and Medical Devices &#40;AEMPS&#41; considers its use contraindicated&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The regulations governing OL use&#44; as well as the medico-legal implications in case of adverse events&#44; are not uniform in all countries&#44; and their discussion is beyond this letter&#46; The AEMPS provides for the responsible use of OL in situations where there are no authorized therapeutic alternatives&#44; respecting the restrictions of prescription and therapeutic treatment protocol&#46; The physician must justify in the clinical history the necessity of using the medication and inform patients of the possible risks and benefits&#44; obtaining their informed consent&#46; The ethical justification for OL prescribing is that it can provide the best treatment available to the patient&#44; not forgetting that its use may give rise to liability for negligence if it does not meet the accepted standards of care&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Non-experimental OL use can be rational and appropriate if it has scientific support&#46; The purpose of this letter is to offer physicians the available scientific evidence that supports the use of colchicine during pregnancy&#46; Ehrenfedl et al&#46;&#44; in 1987&#44; reported that all NB of women exposed to colchicine in pregnancy were healthy&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Rabinovitch et al&#46; reported in 225 pregnancies in women with FMF that the use of chronic colchicine before or during pregnancy did not increase the rate of congenital malformations or alterations in the growth or development of children&#46; In the group exposed&#44; 2 cases of Down syndrome &#40;DS&#41; were presented&#44; which the author considered possibly attributed to chance&#44; since the same author reported that in 430 amniocentesis of women with FMF&#44; no additional cases were identified<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a>&#46; From this publication a possible association of colchicine with DS was raised&#59; however&#44; this association was not demonstrated in other studies &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; The results of these investigations show that the frequency of congenital malformations and chromosomal abnormalities is similar to that expected for the general population or comparison groups&#44; additional cases of DS were not documented&#44; and the frequency of abortions and fetal deaths was similar to that of the non-exposed groups&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">3&#44;4</span></a> On the contrary&#44; its use was associated with a lower frequency of abortions and exacerbations of FMF during pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> Before the use of colchicine&#44; FMF was associated with a higher rate of miscarriage&#46; Control of seizures can reduce the presence of peritonitis&#44; peritoneal adhesions&#44; mechanical infertility and increase their reproductive capacity&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">Noel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> evaluated 76 pregnancies of women with BD&#59; 43 &#40;56&#46;6&#37;&#41; were exposed to colchicine without noticing an increase in obstetric complications and no congenital malformation was documented&#59; on the contrary&#44; they had a lower frequency of exacerbations during pregnancy&#46; There are only case reports of the use of colchicine in women with gout&#44; which is the most frequently used for the treatment of acute attacks of gout during pregnancy&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Considering the theoretical risk of teratogenesis&#44; the suspension of colchicine seems to carry a greater risk than its maintenance in women with FMF&#44; so it is recommended to continue it during pregnancy and to perform amniocentesis between months 4&#8211;5 to determine the fetal karyotype&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> In assessing risk-benefit&#44; consideration should be given to complications of amniocentesis &#40;chorioamnionitis and fetal loss in one out of every 200 procedures&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> Because its association with chromosomal abnormalities has not been demonstrated&#44; some authors consider that there is no justification for recommending amniocentesis in all cases&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> Other authors advise the use of non-invasive methods for the detection of DS&#44; such as nuchal translucency ultrasound and the triple marker test&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">The simple classification of colchicine as authorized or unauthorized in pregnancy is not always possible&#44; since the risk-benefit balance may be different between diseases or duration of pregnancy&#46; For example&#44; the evidence supports not suspending it in FMF for benefit in disease control&#59; however&#44; there is less evidence in the case of BD or gout&#44; in which the risk may be less acceptable due to the scarce available information&#46; However&#44; it should be considered that in the case of rare diseases in pregnancy&#44; they are largely dependent on OL indications&#44; where doctors rely on exposure to these drugs inadvertently and communicated to the scientific community&#44; and observational studies&#46; Frequent clinical use of OL drugs may not be surprising because pregnant women are excluded in clinical trials&#44; which&#44; coupled with the limited number of cases&#44; makes it inconceivable to evaluate their use in accordance with clinical trial criteria&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">One of the limitations of colchicine is its narrow therapeutic range&#59; the use of low doses is associated with a better risk-benefit balance and this drug in overdose is very toxic&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">2</span></a> Studies show that the use of doses between 1 and 1&#46;5<span class="elsevierStyleHsp" style=""></span>mg&#47;day does not entail any substantial teratogenic risk&#46; When prescribed in obstetrics&#44; the recommendations generally come from the clinical guidelines rather than from the summary of product characteristics&#44; and these are the ones that provide the level of care both in practice and legally&#46; In a recent guide published under the auspices of the European League Against Rheumatism&#44; the use of colchicine was considered medically acceptable by experts&#44; since most recommended continuing the drug in the same way as if the patient was not pregnant&#44; and none considered &#8220;never recommending the drug during pregnancy&#8221;&#59; the final recommendation was that colchicine &#40;up to 1<span class="elsevierStyleHsp" style=""></span>mg&#47;day&#41; may be used in pregnancy to maintain remission or in treatment of disease exacerbation &#40;Grade of recommendation B&#41;&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Finally&#44; it is a difficult task and of questionable utility for regulatory agencies to authorize OL applications on a case-by-case basis&#46; Physicians who consider an OL indication may rely on pharmacotherapeutic committees to assess risks and protect the best interests of patients&#46;</p></span>"
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                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Author &#40;year of publication&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Design&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Subjects included&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Exposed group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Group not exposed&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Conflict of interests&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ehrenfedl et al&#46; &#40;1987&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prospective Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">36 women&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">28 pregnancies &#40;11 pregnancies<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">24 pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The percentage of abortions was similar between groups&#46; In the exposed group&#44; 5 therapeutic abortions were performed<br>All newborns exposed &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>6&#41; to colchicine in pregnancy were healthy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not declared&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Rabinovitch et al&#46; &#40;1992&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ambispective cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">116 women&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">91 pregnancies<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><br>40 pregnancies<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">94 pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Spontaneous abortions were more prevalent in the untreated group &#40;20&#46;2 vs 12&#46;2&#37;&#41;<br>Exposure to colchicine did not increase the rate of congenital malformations or alterations in the growth and development of children<br>They reported 2 cases of trisomy 21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not declared&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Berkenstadt et al&#46; &#40;2005&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Retrospective cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">90 men and 326 women with FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">901 Pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No control group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">556 amniocentesis were performed&#44; 3 procedural losses and 3 therapeutic abortions were reported&#46; In the karyotype&#44; a case with 21<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> trisomy&#44; 4 chromosomal abnormalities and a balanced translocation were documented&#46; Seven cases had congenital malformations&#46; Chromosomal abnormalities and congenital malformations were similar to those expected in the population&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not declared&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Diav-Citrin et al&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">4</span></a> &#40;2010&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prospective Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">238 pregnancies<br>FMF&#58; 87&#46;3&#37;<br>Beh&#231;et&#58; 7&#46;5&#37;<br>Gout&#58; 0&#46;4&#37;<br>Others&#58;4&#46;8&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">238 &#40;97&#37; during the first trimester&#41;<br>79&#46;7&#37; pregnancies<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">964 pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No differences were shown in the frequency of congenital malformations &#40;4&#46;7 vs 3&#46;2&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#44; abortions &#40;5 vs 5&#46;7&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41; or fetal deaths &#40;0&#46;8 vs 0&#46;5&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#46;<br>No reported chromosomal abnormality&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Not declared&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Ben-Chetrit et al&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">3</span></a> &#40;2010&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Ambispective cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">132 women with FMF&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">179 pregnancies<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a><br>104 pregnancies<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">197 with FMF<br>312 healthy women&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The number of abortions was lower in the exposed group &#40;18<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> vs 26<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> vs 31&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#46; No differences in congenital malformations &#40;1<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> vs 2<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a> vs 1&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>ns&#41;&#46; No case of trisomy 21 was reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Nabil et al&#46; &#40;2012&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Prospective Cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74 women with FMF and infertility&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">62 exposed women&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No control group&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">26 achieved pregnancy&#46; Maternal-fetal outcomes were similar to those expected for the general population<br>No congenital anomaly was reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry  " colspan="7" align="left" valign="top"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Noel et al&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">5</span></a> &#40;2013&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">Retrospective cohort&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">76 Pregnancies of women with Beh&#231;et&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">43 Pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">33 Pregnancies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">The frequency of exacerbations was lower in the exposed group &#40;27&#46;9 vs 45&#46;4&#37;&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;11&#41;<br>No cases of congenital malformation were reported&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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