Fetal Harm Research Articles

Broadening Indications for Maternal Influenza Vaccination

The primary indication for influenza vaccination of pregnant women is to decrease the risk of serious complications during pregnancy [1]. The case fatality rates for pregnant women during the influenza pandemics of 1918 and 1957 ranged from 20% to 50% in various reports [2]. As a consequence, pregnancy— with or without comorbidities—was considered a high-risk condition by the Surgeon General’s Advisory Committee. A large collaborative perinatal project sponsored by the National Institute for Neurological and Communicative Disorders and Stroke from 1959 to 1965 enrolled over 50 000 pregnant women and their offspring who were intensively followed for all events prior to and after delivery found that influenza vaccine administered to 2291 women during pregnancy had no untoward effects [3, 4]. From this study, it can be estimated that about 2 million women received influenza vaccine during pregnancy between 1959 and 1965. Despite the evidence of safety, influenza vaccine was no longer recommended for pregnant women without chronic underlying conditions after 1966 because ‘‘influenza-associated excess mortality among pregnant women has not been documented except in the pandemics.’’ [5]. Reports of influenzarelated deaths continued to occur, and the sensitivity of the data derived from death certificates was questioned [6, 7]. In the early 1990s, investigators looked at risk of influenza-associated hospitalizations during pregnancy and found significant excess occurrence of pneumonia that increased as the pregnancy progressed. This led to reconsideration of the indication for influenza vaccination during pregnancy. In 1995, influenza vaccine was encouraged for all pregnant women who would be in the third trimester during an influenza season [8]. Two years later, all pregnant women in the second or third trimester during an influenza season were recommended to receive influenza vaccine [9]. The recommendation was extended in 2004 to include all pregnant women and women who will become pregnant during the influenza season [10]. It is logical to assume that vaccineinduced maternal immunoglobin G (IgG) antibodies transmitted to the fetus would provide protection for the infant during the first months of life [11]. Protection against all febrile acute respiratory illness and laboratory-confirmed illness was demonstrated in a controlled trial in Bangladesh by Zaman et al. in 2008 [12]. Subsequently, several reports showed reduced influenza-related hospitalizations of infants born to vaccinated women [13–15]. However, the potential benefit of pregnancy vaccination goes beyond prevention of acute respiratory illness in early infancy. An added observation of the Zaman et al. study in Bangladesh was that the infants born to influenzavaccinated women had significantly higher birth weights than those born to women who received the pneumococcal vaccine. In addition, a cohort analysis of Georgia surveillance data showed reduced likelihood of prematurity associated with maternal influenza vaccination [16]. This observation was confirmed by a 13-year retrospective study in Nova Scotia[17], and a prospective study in Rhode Island of women infected with the 2009 pandemic influenza A (H1N1) virus [18]. Coupled with observations of fetal distress occurring with maternal febrile illness leading to premature labor and emergency cesarean section, this provides a broader view of the potential fetal harm resulting from influenza during pregnancy [6]. The report by Bloom-Feshbach et al [19] in this issue of The Journal of Infectious Diseases provides further evidence of the risk of maternal influenza for the fetus. Significant reductions in live births were observed in the United States and Scandinavian countries after the most intense wave of the 1918 pandemic with the nadir of births 6.1 to 6.8 months after the respective peaks of influenza-related mortality. The authors concluded that the observed drop in birth rates was consistent with the concept that infection with the pandemic influenza virus caused first-trimester miscarriages in approximately 10% of pregnant women. The average decline in Received 20 June 2011; accepted 20 June 2011. Correspondence: W. P. Glezen, MD, MVM Department, One Baylor Plaza, MS:BCM-280, Houston, TX, 77030 (wglezen@bcm.edu). The Journal of Infectious Diseases 2011;204:1151–3 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com 0022-1899 (print)/1537-6613 (online)/2011/2048-0001$14.00 DOI: 10.1093/infdis/jir513

Successful Twin Pregnancy Outcome After In Utero Exposure to FOLFOX for Metastatic Colon Cancer: A Case Report and Review of the Literature

There is limited experience in treating advanced colorectal cancer diagnosed during pregnancy because it is a rare occurrence; however, the incidence of colorectal cancer complicating pregnancy is expected to increase in the future. The combination of cancer and pregnancy is complicated and causes many dilemmas and concerns for the physician and patient. A delay in treatment may compromise maternal survival; however, therapy for the cancer may be harmful to the fetus. We present a case of a 26-year-old woman pregnant with twins who was diagnosed with metastatic colon cancer and treated with 5-fluorouracil, leukovorin, and oxaliplatin (FOLFOX) from 13 weeks gestational age to birth. The patient gave birth to healthy twins without malformations at 33 weeks gestational age. At follow-up examination, the 2-year-old twins are developing normally. The patient herself died 1 year after the initial cancer diagnosis. This shows a case in which the administration of FOLFOX during the second and third trimester of pregnancy caused no fetal harm. These findings are similar to those of previous studies in which systemic chemotherapy administered during the second and third trimester was relatively safe. However, we know that chemotherapy should be avoided during the first trimester.

Prescription drug use during pregnancy in developed countries: a systematic review

To review the literature describing patterns of outpatient prescription drug use during pregnancy by therapeutic category, potential for fetal harm, and overall. We conducted a systematic review of peer-reviewed literature published from 1989 to 2010. We included studies evaluating individual-level exposures to prescription medicines during pregnancy. We selected only studies conducted in developed (Organization of Economic Co-operation and Development) countries and published in English. Published drug utilization studies reveal wide variation in estimates of overall prescription drug use in pregnancy (27-93% of pregnant women filling at least one prescription excluding vitamins and minerals). Among studies of similar design, estimates were lowest in Northern European countries (44-47%) and highest in France (93%) and Germany (85%). Measured rates of use of contraindicated medicines in pregnancy ranged from 0.9% (Denmark, 1991-1996) to 4.6% (USA, 1996-2000). The use of medicines with positive evidence of risk ranged from 2.0% (Italy, 2004) to 59.3% (France, 1996). Avoidable inconsistencies in study design and reporting attenuate conclusions that can be drawn from the literature on antenatal drug utilization. Nevertheless, the body of published research shows that antenatal prescription drug use is common, with many studies finding that a majority of women use one or more prescription medicine during pregnancy. Similarly, studies consistently report the use of drugs recognized as having potential risks in pregnancy. Given this widespread use, it is particularly important to develop standards for calculating and reporting antenatal exposures to improve the value of future research in this area.

Chemotherapy for Gynecologic Cancers Occurring During Pregnancy

Chemotherapy treatment of gynecologic malignancies during pregnancy should provide maternal benefit without undue fetal harm. We review the treatment regimens for gynecologic cancers occurring during pregnancy and the effects of chemotherapy on fetal development, parturition, and lactation. Women diagnosed with a gynecologic cancer during pregnancy require individualized treatment plans from a multidisciplinary team. Obstetricians & gynecologists, family physicians. After completing this CME activity, physicians should be better able to specify the indications for chemotherapy in gynecologic cancers during pregnancy and postpartum periods, discuss the risks and benefits of chemotherapy for gynecologic cancer during pregnancy and postpartum periods. In addition, they should also be able to distinguish the mechanism of action of various chemotherapy agents to choose the best treatment options for patients and monitor for impacts of chemotherapy on fetal growth to determine the best treatment and management strategies.

Medication use for chronic health conditions by pregnant women attending an Australian maternity hospital

Most women use medications at some stage in their pregnancy. Medication nonadherence during pregnancy could be detrimental to both mother and fetus. To study the extent and nature of the use of prescribed medications during pregnancy and factors associated with medication nonadherence. All women≥18 years presenting for their 36th week antenatal visit at the pregnancy clinic of a maternity hospital were invited to complete an anonymous questionnaire that contained 61 items, including the Morisky scale. Factors associated with nonadherence were identified in univariate analysis; factors with P<0.1 were further analysed in a binary logistic regression model. The participants (n=819) had a mean age of 30.8±5.3 years. Most participants were born in Australia, lived with a partner, had university education, were nulliparous, carried one fetus and were nonsmokers. Of these participants, 322 (39.3%) reported a chronic health condition during pregnancy, the most common being asthma (104; 12.7%). Two hundred and seventeen (26.5%) were using prescribed medications, which included anti-anaemics (68; 8.3%), medicines for chronic airway conditions (64; 7.8%), vitamins and minerals (59; 7.2%) and anti-diabetics (43; 5.2%). Nonadherence was reported by 107 (59.1%) participants, mainly because of forgetting (79; 43.6%). Factors associated with nonadherence were having asthma (OR 0.26 (95% CI 0.095-0.72), P=0.009) and using nonprescription dietary minerals (0.30 (0.10-0.87), P=0.027). Adherence to prescribed medicines during pregnancy is alarmingly low. Health professionals should be more proactive in promoting adherence and assisting women avoid potential fetal harm because of nonadherence.

Commentary: Routine Cesarean Section for Breech: The Unmeasured Cost

Historically, partial breech extraction under maternal sedation was accompanied by high perinatal mortality rates (1). With the safety of modern cesarean section techniques, many deemed the avoidance of this fetal risk worth the maternal risk of cesarean section, and the proportion of breech fetuses delivered by cesarean section steadily increased. This trend reached its peak after publication of the term breech trial in 2000 (2). This trial implied that cesarean section was safer than vaginal birth for all breech fetuses at term. Professional obstetrical associations in the United Kingdom, United States, and Canada issued guidelines mandating cesarean section for term breech presentation. Across much of the world, vaginal breech birth is no longer ‘‘offered’’ to women. A new generation of specialist obstetricians lacks the skill and confidence to attend even the most straightforward vaginal breech birth, and maternal and perinatal deaths have resulted. The conclusions of the term breech trial were simplistic and erroneous. An overly liberal selection and labor management protocol allowed poorly selected infants to labor without adequate attention to progress. Half of the perinatal deaths in the trial were in growth-restricted fetuses, and infants born after prolonged labor had poorer outcomes compared with those whose labor was shorter (1,3). Inclusion of multiple centers with disparate levels of in-house specialist and surgical capability provided an inconsistent safety net. These factors led to fetal and neonatal harm attributed erroneously to breech presentation rather than to inappropriate management. Use of short-term surrogate outcomes overestimated the long-term risk of the questionable level of care provided. Breech birth technique has evolved. Particularly in Europe, centers with consistent specialist backup and cautious protocols convincingly demonstrated that a significant proportion of breech babies can be delivered safely vaginally (4,5). The professional obstetrical associations of the United Kingdom, United States, and Canada have reversed their restrictive stances and are supportive of selected vaginal breech birth (5‐7). Given the tenuous efforts to reestablish systems to provide safe breech birth, it is important to recognize the dangers of a system that is unwilling to do so.

Prescriptions Filled During Pregnancy for Drugs With the Potential of Fetal Harm

Prescriptions Filled During Pregnancy for Drugs With the Potential of Fetal Harm

Ethical Barriers to Perinatal Mental Health Research and Evidence-Based Treatment: An Empirical Study

Although more than 500,000 women annually experience a psychiatric illness during pregnancy, and approximately 30% will be prescribed medication, no psychotropic medications are approved by the Food and Drug Administration (FDA) for use during pregnancy. In the absence of an evidence base, investigators, clinicians, and patients are concerned that we are “operating in a vast sea of ignorance.” International pregnancy registries and observational studies exist, but there are few randomized controlled trials (RCTs), the gold standard of evidence-based medicine, due to the fear of fetal harm, even in non-pharmacological research. Current research guidelines reflect the ambivalence of regulatory agencies regarding pregnant research participants and use ambiguous language unhelpful to institutional review boards (IRBs), leaving perinatal women the last “therapeutic orphans.” This is a review of the issues as identified by perinatal investigators and a proposal to draft new collaborative guidelines to facilitate perinatal mental health research necessary for empirically-based treatment.

Use of Drugs Known to Cause Fetal Harm Among Women Delivering Infants in Haiti

Objective To estimate the prevalence of use of fetal-harm drugs among women who received postpartum care in hospitals in Haiti and to identify groups of women at higher risk for potentially harmful medication exposures. Methods Women who received postpartum care in 2 large hospitals in Port-au-Prince, Haiti, from August 18 to December 1, 2008, were surveyed in Creole about their use of medications in pregnancy, including fetal-harm drugs. Results We surveyed 482 women who had a median age of 26 years. Approximately 75% reported using at least 1 medicine in pregnancy, with the most common being amoxicillin (n = 127), acetaminophen (n = 109), metronidazole (n = 79), and misoprostol (n = 38). More than 13% used fetal-harm drugs, including misoprostol and tetracycline. Unmarried women (adjusted relative risk [RR] 2.2; 95% confidence interval [CI], 1.0–4.7) and separated women (adjusted RR 4.6; CI, 1.8–11.9) were more likely than married women to report use of fetal-harm drugs. In addition, women with 4 or more children were more likely to report use of medications known to cause fetal harm (adjusted RR 4.3; CI, 1.9–9.9). Conclusion Women who delivered infants in Haiti commonly report use of fetal-harm drugs. The public health implications of these findings are broad and relate to complex issues such as pregnancy planning and regulation of medications to prevent potentially harmful exposures.

Epoprostenol treatment for idiopathic pulmonary arterial hypertension in pregnancy

Idiopathic pulmonary arterial hypertension is a rare condition associated with significant maternal mortality. We report the management of a 37-year-old multigravida with severe disease using epoprostenol, a multidisciplinary approach, and a planned delivery. Although the patient survived the pregnancy, her pulmonary function significantly worsened. Epoprostenol, a pulmonary vasodilator, should be considered when indicated during pregnancy. Neither fetal nor neonatal harm was identified.

Alcohol Use and Pregnancy Consensus Clinical Guidelines

ObjectiveTo establish national standards of care for the screening and recording of alcohol use and counselling on alcohol use of women of child-bearing age and pregnant women based on the most up-to-date evidence. EvidencePublished literature was retrieved through searches of PubMed, CINAHL, and the Cochrane Library in May 2009 using appropriate controlled vocabulary (e.g., pregnancy complications, alcohol drinking, prenatal care) and key words (e.g., pregnancy, alcohol consumption, risk reduction). Results were restricted to literature published in the last five years with the following research designs: systematic reviews, randomized control trials/controlled clinical trials, and observational studies. There were no language restrictions. Searches were updated on a regular basis and incorporated in the guideline to May 2010. Grey (unpublished) literature was identified through searching the websites of health technology assessment (HTA) and HTA-related agencies, national and international medical specialty societies, clinical practice guideline collections, and clinical trial registries. Each simple-article was screened for relevance and the full text acquired if determined to be relevant. The evidence obtained was reviewed and evaluated by the members of the Expert Workgroup established by the Society of Obstetricians and Gynaecologists of Canada. The quality of evidence was evaluated and recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. ValuesThe quality of evidence was rated using the criteria described by the Canadian Task Force on Preventive Health Care (Table 1). SponsorThe Public Health Agency of Canada and the Society of Obstetricians and Gynaecologists of Canada. EndorsementThese consensus guidelines have been endorsed by the Association of Obstetricians and Gynecologists of Quebec; the Canadian Association of Midwives; the Canadian Association of Perinatal, Women’s Health and Neonatal Nurses (CAPWHN); the College of Family Physicians of Canada; the Federation of Medical Women of Canada; the Society of Rural Physicians of Canada; and Motherisk. Summary Statements1.There is evidence that alcohol consumption in pregnancy can cause fetal harm. (II-2) There is insufficient evidence regarding fetal safety or harm at low levels of alcohol consumption in pregnancy. (III)2.There is insufficient evidence to define any threshold for low-level drinking in pregnancy. (III)3.Abstinence is the prudent choice for a woman who is or might become pregnant. (III)4.Intensive culture-, gender-, and family-appropriate interventions need to be available and accessible for women with problematic drinking and/or alcohol dependence. (II-2) Recommendations1.Universal screening for alcohol consumption should be done periodically for all pregnant women and women of child-bearing age. Ideally, at-risk drinking could be identified before pregnancy, allowing for change. (II-2B)2.Health care providers should create a safe environment for women to report alcohol consumption. (III-A)3.The public should be informed that alcohol screening and support for women at risk is part of routine women’s health care. (III-A)4.Health care providers should be aware of the risk factors associated with alcohol use in women of reproductive age. (III-B)5.Brief interventions are effective and should be provided by health care providers for women with at-risk drinking. (II-2B)6.If a woman continues to use alcohol during pregnancy, harm reduction/treatment strategies should be encouraged. (II-2B)7.Pregnant women should be given priority access to withdrawal management and treatment. (III-A)8.Health care providers should advise women that low-level consumption of alcohol in early pregnancy is not an indication for termination of pregnancy. (II-2A)

Medication use in early pregnancy‐prevalence and determinants of use in a prospective cohort of women

To examine the extent, nature and determinants of medication use in early pregnancy. We reviewed early pregnancy medication use, as reported to a midwife at the booking interview, in women delivering between 2000 and 2007 in a large maternity hospital in Dublin, Ireland (n = 61 252). Excluding folic acid, at least one medication was reported in 23 989 (39.2%) pregnancies. Over the counter (OTC) medications were reported in 11 970 (19.5%) pregnancies, illicit drugs or methadone in 545 (0.9%) and herbal medicines/supplements in 352 (0.58%). FDA category D and X medications were reported by 1532 (2.5%) and 1987 (3.2%) women. Asthma, depression and hypertension were among the most commonly reported chronic medical disorders. Medications with potential for foetal harm were reported by 86 (15.7%) women treated for depression and 68 (20%) women treated for hypertension. Factors associated with reporting the use of medications with potential for foetal harm included unplanned pregnancy (adjusted odds ratio [aOR] 1.31, 95% confidence interval [CI] 1.12-1.52), booking at less than 12 weeks gestation (aOR 1.83, 95%CI 1.58-2.13), being above 25 years of age, unemployed (aOR 2.58, 95%CI 2.03-3.29), nulliparous (aOR 1.41; 95%CI 1.22-1.63), single (aOR 1.28; 95%CI 1.06-1.54) or smoking during pregnancy (aOR 1.96, 95%CI 1.67-2.28). Women frequently report medication use in early pregnancy. Women and prescribers need to be aware of the lack of pregnancy safety data for many medications, and the need for pre-pregnancy planning. Prescribers should ensure that optimal medications are used when treating women of childbearing potential with chronic medical disorders.

Erratum

BJOG: An International Journal of Obstetrics & GynaecologyVolume 117, Issue 3 p. 373-373 Free Access Erratum This article corrects the following: Prescriptions filled during pregnancy for drugs with the potential of fetal harm S Kulaga, A Zagarzadeh, A Bérard, Volume 116Issue 13BJOG: An International Journal of Obstetrics & Gynaecology pages: 1788-1795 First Published online: October 13, 2009 First published: 12 January 2010 https://doi.org/10.1111/j.1471-0528.2009.02488.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL In [1] the second author name had a spelling error. The correct name is Zargarzadeh AH. We apologise for this error. Reference 1 Kulaga S, Zargarzadeh AH, Bérard A. Prescriptions filled during pregnancy for drugs with the potential of fetal harm. BJOE 2009; 116: 1788– 95. Volume117, Issue3February 2010Pages 373-373 ReferencesRelatedInformation

Response to Mahadevan and Kane

1Istituto di Medicina Interna e Geriatria, Università Cattolica del S. Cuore, Roma, Italy Correspondence: Alfredo Papa, MD, Istituto di Medicina Interna e Geriatria, Università Cattolica del S. Cuore, L.go A. Gemelli, 8, 00168 Roma, Italy. E-mail: [email protected]

Pregnancy and Infant Outcomes in the Clinical Trials of a Human Papillomavirus Type 6/11/16/18 Vaccine

To present a combined analysis of the pregnancy outcomes for women aged up to 45 years enrolled in five phase III clinical studies of the prophylactic quadrivalent human papillomavirus 6/11/16/18 vaccine. Twenty thousand five hundred fifty-one women aged 15-45 years received quadrivalent HPV vaccine or placebo at day 1 and months 2 and 6. Urine pregnancy tests were performed immediately before each injection; participants testing positive were not vaccinated. Women who became pregnant after enrollment were discontinued from further vaccination until resolution of pregnancy. All pregnancies were followed for outcomes. During the studies, 1,796 vaccine and 1,824 placebo recipients became pregnant, resulting in 2,008 and 2,029 pregnancies with known outcomes. No significant differences were noted overall for the proportions of pregnancies resulting in live birth, fetal loss, or spontaneous abortion. A total of 40 neonates born to vaccinated women and 30 neonates born to women given placebo had one or more congenital anomalies (P=.20). The anomalies were diverse and consistent with those most commonly observed in the general population. The vaccine was well tolerated among women who became pregnant. Administration of quadrivalent human papillomavirus vaccine to women who became pregnant during the phase III clinical trials did not appear to negatively affect pregnancy outcomes. The vaccine is a U.S. Food and Drug Administration pregnancy category B medication (animal studies revealed no evidence of fetal harm, but there are no adequate and well-controlled studies in pregnant women); however, vaccination is not recommended during pregnancy. Postlicensure surveillance is ongoing. ClinicalTrials.gov, www.clinicaltrials.gov, NCT00092521, NCT00092534, NCT00092495, NCT00092547 and NCT00090220. II.

Prescriptions filled during pregnancy for drugs with the potential of fetal harm

To assess the extent of prescriptions filled by pregnant women for drugs with recognised potential of fetal harm, and to document the outcomes of these pregnancies. Cross-sectional study. Quebec Pregnancy Registry. We identified women who were pregnant during a five-year period and who were insured for prescription medications under the provincial drug plan. We obtained information on prescriptions filled during pregnancy for drugs with known potential of fetal harm. Prescriptions filled for study drugs during the first, second and third trimesters of pregnancy; termination of pregnancy (TOP) or delivery, and whether the baby was diagnosed with a major congenital malformation (MCM). Of 109 344 women, 56% filled at least one prescription for a medication during pregnancy; 6.3% filled at least one prescription for a drug known to pose a risk to the fetus. Overall, 47% (95% CI, 45.8-48.2) of pregnancies exposed to drugs under study ended in TOP versus 36.2% (95% CI, 35.9-36.5) of those not exposed; 8.2% (95% CI, 8.0-10.0) of live births were diagnosed with an MCM during the first year of life versus 7.1% (95% CI, 6.9-7.3) of those not exposed. This study documents an important level of prescriptions filled during pregnancy for drugs harmful to the developing fetus. The proportions of both TOPs and babies born with MCMs were elevated compared with the expected values. Clinicians caring for women during pregnancy should conduct a medication inventory prior to a planned pregnancy, or as soon as an unplanned pregnancy is recognised.

New Pharmacological Agents for Arrhythmias

Despite advances in catheter ablation techniques and device-based therapies for cardiac arrhythmias, antiarrhythmic drugs remain essential components of any comprehensive therapeutic strategy. Antiarrhythmic drug therapy, however, has been limited by both incomplete efficacy and a substantial potential for cardiac and extracardiac toxicity. As a result, only a few new antiarrhythmic agents have successfully completed clinical development programs and reached routine clinical usage over the past 20 years. Antiarrhythmic drugs may be indicated for ventricular tachycardia, sudden death prevention, or specific types of supraventricular arrhythmia. Implantable cardioverter-defibrillator (ICD) therapy has evolved as the primary treatment for most life-threatening ventricular arrhythmias, and antiarrhythmic drugs for these rhythms are currently mostly used either as acute interventions or as adjuncts to chronic ICD therapy. Although numerous trials have evaluated the effect of antiarrhythmic drugs to decrease ICD shocks or therapies, such data have yet to provide the sole basis for approval for any new agent. At the same time, drug therapy for atrial arrhythmias is often limited by the drug’s simultaneous effects on the ventricles, which has led to efforts to identify ionic channel targets specific to or preferentially located in the atria. The sustained outward K+ current (IKur, encoded by the Kv 1.5 subunit), the acetylcholine-activated outward K+ current (IKAch), and both peak and late atrial Na+ currents have therefore become potential targets for antiarrhythmic drug developers.1–4 Another approach has been to seek agents that synergistically affect multiple channels simultaneously, resulting in a net beneficial effect while minimizing toxicity. Other nontraditional targets for drug therapy that do not directly involve ion channels have also emerged as our understanding of the mechanisms of arrhythmias has improved. As a result, several new compounds are now at or near completion of phase 3 clinical trials, and other promising …

Retinal folding in the term rabbit fetus—Developmental abnormality or fixation artifact?

Preclinical reproductive toxicology studies must be performed to provide information on the risk of causing fetal harm in pregnant patients. These studies detect fetal malformations, which may or may not be drug-related adverse events. In the rabbit fetus, “slight retinal folding” is commonly observed; there is anecdotal evidence that these folds may be caused by routine (Bouin’s fluid) fixation. This study used magnetic resonance imaging (MRI) to assess rabbit retinal architecture in fresh specimens, which was then reassessed following Bouin’s fluid fixation. A total of 30 fetuses from 5 litters were imaged. No retinal folding was detected in fresh specimens but it was observed in a majority of fetuses post-fixation. The use of Davidson’s fixative followed by Bouin’s fluid showed a markedly lower incidence of “slight retinal folding”. Conclusion: slight retinal folds in the rabbit fetus are likely artifactual and can be reduced using Davidson’s fixation prior to Bouin’s.

Pierre Robin sequence associated with first trimester fetal tamoxifen exposure

Tamoxifen is a nonsteroidal antiestrogen used as the current adjuvant endocrine treatment of choice for premenopausal women treated for breast cancer and its potential for causing fetal harm during pregnancy remains inconclusive. While the evidence of tamoxifen's effects on humans in utero is minimal, animal studies have shown evidence of teratogenicity, hence the FDA's class D categorization of the drug. In 1994 Cullins et al. published a case report entitled "Goldenhar's Syndrome Associated with Tamoxifen Given to the Mother During Gestation." At the time of publication, the authors noted that the manufacturer of tamoxifen knew of two cases associated with tamoxifen administration which resulted in congenital craniofacial defects. Cullins' case of Goldenhar syndrome is also a craniofacial disorder and thus represented the third such case. We report on the fourth case of a tamoxifen-associated craniofacial anomaly. The mother became pregnant while undergoing tamoxifen therapy for breast cancer. A child with severe micrognathia and cleft palate was born. It is noteworthy that the two patterns of craniofacial malformations in tamoxifen exposed infants--Goldenhar syndrome in Cullins' et al. case and Pierre Robin sequence reported here--have also both been observed in isotretinoin exposed infants. While a larger spectrum of anomalies is characteristic of retinoic acid embryopathy, the specific craniofacial anomalies include facial asymmetry, microtia, micrognatha and U-shaped cleft of the secondary palate, that is, malformations seen in the two tamoxifen exposed infants. Therefore, it is conceivable that these two agents could produce comparable embryotoxic effects if they function in a like way during embryogenesis. While the majority of tamoxifen exposed infants are normal, the ascertainment of teratogenic effects from tamoxifen will best be determined by data from teratogen registries.

Parenthood Posttransplantation: 50 Years Later

Parenthood Posttransplantation: 50 Years Later