Middle cerebral artery peak systolic velocity monitoring of fetal anemia during chemotherapy in pregnancy.

INTRODUCTION: Chemotherapy during pregnancy can increase the risk of fetal anemia. Severe fetal anemia can lead to the development of hydrops fetalis and potentially fetal demise. Hence, it is imperative to implement consistent monitoring methods in the context of chemotherapy treatment. This study aimed to diagnose and monitor fetal anemia using middle cerebral artery peak systolic velocity (MCA-PSV) as a diagnostic tool during chemotherapy in pregnant women. MATERIAL AND METHODS: The study employed a prospective analysis involving a case series of 15 patients diagnosed with cancer during pregnancy and subsequently underwent chemotherapy. MCA-PSV was used to identify fetal anemia. The patients were scheduled for ultrasound examinations of the MCA-PSV. The first examination was performed on the same day as the administration of chemotherapy, while the second occurred on the 10th day after chemotherapy. The measurement technique used in the study was based on the methodology proposed by Mari and Barr. The multiples of the median were calculated using the calculators provided by Medicina Fetal Barcelona. Based on these values anemia severity was determined. When moderate or severe anemia was identified, chemotherapy was individually modified. Additionally, a blood count analysis was conducted immediately after the delivery of the newborn. RESULTS: Five patients were diagnosed with fetal or newborn anemia. With MCA-PSV, we identified moderate fetal anemia in two patients and severe fetal anemia in one. The complete blood count testing of newborns revealed mild anemia in three patients. One case was unrelated to chemotherapy-induced anemia. During treatment, fetal anemia did not corelate with maternal anemia. CONCLUSIONS: In four cases of anemia the combination of cisplatin and iphosphamide was used as a chemotherapy agent. No anemia was observed in other drug combinations. Our findings suggest that MCA-PSV is a reliable method for identifying anemia and should be included in the treatment protocol for chemotherapy-induced fetal anemia.

Antenatal intravenous immunoglobulins in pregnancies at risk of fetal and neonatal alloimmune thrombocytopenia: comparison of neonatal outcome in treated and nontreated pregnancies.

BACKGROUND: Maternal alloantibodies to human platelet antigen-1a can cause severe intracranial hemorrhage in a fetus or newborn. Although never evaluated in placebo-controlled clinical trials, most Western countries use off-label weekly administration of high-dosage intravenous immunoglobulin in all pregnant women with an obstetrical history of fetal and neonatal alloimmune thrombocytopenia. In Norway, antenatal intravenous immunoglobulin is only recommended in pregnancies wherein a previous child had intracranial hemorrhage (high-risk) and is generally not given in other human platelet antigen-1a alloimmunized pregnancies (low-risk). OBJECTIVE: To compare the frequency of anti-human platelet antigen-1a-induced intracranial hemorrhage in pregnancies at risk treated with intravenous immunoglobulin vs pregnancies not receiving this treatment as a part of a different management program. STUDY DESIGN: This was a retrospective comparative study where the neonatal outcomes of 71 untreated human platelet antigen-1a-alloimmunized pregnancies in Norway during a 20-year period was compared with 403 intravenous-immunoglobulin-treated pregnancies identified through a recent systematic review. We stratified analyses on the basis of whether the mothers belonged to high- or low-risk pregnancies. Therefore, only women who previously had a child with fetal and neonatal alloimmune thrombocytopenia were included. RESULTS: Two neonates with brain bleeds were identified from 313 treated low-risk pregnancies (0.6%; 95% confidence interval, 0.2-2.3). There were no neonates born with intracranial hemorrhage of 64 nontreated, low-risk mothers (0.0%; 95% confidence interval, 0.0-5.7). Thus, no significant difference was observed in the neonatal outcome between immunoglobulin-treated and untreated low-risk pregnancies. Among high-risk mothers, 5 of 90 neonates from treated pregnancies were diagnosed with intracranial hemorrhage (5.6%; 95% confidence interval, 2.4-12.4) compared with 2 of 7 neonates from nontreated pregnancies (29%; 95% confidence interval, 8.2-64.1; P=.08). CONCLUSION: The most reliable data hitherto for the evaluation of intravenous immunoglobulins treatment in low-risk pregnancies is shown herein. We did not find evidence that omitting antenatal intravenous immunoglobulin treatment in low-risk pregnancies increases the risk of neonatal intracranial hemorrhage.

Fetal Hypothyroidism Impairs Aortic Vasorelaxation Responses in Adulthood: Involvement of Hydrogen Sulfide and Nitric Oxide Cross talk.

ABSTRACT: Thyroid hormones have a wide range of effects on growth, differentiation, evolution, metabolism, and physiological function of all tissues, including the vascular bed. In this study, the effect of fetal hypothyroidism on impairment of aortic vasorelaxation responses in adulthood was investigated with emphasis on possible involvement of hydrogen sulfide (H2S)/nitric oxide interaction. Two groups of female rats were selected. After mating and observation of vaginal plaque, one group received propylthiouracil (200 ppm in drinking water) until the end of pregnancy and another group had no propylthiouracil treatment during the fetal period. In adult rats, aortic relaxation responses to l-arginine and GYY4137 were assessed in the presence or absence of Nω-nitro-L-arginine methyl ester hydrochloride and dl-propargylglycine in addition to the biochemical measurement of thyroid hormones and some related factors. Obtained findings showed a lower vasorelaxation response for GYY4137 and l-arginine in the fetal hypothyroidism group, and preincubation with Nω-nitro-L-arginine methyl ester hydrochloride or dl-propargylglycine did not significantly aggravate this weakened relaxation response. In addition, aortic levels of sirtuin 3, endothelial nitric oxide synthase, cystathionine gamma-lyase, and H2S were significantly lower in the fetal hypothyroidism group. Meanwhile, no significant changes were obtained regarding serum levels of thyroid hormones including free triiodothyronine;, total triiodothyronine, free thyroxine, total thyroxine, and thyroid-stimulating hormone in adult rats. It can be concluded that hypothyroidism in the fetal period has inappropriate effects on the differentiation and development of vascular bed with subsequent functional abnormality that persists into adulthood, and part of this vascular abnormality is mediated through weakened interaction and/or cross talk between H2S and nitric oxide.

Quantifying Proximal Collecting Tubule Deficiency in Angiotensin-Converting Enzyme Inhibitor and Angiotensin II Receptor Blocker Fetopathy.

INTRODUCTION: Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers (AAs) are used for several indications, with cessation recommended in pregnancy due to toxic effects. AA fetopathy phenotype is similar to renal tubular dysgenesis including reduced proximal convoluted tubules (PCTs). Our study aimed to quantify the reduction of PCTs in fetuses and infants with prenatal exposure to AAs. MATERIALS AND METHODS: We identified 5 fetal AA exposure cases that underwent autopsy at our institution between 2011 and 2018 and compared with 5 gestational age-matched controls. Immunohistochemistry with CD10 and epithelial membrane antigen (EMA) was utilized. RESULTS: CD10 and EMA identified a median PCT density of 19.0% ± 12.3% in AA fetopathy patients, significantly less than controls (52.8% ± 4.4%; p < 0.0001). One case with in utero cessation had a PCT density of 34.2% ± 0.2%. Among other AA fetopathy findings, 1 case demonstrated unilateral renal vein thrombosis and 4 had hypocalvaria. CONCLUSIONS: We have quantified the reduction in AA fetopathy PCT density, and demonstrated in utero cessation may recover PCT differentiation. Future studies may benefit from calculating PCT percentage as a potential biomarker to correlate with post-natal renal function and maternal factors including medication type, dosage, duration, and time from medication cessation.

Melatonin for prevention of fetal lung injury associated with intrauterine inflammation and for improvement of lung maturation.

Inflammation is associated with injury to immature lungs, and melatonin administration to preterm newborns with acute respiratory distress improves pulmonary outcomes. We hypothesized that maternally administered melatonin may reduce inflammation, oxidative stress, and structural injury in fetal lung and help fetal lung maturation in a mouse model of intrauterine inflammation (IUI). Mice were randomized to the following groups: control (C), melatonin (M), lipopolysaccharide (LPS; a model of IUI) (L), and LPS with melatonin (ML). Pro-inflammatory cytokines, components of the Hippo pathway, and Yap1/Taz were analyzed in the fetal lung at E18 by real-time RT-qPCR. Confirmatory histochemistry and immunohistochemical analyses (surfactant protein B, vimentin, HIF-1ß, and CXCR2) were performed. The gene expression of IL1ß in the fetal lung was significantly increased in L compared to C, M, and ML. Taz expression was significantly decreased in L compared to C and M. Taz gene expression in L was significantly decreased compared with those in ML. Immunohistochemical analyses showed that the expression of HIF-1ß and CXCR2 was significantly increased in L compared to C, M, and ML. The area of surfactant protein B and vimentin were significantly decreased in L than C, M, or ML in the fetal and neonatal lung. Antenatal maternally administered melatonin appears to prevent fetal lung injury induced by IUI and to help lung maturation. The results from this study results suggest that melatonin could serve as a novel safe preventive and/or therapeutic medicine for preventing fetal lung injury from IUI and for improving lung maturation in prematurity.

An update on maternal medication-related embryopathies.

There is a general perception that any exposure to medication during pregnancy poses a potential risk to the fetus. Most available data about teratogenic drugs is derived from animal studies, case reports, or cohort studies. As a result, counseling women and their partners about the safety of drugs during pregnancy can be difficult due to limited information about efficacy, pharmacokinetics, and teratogenicity of some drugs. However, this should always be done in the context of weighing up potential teratogenic risks with the perinatal risks of an untreated medical or psychiatric condition. Ideally, this counseling should occur prior to a planned pregnancy so that medications and treatment of chronic medical conditions can be optimized. It is important that clinicians providing antenatal care are able to confidently manage women including utilizing appropriate resources. This paper aims at reviewing a selected (non-exhaustive) list of the most commonly prescribed medications considered significant human teratogens and provides recommendations for pre-conception and antenatal counseling.

Oxidative stress in lymphoid tissues and complement activation in alcoholic mother rats and their newborns.

Pregnant Wistar rats were exposed to ethanol under chronic conditions using the gavage method to assess the complement activation and effects of oxidative stress on fetus lymphoid organs and liver. The effects were monitored on both the 10th (G10) and the 30th (G30) day of the offspring of alcoholic mother rats. Maternal ethanol caused a significant decrease in the glutathione level, whereas malondialdehyde and carbonyl levels increased in the liver and lymphoid tissues. Na+,K+-ATPase, glutathione peroxidase, glutathione reductase, superoxide dismutase, and catalase activities in these organs also decreased. Furthermore, complement C3 and C5 activities of G10 and G30 groups were significantly higher compared with those of the control group. In conclusion, the results demonstrated that alcohol was capable of triggering damage to the membranes of the liver and lymphoid tissues of G10 and G30 groups, and C3 and C5 contributed to the development of alcohol-induced fetal tissue injury.

Opioid use disorder during pregnancy: An overview.

Women with opioid use disorder who become pregnant are a particularly vulnerable population and require a comprehensive treatment approach for mother and fetus. Research is continuing on opioid use disorder, effects of opioid use on the fetus, and best treatment approaches. This article reviews current recommendations and guidelines for treatment.

Assessment of Congenital Vascular and Organ Anomalies in Subjects With Thalidomide Embryopathy Using Non-Contrast Magnetic Resonance Angiography.

BACKGROUND: To determine the type and frequency of vascular and organ malformations in adults with thalidomide embryopathy (TE) using non-contrast magnetic resonance angiography (MRA) and to assess the effect of the observed malformations on renal function. Methods and Results: The institutional ethics committee approved this prospective study and written informed consent was given by all 78 subjects (50 females) with TE (mean age: 55±1.1 years), who were examined by non-contrast MRA at 3T. ECG-triggered balanced turbo field echo images of the chest, abdomen and pelvis were obtained in coronal and sagittal orientations. Two observers assessed the frequency of vascular and organ malformations. Serum creatinine and estimated glomerular filtration rate (eGFR) were obtained to assess renal function. In 58 subjects, 99 vascular anomalies were observed, including 68 arterial (69%) and 31 venous anomalies (31%); 15 patients had 16 abdominal organ malformations including 12 kidney anomalies and 4 cases of gallbladder agenesis. Most vascular anomalies affected the renal vessels (n=66, 67%) or supraaortic arteries (n=28, 28%). Serum creatinine and eGFR revealed normal renal function in all subjects. CONCLUSIONS: Vascular and organ anomalies occurred in a high number of subjects with TE without evidence of renal dysfunction. Information about the presence of malformations may be important for future surgical interventions in subjects with TE.

Experience with dasatinib and nilotinib use in pregnancy.

Pregnancy in a patient with chronic myeloid leukemia presents a therapeutic challenge. Both dasatinib and nilotinib are indicated for first-line treatment as well as for treatment-resistant chronic myeloid leukemia. Animal studies with dasatinib or nilotinib demonstrate fetal skeletal malformations as well as significant mortality during organogenesis. The goal of this article is to review the experience to date of dasatinib and nilotinib in human pregnancy, specifically dasatinib and nilotinib dose, length of exposure, trimester of use, as well as patient and fetal outcomes. Based on the limited data, both dasatinib and nilotinib may cause fetal harm. Additionally, thorough analysis of the available literature indicates no correlation between dasatinib nor nilotinib dose, length of exposure, trimester of use, and deleterious patient or fetal outcomes can be concluded. Therefore, health care professionals need to regularly counsel women of child bearing potential with chronic myeloid leukemia regarding the risks of taking dasatinib or nilotinib during pregnancy. The safest potential therapeutic options for the management of chronic myeloid leukemia in pregnancy include temporary discontinuation of the tyrosine kinase inhibitor followed by observation or intervention with interferon alfa and/or leukapheresis.

High-Versus Low-Dose Warfarin-Related Teratogenicity: A Case Report and Systematic Review.

OBJECTIVE: The optimal anticoagulant therapy during pregnancy in women with mechanical heart valves remains controversial. This study highlights a case of high-dose warfarin ingestion throughout pregnancy and performed a systematic review to assess rates of teratogenicity with high versus low warfarin dosing (≤5 mg daily). METHODS: A literature search for all case reports and available literature was conducted in PubMed, Medline, and EMBASE up to December 2016 using medical subject heading terms "mechanical prosthetic valves," "pregnancy," "oral anticoagulants," "warfarin," "coumarins," "heparin, low-molecular-weight," and "thromboembolism." To be included, warfarin had to be administered anytime between 6 and 12 weeks of gestation with the dose being specified. The Newcastle-Ottawa Scale was used to assess quality of the cohort data. RESULTS: The woman in the studied case received the highest reported warfarin doses throughout pregnancy (14.5-16.5 mg daily) and delivered a baby with no evidence of teratogenicity to the current age of 5 years. The study identified 23 case reports, with all demonstrating warfarin teratogenicity regardless of high-dose (n = 12) or low-dose (n = 11) warfarin. Twelve cohort studies identified a warfarin teratogenicity rate of 5.0%, with rates of 2.4% and 10.5% with low- and high-dose warfarin, respectively. Risk of bias was moderate (median Newcastle-Ottawa Scale score of 6) for all of the cohort studies. CONCLUSION: Although a lower prevalence of warfarin-induced teratogenicity is reported with low-dose warfarin, a safe "cut-off" dose is misleading. Teratogenic risk with warfarin is unpredictable, mandating individual decisions regardless of the dose.

Anticoagulation for pregnant women with mechanical heart valves: a systematic review and meta-analysis.

AIMS: To review maternal and foetal outcomes in women with mechanical heart valves (MHVs) treated with vitamin-K antagonists (VKAs), first-trimester heparin followed by VKAs (sequential treatment), low molecular weight heparin (LMWH) and unfractionated heparin (UFH) during pregnancy, in order to inform practice. METHODS AND RESULTS: Medline, Embase and Central were searched from inception until February 2016. Two reviewers independently screened 1786 titles, reviewed 110 full-texts and extracted data and assessed risk-of-bias from 46 articles. Pooled incidence (95% confidence intervals) was calculated for maternal and foetal outcomes. Included studies had a moderate or high risk-of-bias. With VKAs, sequential treatment and LMWH, maternal mortality occurred in 0.9% (0.4-1.4), 2.0% (0.8-3.1) and 2.9% (0.2-5.7), thromboembolic complications in 2.7% (1.4-4.0), 5.8% (3.8-7.7) and 8.7% (3.9-13.4), livebirths in 64.5% (48.8-80.2), 79.9% (74.3-85.6) and 92.0% (86.1-98.0) and anticoagulant-related foetal/neonatal adverse events (embryopathy or foetopathy) in 2.0% (0.3-3.7), 1.4% (0.3-2.5) and 0%, respectively. When UFH is used throughout pregnancy, 11.2% (2.8-19.6) suffered thromboembolic complications. Foetal loss and adverse events occurred with first-trimester warfarin doses ≤ 5 mg/day, although there were more livebirths [83.6% (75.8-91.4) vs. 43.9% (32.8-55.0)] and fewer foetal anomalies [2.3% (0.7-4.0) vs. 12.4% (3.3-21.6)] with lower doses than with warfarin > 5 mg/day. CONCLUSIONS: VKAs are associated with fewest maternal complications but also with fewest livebirths. Sequential treatment does not eliminate anticoagulant-related foetal/neonatal adverse events. LMWH is associated with the highest number of livebirths. The safety of UFH throughout pregnancy and first-trimester warfarin ≤ 5 mg/day remains unconfirmed.

Protective effect of garlic extract against maternal and foetal cerebellar damage induced by lead administration during pregnancy in rats.

BACKGROUND: In spite of its industrial usefulness and varied daily uses, lead (Pb) pollution is a widespread ecological problem that faces the humans in the 21th century. Pb was found to produces a wide range of toxic effects including neurotoxicity especially to the developing and young offspring. Recently, the utilisation of herbal plants has received a significant attention where there has been rising awareness in their therapeutic use; among these is the garlic. In light of the above, the current study is designed experimentally in female pregnant rats in order to investigate the beneficial role of garlic extract in the protection from the maternal and foetal cerebellar damage produced by administration of different doses of Pb during pregnancy. MATERIALS AND METHODS: Positively pregnant female rats were divided into five groups; one control group, two Pb-treated groups (exposed to 160 and 320 mg/kg b.w. of Pb, respectively) and two groups treated with both Pb and garlic (exposed to Pb as previous groups together with 250 mg/kg b.w./day of garlic extract). Treatments started from day 1 to day 20 of pregnancy, where the mother rats of different experimental groups were sacrificed to obtain the foetuses. Pb level in the maternal and foetal blood and cerebellum was estimated by spectrophotometry. Specimens of the cerebellum of different mother and foetal groups were processed to histological and immunohistochemical staining for microscopic examination. RESULTS: The results showed that administration of Pb to pregnant rats resulted in a dose-dependent toxicity for both mothers and foetuses in the form of decrease in maternal weight gain, placental and foetal weights, brain weight and diminished foetal growth parameters, which were prominent in rat's group treated with larger dose of Pb. In Pb-treated rats, Pb level in blood and cerebellum was high when compared with the control group. The histopathological examination of the cerebellum of treated dams and foetuses showed marked alterations mainly in the form of Purkinje cell degeneration and lack of development of foetal cerebellum. Co-treatment of garlic extract along with Pb resulted in a significant decrease in Pb levels as compared with those treated with Pb alone with improvement of the histopathological changes. CONCLUSIONS: This study was useful in evaluating the hazardous effects of uncontrolled use of Pb in general and in assessing the developmental and neurotoxicity of foetuses due to exposure during pregnancy in particular. Co-administration of garlic has beneficial effects in amelioration of Pb-induced neurotoxicity and reversing the histopathological changes of the cerebellum of mother rats and foetuses. (Folia Morphol 2018; 77, 1: 1-15).

Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain.

UNLABELLED: Maternal inflammation during pregnancy affects placental function and is associated with increased risk of neurodevelopmental disorders in the offspring. The molecular mechanisms linking placental dysfunction to abnormal fetal neurodevelopment remain unclear. During typical development, serotonin (5-HT) synthesized in the placenta from maternal l-tryptophan (TRP) reaches the fetal brain. There, 5-HT modulates critical neurodevelopmental processes. We investigated the effects of maternal inflammation triggered in midpregnancy in mice by the immunostimulant polyriboinosinic-polyribocytidylic acid [poly(I:C)] on TRP metabolism in the placenta and its impact on fetal neurodevelopment. We show that a moderate maternal immune challenge upregulates placental TRP conversion rapidly to 5-HT through successively transient increases in substrate availability and TRP hydroxylase (TPH) enzymatic activity, leading to accumulation of exogenous 5-HT and blunting of endogenous 5-HT axonal outgrowth specifically within the fetal forebrain. The pharmacological inhibition of TPH activity blocked these effects. These results establish altered placental TRP conversion to 5-HT as a new mechanism by which maternal inflammation disrupts 5-HT-dependent neurogenic processes during fetal neurodevelopment. SIGNIFICANCE STATEMENT: The mechanisms linking maternal inflammation during pregnancy with increased risk of neurodevelopmental disorders in the offspring are poorly understood. In this study, we show that maternal inflammation in midpregnancy results in an upregulation of tryptophan conversion to serotonin (5-HT) within the placenta. Remarkably, this leads to exposure of the fetal forebrain to increased concentrations of this biogenic amine and to specific alterations of crucially important 5-HT-dependent neurogenic processes. More specifically, we found altered serotonergic axon growth resulting from increased 5-HT in the fetal forebrain. The data provide a new understanding of placental function playing a key role in fetal brain development and how this process is altered by adverse prenatal events such as maternal inflammation. The results uncover important future directions for understanding the early developmental origins of mental disorders.

Fingolimod against endotoxin-induced fetal brain injury in a rat model.

AIM: Fingolimod is a sphingosine-1-phosphate receptor modulator used for multiple sclerosis treatment and acts on cellular processes such as apoptosis, endothelial permeability, and inflammation. We hypothesized that fingolimod has a positive effect on alleviating preterm fetal brain injury. METHODS: Sixteen pregnant rats were divided into four groups of four rats each. On gestational day 17, i.p. endotoxin was injected to induce fetal brain injury, followed by i.p. fingolimod (4 mg/kg maternal weight). Hysterotomy for preterm delivery was performed 6 h after fingolimod. The study groups included (i) vehicle controls (i.p. normal saline only); (ii) positive controls (endotoxin plus saline); (iii) saline plus fingolimod; and (iv) endotoxin plus fingolimod treatment. Brain tissues of the pups were dissected for evaluation of interleukin (IL)-6, caspase-3, and S100ß on immunohistochemistry. RESULTS: Maternal fingolimod treatment attenuated endotoxin-related fetal brain injury and led to lower immunoreactions for IL-6, caspase-3, and S100ß compared with endotoxin controls (P < 0.0001 for all comparisons). CONCLUSION: Antenatal maternal fingolimod therapy had fetal neuroprotective effects by alleviating preterm birth-related fetal brain injury with inhibitory effects on inflammation and apoptosis.

Medicolegal Review of Methotrexate Administration to Viable Intrauterine Pregnancies.

Objective: To examine 3 legal cases in which physicians prescribed methotrexate to women with a viable intrauterine pregnancy, presumed to be ectopic, resulting in adverse fetal outcomes. Study Design: We conducted an electronic literature search for legal cases using the keywords "methotrexate" and "pregnancy" in the LexisNexis legal research engine as well as an Internet-wide search using the additional keyword "verdict." We manually searched the resultant list of identified cases and categorized the studies identified in the search by verdict, award amount, and outcome of the embryo exposed to methotrexate. Results: The monetary awards are typically greater when the embryo exposed to methotrexate lives and requires continuous medical and custodial care as compared to when the fetus dies in utero or shortly after birth. Conclusion: Physicians who, with all good intentions, prescribe methotrexate to women with a viable pregnancy, presumed to be ectopic, could find them-selves liable for an adverse fetal outcome. For the benefit of patients, their unborn offspring, and the liability exposure of the physician, it is important to be very cautious when prescribing methotrexate.

Nasoethmoidal meningocele in a child presenting bilateral congenital cystic adenomatoid malformation: Evidence for a new entity or consequence of gestational exposures?

BACKGROUND: Nasoethmoidal meningocele is considered an uncommon type of cephalocele, and congenital cystic adenomatoid malformation (CCAM) is a rare lung disorder characterized by overgrowth of the terminal bronchioles. CASE: We report the unusual association between a nasoethmoidal meningocele and CCAM type II in a fetus exposed to valproic acid and misoprostol. The mother was an 18-year-old woman on her first pregnancy. She had a history of absence seizures since she was 5 years old. She took valproic acid from the beginning of the gestation until the end of the third month. At the end of the third month, she attempted interruption of her pregnancy using misoprostol. The fetal nasoethmoidal meningocele and CCAM type II were identified through morphological ultrasound examination and magnetic resonance imaging. A genome-wide study detected one copy number variation classified as rare, entirely contained into the SPATA5 gene. However, it does not seem to be associated to the clinical findings of the patient. CONCLUSION: To our knowledge, there is only one case reported in the literature showing the same association between a nasoethmoidal meningocele and CCAM. Thus, the malformations observed in our patient may be related to the gestational exposures. Also, we cannot rule out that the patient may present the same condition characterized by a cephalocele and CCAM described by some authors, or even an undescribed entity, because some hallmark features, such as laryngeal atresia and limb defects, were not observed in our case. Further reports will be very important to better understand the associations described in our study.

Prediction of fetal ductus arteriosus constriction by systemic and local dermatological formulations of NSAIDs based on PK/PD analysis.

AIM: Use of nonsteroidal antiinflammatory drugs (NSAIDs) during the final trimester of pregnancy can cause fetal toxicity, such as ductus arteriosus (DA) constriction. The aim of this study was to predict quantitatively the fetal DA-constrictive effects of NSAIDs after various routes of administration to the mother by means of harmacokinetic/pharmacodynamic (PK/PD) modeling. METHODS: We evaluated acetaminophen, which is a first-line analgesic/antipyretic for the third trimester of pregnancy, together with the following NSAIDs: indometacin, diclofenac, ibuprofen, flurbiprofen, ketoprofen, loxoprofen, felbinac, naproxen, and celecoxib. Drug concentration data obtained in rats and humans were collected from the literature to calculate PK parameters. Next, the PD parameters for DA constriction in rats were obtained by fitting an Emax model to the DA/pulmonary artery (PA) inner diameter ratio after oral administration of each drug to full-term pregnant rats (data taken from the literature) and the unbound plasma concentration in rat dams estimated from the obtained PK parameters. Finally, the inner DA diameter profile after administration of each drug to human mothers was predicted. RESULTS: This PK/PD model predicted continuous fetal DA constriction in third-trimester women after repeated systemic use of nearly all the NSAIDs evaluated. Local dermatological formulations of NSAIDs were also predicted to potentially cause DA constriction. CONCLUSION: These results suggest that risk to the fetus should be carefully considered before administration of NSAIDs (especially systemic formulations, but including dermatological formulations) to women in the third trimester of pregnancy.

Constriction of the ductus arteriosus, severe right ventricular hypertension, and a right ventricular aneurysm in a fetus after maternal use of a topical treatment for striae gravidarum.

Fetal constriction of the ductus arteriosus is a complication of maternal non-steroidal anti-inflammatory drug use and polyphenol-rich food intake. It is unclear as to whether polyphenol-containing topical treatments have similar effects. We present a case of fetal constriction of the ductus arteriosus, severe right ventricular hypertension, and a right ventricular aneurysm associated with maternal use of a topical treatment for striae gravidarum.

Craniosynostosis Following Fetal Methotrexate Exposure.

Methotrexate (MTX) is an antimetabolite, folic acid antagonist that inhibits purine nucleotide production, DNA synthesis, and cellular proliferation. Despite widespread therapeutic uses, MTX remains a potent teratogen. Methotrexate embryopathy encompasses multiorgan system dysfunction, including intrauterine growth restriction as well as cardiac, craniofacial, renal, genital, and skeletal abnormalities. Effects of MTX exposure on fetal development continue to be described. This series of 4 patients with MTX-associated craniosynostosis represents the largest published association between prenatal MTX exposure and premature cranial suture closure.