Planned Pregnancy in Kidney Transplantation. A Calculated Risk

Pregnancy is not contraindicated in kidney transplant women but entails risks of maternal and fetal complications. Three main conditions can influence the outcome of pregnancy in transplant women: preconception counseling, maternal medical management, and correct use of drugs to prevent fetal toxicity. Preconception counseling is needed to prevent the risks of an unplanned untimely pregnancy. Pregnancy should be planned ≥2 years after transplantation. The candidate for pregnancy should have normal blood pressure, stable serum creatinine <1.5 mg/dL, and proteinuria <500 mg/24 h. Maternal medical management is critical for early detection and treatment of complications such as hypertension, preeclampsia, thrombotic microangiopathy, graft dysfunction, gestational diabetes, and infection. These adverse outcomes are strongly related to the degree of kidney dysfunction. A major issue is represented by the potential fetotoxicity of drugs. Moderate doses of glucocorticoids, azathioprine, and mTOR inhibitors are relatively safe. Calcineurin inhibitors (CNIs) are not associated with teratogenicity but may increase the risk of low birth weight. Rituximab and eculizumab should be used in pregnancy only if the benefits outweigh the risk for the fetus. Renin–angiotensin system inhibitors, mycophenolate, bortezomib, and cyclophosphamide can lead to fetal toxicity and should not be prescribed to pregnant women.

Medications prescriptions in COVID-19 pregnant and lactating women: the Bergamo Teratology Information Service experience during COVID-19 outbreak in Italy

ObjectivesThe severe acute respiratory syndrome coronavirus 2 (COVID-19) outbreak in Italy, especially in Lombardy and Bergamo city, represented probably nowadays one of the first major clusters of COVID-19 in the world. The aim of this report is to describe the activity of Bergamo Teratology Information Service (TIS) in supporting the public and health-care personnel in case of drug prescriptions in suspected/confirmed COVID-19 pregnant and lactating patients during COVID-19 outbreak in Italy.MethodsAll Bergamo TIS requests concerning COVID-19 pregnant and lactating women have been retrospectively evaluated from 1 March to 15 April 2020. Type of medications, drug’s safety profile and compatibility with pregnancy and lactation are reported.ResultsOur service received information calls concerning 48 (9 pregnant, 35 lactating) patients. Among pregnant and lactating women, the requests of information were related to 16 and 60 drugs prescriptions respectively. More than half concerned drugs prescriptions during the first and second trimester (13/16) and during the first six months of lactation (37/60). Hydroxychloroquine and azithromycin were the most involved.ConclusionsHydroxychloroquine and azithromycin at dosages used for COVID-19 may be considered compatible and reasonably safe either in pregnancy and lactation. Antivirals may be considered acceptable in pregnancy. During lactation lopinavir and ritonavir probably exhibit some supportive data from literature that darunavir and cobicistat do not. Tocilizumab may be considered for COVID-19 treatment because no increased malformation rate were observed until now. However caution may be advised because human data are limited and the potential risk of embryo-fetal toxicity cannot be excluded.

Gestational breast cancer: current challenges in staging and treatment of breast cancer

Gestational breast cancer (GBC) is the most common form of invasive cancer in pregnancy and has unique challenges in both staging and treatment given the dual goal of appropriate cancer management and minimising the risk of fetal toxicity. A 38-year-old woman with no significant medical history and 21 weeks pregnant presented with a palpable right breast mass. She was diagnosed with human epidermal growth factor receptor 2-positive infiltrating ductal carcinoma with advanced disease. The patient underwent treatment; however, unfortunately, she passed away after developing devastating distant disease recurrence.We highlight both the challenges and current guidelines for management of GBC. Our goal is to discuss the current limitations of GBC management and the necessity of further investigation for safe novel imaging and treatment modalities for pregnant women. It is crucial to increase awareness across multiple subspecialities, as a multidisciplinary team is necessary for proper treatment of GBC.

Hydrodynamics-Based Transplacental Delivery as a Useful Noninvasive Tool for Manipulating Fetal Genome

We previously demonstrated that the injection of pregnant wild-type female mice (carrying enhanced green fluorescent protein (EGFP)-expressing transgenic fetuses) at embryonic day (E) 12.5 with an all-in-one plasmid conferring the expression of both Cas9 and guide RNA (targeted to the EGFP cDNA) complexed with the gene delivery reagent, resulted in some fetuses exhibiting reduced fluorescence in their hearts and gene insertion/deletion (indel) mutations. In this study, we examined whether the endogenous myosin heavy-chain α (MHCα) gene can be successfully genome-edited by this method in the absence of a gene delivery reagent with potential fetal toxicity. For this, we employed a hydrodynamics-based gene delivery (HGD) system with the aim of ensuring fetal gene delivery rates and biosafety. We also investigated which embryonic stages are suitable for the induction of genome editing in fetuses. Of the three pregnant females injected at E9.5, one had mutated fetuses: all examined fetuses carried exogenous plasmid DNA, and four of 10 (40%) exhibited mosaic indel mutations in MHCα. Gene delivery to fetuses at E12.5 and E15.5 did not cause mutations. Thus, the HGD-based transplacental delivery of a genome editing vector may be able to manipulate the fetal genomes of E9.5 fetuses.

Nanoparticles induced embryo–fetal toxicity

Applications of nanomaterials cause a general concern on their toxicity when they intentionally (such as in medicine) or unintentionally (environment exposure) enter into the human body. As a special subpopulation, pregnant women are more susceptible to nanoparticle (NP)-induced toxicity. More importantly, prenatal exposures may affect the entire life of the fetus. Through blood circulation, NPs may cross placental barriers and enter into fetus. A cascade of events, such as damage in placental barriers, generation of oxidative stress, inflammation, and altered gene expression, may induce delayed or abnormal fetal development. The physicochemical properties of NPs, exposure time, and other factors directly affect nanotoxicity in pregnant populations. Even though results from animal studies cannot directly extrapolate to humans, compelling evidence has already shown that, for pregnant women, caution must be taken when dealing with nanomedicines or NP pollutants.

Embryo-fetal developmental toxicity study of alpha-glycosyl isoquercitrin administered orally to New Zealand White rabbits

An embryo-fetal survival and development study was conducted to augment the toxicity database for alpha-glycosyl isoquercitrin (AGIQ), a generally recognized as safe (GRAS) additive and flavor in food and beverages. In Phase I, 24 naturally mated New Zealand white (NZW) female rabbits per group were administered AGIQ by oral gavage at 0, 250, 500, or 1000 mg/kg/day once daily during gestation days 6–28, followed by necropsy. There was no evidence of maternal or fetal toxicity except for equivocal findings of unilateral absent kidney and ureter in one and two unrelated fetuses at 500 and 1000 mg/kg/day, respectively. To more thoroughly assess fetal kidney/ureter development, in Phase II groups of time mated NZW rabbits were administered AGIQ at 0, 500, or 1000 mg/kg/day, under the same conditions as Phase I. No occurrences of absent kidney/ureter were noted in the AGIQ-treated Phase II dams or fetuses; although, one control fetus had unilateral missing kidney/ureter. Given the lack of reproducibility following treatment with AGIQ in Phase II using 48 animals per group, the missing kidney/ureter observations in Phase I were considered unrelated to treatment. Since oral gavage administration of AGIQ to pregnant female NZW rabbits at dose levels of 250, 500, or 1000 mg/kg/day was well-tolerated with no adverse treatment-related effects on the maternal animal, pregnancy, or the developing conceptus, the no-observed-adverse-effect-level (NOAEL) for maternal toxicity and embryo-fetal survival, growth, and development was 1000 mg/kg/day.

Maternal and Fetal Toxicity of Carisoprodol Drug (Somadril Compound) on Pulmonary Tissues of Albino Rats

Carisoprodol is a common muscle relaxant indicated as adjunctive therapy in acute, painful musculoskeletal cases. This current study aimed to investigate the histopathological, histochemical and immunohistochemical effects in the lung tissue of the pregnant rats and their fetuses after carisoprodol treatment. The present study was applied on twenty seven pregnant female rats and they were randomly divided into three groups (nine pregnant female rats in each group). Rats of the first (control) group were administered oral doses of distilled water. Rats of the second (S1) and third groups (S2) were administered oral doses of carisoprodol in the distilled water equivalent to 10.8 mg and 21.6 mg/100g body weight/day respectively for fifteen days from the six to the twenty day of gestation. Several histopathological, histochemical and some immunohistochemical changes were studied to detect the pathological changes. Maternal and fetal pulmonary tissues of both treated groups showed numerous degenerative changes post-treatment with carisoprodol, the severity of these changes was more obvious in the fetal lung tissue of both groups. Also, carisoprodol treated rats showed a marked increase in caspase-3 content in the maternal and fetal pulmonary tissues. Treatment of pregnant rats with carisoprodol drug led to numerous dystrophic changes in both maternal and fetal lung tissues.

In Utero and Lactational Exposure to Diisopentyl Phthalate Induces Fetal Toxicity and Antiandrogenic Effects in Rats

A previous study has demonstrated exposure of Brazilian pregnant women to diisopentyl phthalate (DiPeP), which reduces fetal rat testosterone production in a dose-responsive manner. In this study, we examined gene expression of steroidogenic proteins in rat fetal testes and investigated the effects of in utero and lactational DiPeP exposure on male rat reproductive development and function. For the prenatal experiment, we orally exposed pregnant Wistar rats to DiPeP or di-n-butyl phthalate (reference phthalate) at 0, 125, 250, and 500 mg/kg/day from gestation day 14–18 and the fetal testis was evaluated for transcript expression of Star, Cyp11a1, Cyp17a1, Cyp19a1, Insl3, Ar, Esr1, Esr2, and Gper1 by real-time quantitative PCR (RT-qPCR). Diisopentyl phthalate lowered mRNA levels of key steroidogenic proteins, lending support to the previously reported reductions in fetal testosterone production. Diisopentyl phthalate also lowered fetal testis transcript levels of Insl3 and changed gene expression of some steroid hormones receptors. For the postnatal experiment, pregnant rats were exposed orally to vehicle (canola oil) and 4 DiPeP doses (1, 10, 100, and 300 mg/kg/day) between gestation day 10 and postnatal day 21. Diisopentyl phthalate induced a range of reproductive and antiandrogenic effects that are typical of the rat phthalate syndrome, including reduced anogenital distance at the highest dose, reduced weight of seminal vesicles at 10 mg/kg/day and above, and testicular morphological and functional changes. Signs of fetal toxicity were observed at the highest dose. Together, our results indicate that DiPeP, a compound relevant to the human exposure scenario, is one of the most active antiandrogenic phthalates.