Blood Placenta Barrier

The drug passes the placental barrier and may lead to spontaneous abortion, fetal hemorrhage, mental retardation, and birth malformations, particularly when used during the first trimester.

From: Electrophysiological Disorders of the Heart (Second Edition), 2012

Chapters and Articles

Anticoagulants, thrombocyte aggregation inhibitors, fibrinolytics and volume replacement agents

Janine E. Polifka, Juliane Habermann, in Drugs During Pregnancy and Lactation (Third Edition), 2015

Coumarin embryopathy

VKAs readily cross the placental barrier and can reach the fetus. The teratogenic risk associated with the use of VKA during pregnancy continues to be of importance because maintaining long-term anticoagulation is essential in women with heart valve replacement. Substitution with LMWH in sufficient doses during the first trimester of pregnancy and prior to delivery improves fetal outcome but increases maternal morbidity and mortality (McLintock 2011, 2013, Abildgaard 2009, Vitale 1999). However, recent studies on the use of warfarin during pregnancy have shown that both maternal and fetal outcomes are greatly improved if low-dose warfarin (≤5 mg/d) is used throughout pregnancy and replaced with LMWH close to delivery (McLintock 2013, De Santo 2012, Malik 2012, Geelani 2005).

The embryotoxicity of VKA, particularly that of warfarin, is well-known. Warfarin has been found to produce a characteristic pattern of malformations in the children of women who took this drug during pregnancy. Common features of this pattern of malformations, collectively called coumarin embryopathy or fetal warfarin syndrome, include nasal hypoplasia, stippled epiphyses, and growth retardation (Hall 1980). In a review of 63 case reports of coumarin embryopathy published after 1955, van Driel (2002a) found that anomalies of the skeleton were the most predominant feature, occurring in 51 (81%) of the 63 cases. Midfacial hypoplasia, that included a small upward pointing nose with indentations between the tip of the nose and nares, depressed nasal bridge, defective development of the nasal septum, micrognathia, a prominent forehead, and a flattened appearance of the face, was described in 47 of the cases. Stippling in the epiphyseal regions (chondrodysplasia punctata) was described in 32 (51%) of the 63 cases, mostly along the axial skeleton, at the proximal femora and in the calcanei. Limb hypoplasia, primarily involving the distal digits, may be found in up to one-third of children with coumarin embryopathy (Pauli 1993). Other anomalies reported and summarized by van Driel (2002a) were CNS abnormalities, disturbances of eye and ear development, abnormal heart development, asplenia syndrome, kidney agenesis, cleft lip, jaw and palate and pulmonary hypoplasia. Minor physical anomalies reported were lowset or poorly developed ears, a high-arched palate, hypertelorism, antimongoloid palpebral fissures, and widely spaced nipples. Hepatopathy lasting up to 4 months of age in addition to features typical of coumarin embryopathy were described in a premature infant whose mother had been treated with phenprocoumon up until 24 weeks of pregnancy (Hetzel 2006). It is likely that the liver dysfunction observed in this infant resulted from a toxic effect of phenprocoumon on the fetus similar to that which occasionally occurs with the drug in adults.

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Anesthesia for Fetal Surgery

Jeffrey L. Galinkin, ... Etsuro K. Motoyama, in Smith's Anesthesia for Infants and Children (Seventh Edition), 2006

UTEROPLACENTAL ANESTHETIC CONSIDERATIONS

Uterine and umbilical blood flow and placental barriers to diffusion influence fetal oxygen delivery. Maternal systemic blood pressure and myometrial tone directly correlate with uterine artery blood flow. Volatile anesthetics decrease myometrial tone and tend to decrease maternal blood pressure and maternal placental blood flow. This can result in a decrease in fetal oxygenation (Heymann and Rudolph, 1967; Luks et al., 1996; Parry et al., 2001). Umbilical artery blood flow is influenced by fetal cardiac output and vascular resistance, both intrinsic and extrinsic (e.g., compression by a “nuchal cord”). Maintenance of a patent umbilical artery and a near-baseline maternal arterial pressure are critical (maternal systemic pressure within 10% of baseline).

Studies in fetal lambs have shown that fetal-placental blood flow is significantly affected by maternal arterial Pco2 and pH. Maternal hypocapnea markedly reduces umbilical venous blood flow and results in fetal hypoxia and metabolic acidosis (Motoyama et al., 1966). In contrast, maternal hypercapnea (Paco2 > 60 mm Hg) and acidosis (pH < 7.3) increase umbilical venous blood flow and increase umbilical venous and fetal carotid Po2 above the physiologic ranges (Motoyama et al., 1967). The results of this study also show that with the same maternal Pco2, maternal hyperoxia was associated with an increase in fetal carotid Po2(Rivard et al., 1967). These findings in animal studies were corroborated in a clinical study in 38 parturient women during cesarean section under general inhalation anesthesia (Peng et al., 1972). In this study, the group of parturients, whose arterial Pco2 (Paco2) was kept between 30 and 50 mm Hg with the addition of 2% CO2, had significantly higher umbilical (postductal) arterial Po2 and lower fetal base deficit than those who were ventilated with the equivalent ventilator setting but without added CO2 and with lower Paco2 (20 to 30 mm Hg). There was a significant correlation between the maternal Paco2 and umbilical arterial Po2 as well as fetal base deficit (Peng et al., 1972). Maternal hypocapnia should be avoided during maternal-fetal procedures. Possible efficacy of hypercapnea to enhance fetoplacental circulation should be explored in the future.

Control of myometrial tone by general inhalation anesthesia is necessary for open fetal surgery to provide optimal operative exposure. Epidural anesthesia alone does not provide uterine relaxation. Epidural anesthesia may help prevent premature labor in the postoperative period (Tame et al., 1999). Magnesium sulfate, terbutaline, nifedipine, and indomethacin are also used alone or in combination to maintain uterine quiescence in the postoperative period.

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Antiandrogens and Androgen Inhibitors

Najwa Somani, Marty E. Sawaya, in Comprehensive Dermatologic Drug Therapy (Fourth Edition), 2021

Pregnancy and Lactation

Spironolactone and its metabolites can cross the placental barrier. Studies in rats demonstrate feminization of the male rat fetus during gestation. Limited reports in humans have not shown adverse pregnancy outcomes. Although FDA labeled as a pregnancy category C drug, because of the potential risk based on animal studies and the antiandrogenic properties of spironolactone, it should be avoided in pregnant women and women should be advised of the potential risk to a male fetus.49 (see Box 34.4) The spironolactone metabolite canrenone has been detected in breast milk of nursing women.21

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Pharmacokinetics and Pharmacodynamics

Lara S. Lemon, ... Steve N. Caritis, in Fetal Medicine (Third Edition), 2020

Placental Transport

Most xenobiotics are capable of crossing the placental barrier by simple diffusion; therefore, the amount that reaches the fetus is blood flow dependent. Four primary characteristics contribute to a drug’s likelihood of transport across the placenta: (i) protein binding, (ii) degree of ionisation, (iii) lipid solubility and (iv) molecular weight. Typically, drugs that cross easily are poorly protein bound, nonionized, lipid soluble and small (specifically <1000 daltons).33

The trophoblast cells in the placenta express an array of DMEs and transporters. Many of the same enzymes expressed in the liver exist in the placenta, but placental metabolic activity is generally lower than that seen in the liver.9 Although the role of the placental CYP enzymes is relatively small,9 they can impact the effect of the drug in the fetus and the mother. Table 48.2 above describes the expression of CYP enzymes in the placenta relative to expression in the liver, kidney and small intestine. Interestingly, the expression of CYP enzymes in the placenta decreases throughout gestation. This is thought to occur to protect the fetus in the first trimester, when it is undergoing organogenesis and therefore most susceptible to teratogens.

Beyond serving as a barrier to xenobiotics, the placenta is also responsible for transporting nutrients to the fetus and removing waste produced by the fetus.33 It accomplishes this through not only passive diffusion but also active diffusion via transporters. Such transporters are located on both the maternal and fetal sides of the syncytiotrophoblast, the functional cell unit of the placenta. Transporters are responsible for transport of both endogenous substances and certain xenobiotics, which typically have a similar structure to endogenous compounds.13

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Aflatoxins, ochratoxins and citrinin

Ramesh C. Gupta, in Reproductive and Developmental Toxicology, 2011

Reproductive and developmental toxicity

It is well established that OTA crosses the placental barrier and can also be transferred to newborn rats and mice via lactation (Applegreen and Arora, 1983a,b; Fukui et al., 1987; Hallen et al., 1998). In addition, OTA-DNA adducts are formed in the liver, kidney and other tissues of progeny (Pfohl-Leszkowicz et al., 1993; Petkova-Bocharova et al., 1998).

There is strong evidence that OTA causes birth defects in rodents (Hayes et al., 1974; Brown et al., 1976; Wangikar et al., 2004a,b), chickens (Gilani et al., 1978) and pigs (Shreeve et al., 1977). In rodent fetuses, the major target is the developing CNS. In other words, OTA is also considered a neurotoxicant. In mice, damage to the neural plates and folds, midbrain and forebrain was reported in one study, while the second study showed cell death in the telencephalon. Other abnormalities included necrosis of the brain (mice), fetal resorption, visceral and skeletal defects in rats, mice and hamsters (Singh and Hood, 1985; NLM, 2002b), craniofacial (exencephaly, midfacial and lip clefts, hypotelorism and synophthalmia) and body wall malformations in mice (Wei and Sulik, 1993), and a reduction of synapses per neuron in the somatosensory cortex of mice (Fukui et al., 1992). While the mechanism involved in OTA-induced teratogenesis still remains unclear, it seems to directly affect both the progenitor cells and the embryo.

In a dose–response study, Patil et al. (2006) observed that a single oral dose of 2.75 mg/kg body weight OTA was found to be the minimum effective teratogenic dose and GDs 6 and 7 were found to be the most critical for the induction of teratogenicity in pregnant Wistar rats.

OTA at 2.75 mg/kg administered on one of the GDs 6–15 caused significant maternal toxicity and various gross, visceral and skeletal anomalies in the fetus. The major gross malformations were external hydrocephaly, incomplete closure of skull and omphalocele. Internal hydrocephaly, microphthalmia, enlarged renal pelvis and renal hypoplasia were the main internal soft tissue anomalies. Major skeletal anomalies were developmental defects in skull bones, sternebrae, vertebrae and ribs. By now, there is compelling evidence that OTA is a teratogen affecting the nervous system, skeletal structures and immune system of research animals. In a teratogenic study in rabbits, Wangikar et al. (2005b) found that simultaneous exposure to OTA and AFB1 produced an antagonistic interaction.

In a recent study, Singh et al. (2007) exposed female Wistar rats during GD 6–20 with citrinin at 10 mg/kg food to assess maternal toxicity. The rate of fetal resorptions was 12.5% compared to 3.86% in controls. The histopathological changes were primarily in the kidney. The proximal convoluted tubules (PCT) epithelial cells showed extensive degeneration with vacuolations and desquamation of epithelial cells, and these cells occluded the lumen of the PCT. Large vacuoles were also seen in the epithelial lining cells of the PCT. The cells were swollen with pinkish granular cytoplasm and occasionally karyomegaly of the nuclei. Medullary tubules revealed pinkish, homogeneous proteinaceous materials in their lumina. The intertubular blood vessels were found to be consistently dilated and engorged. Histological changes in the uterus were evident only in cases of abortion or at the resorption sites. The changes included intense congestion of blood vessels both in the endometrium and myometrium. In a follow-up study, using the same treatment regimen, these investigators histopathologically examined the liver and kidneys of rat fetuses (Singh et al., 2008). Evaluation of the fetal liver revealed only sinusoidal dilation and mild vacuolar degeneration, whereas consistent changes in the fetal kidney included tubular degeneration, medullary tubular necrosis, cystic dilatation of tubules, distortion of glomerular capillary tuft and interstitial fibroblastic proliferation. Several investigators have reported similar changes with citrinin in PCT of rats (Jordan et al., 1978a; Lockard et al., 1980), hamsters (Jordan et al., 1978b), dogs (Carlton et al., 1974), mice (Bilgrami and Jeswal, 1993) and poultry (Maryamma et al., 1990; Uma and Vikram Reddy, 1995; Ahamad and Vairamuthu, 2001). Observations of all these studies are consistent with the fact that the kidney is the target organ for citrinin and therefore citrinin is regarded as a nephrotoxic mycotoxin (Ribeiro et al., 1997).

In conclusion, OTA and its analogs can produce a variety of toxic effects, referred to as “ochratoxicosis”, including mutagenesis, carcinogenesis, BEN, embryotoxicity, teratogenesis and immune suppression, by damaging mitochondria, DNA, protein and RNA by oxidative injury (lipid peroxidation). OTA causes mitochondrial damage, oxidative burst, lipid peroxidation and interferes with oxidative phosphorylation. In addition, OTA causes cell death by apoptosis.

In contrast to OTA, citrinin is studied to a lesser extent, but citrinin exerts similar toxic effects. Citrinin is embryo/fetotoxic and embryocidal in mice and rats. Yang et al. (1993) examined developmental toxicity of citrinin in Hydra attenuata (HA) and rat whole embryo culture (WEC). The Hydra developmental hazard index (A/D ratio) was equal to 1.5, classifying citrinin as a co-affective developmental toxin. Using whole embryo culture, rat embryos were cultured in homologous (rat) serum containing citrinin at concentrations ranging from 0 to 300 μg/ml for a period of 45 h. The results indicated a concentration-dependent reduction in yolk sac diameter, crown–rump length, somite number, protein and DNA content. Histopathological examination revealed severe diffuse mesodermal and ectodermal necrosis in embryos treated with 250 μg/ml citrinin. Based on both bioassays, citrinin is not found to be a primary developmental mycotoxin.

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ASSOCIATED DISORDERS AND SPECIAL MANAGEMENT PROBLEMS OF ULCERATIVE COLITIS

In Surgery of the Anus, Rectum & Colon (Third Edition), 2008

Sulphasalazine

Sulphasalazine and 5-aminosalicylic acid cross the placental barrier (Azad Khan and Truelove, 1979; Jarnerot et al, 1981) and are secreted into breast milk, hence they are absorbed by the breastfed child (Jarnerot and Into-Malmberg, 1979). Maternal milk and serum 5-aminosalicylic acid levels are very low because of poor absorption. The sulphapyridine moiety of sulphasalazine may bind to albumin and displace unconjugated bilirubin, leading to kernicterus (Hensleigh and Kauffman, 1977). This complication is not anticipated with the 5-aminosalicylic compounds. Despite these theoretical considerations, kernicterus has not been a recorded complication in the literature (Baiocco and Korelitz, 1984).

Sulphasalazine may have teratogenic effects in animals but there are no reports of induced congenital malformations in humans. Since the risk of congenital abnormality is not increased in children of mothers taking maintenance therapy (Mogadam et al, 1981), and in view of the known protective role of sulphasalazine in preventing relapse (Misiewicz et al, 1965; Dissanayake and Truelove, 1973), maintenance sulphasalazine should be continued in patients who became pregnant, since the risks to the fetus are greater if relapse occurs than they are from the drug itself. There are no known teratogenic side-effects using the 5-aminosalicylates (Marteau et al, 1998).

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Nutrition for a healthy pregnancy and environment

Guillermo Molina-Recio, in Fertility, Pregnancy, and Wellness, 2022

Consumption of other substances

It has been seen that caffeine easily crosses the placental barrier and is distributed over all the fetal tissues; there are different studies relating its consumption to low weight in neonates and to the probability of a miscarriage [23]. However, and in view of the difficulty in estimating the daily caffeine intake of the pregnant woman, the “safe” threshold dose is not known. At any rate, it is known that intakes of below 300 mg daily are not associated with premature births or other adverse effects, but moderation in its consumption should be recommended, both during pregnancy and in lactation, reminding the mother that it is not only found in coffee and tea, but also in chocolate, energy beverages, cocoa, and cola drinks.

An elevated consumption of alcohol (80 g or more) during gestation has been linked to miscarriages, low birth weight, diverse malformations, fetal death, and the fetal alcohol syndrome (characterized by IUGR, mental retardation, heart, renal and genital defects, syndactyl, learning, behavior or emotional problems, etc.) and, although it appears that an intake in small amounts is not related to these effects, neither has a “safe” dose been fixed, so that avoiding its consumption should be recommended.

A moderate intake of some artificial sweeteners (potassium acesulfame, aspartame, sucralose, or neotame) is considered to be safe during pregnancy, whereas that of saccharin and of cyclamates are more controversial due to it not being known what effects they may have on fetal development. However, and although the safety of sugar substitutes during gestation has not been studied with rigor, no adverse effects during pregnancy and lactation have been reported at the present time.

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Pituitary Disorders During Pregnancy and Lactation

Raquel Soares Jallad, ... Marcello D. Bronstein, in Maternal-Fetal and Neonatal Endocrinology, 2020

18.3.3 Impact of Acromegaly During Pregnancy

Maternal GH and IGF-1 do not cross the placental barrier and do not adversely affect fetal growth and development.89,90,95 Therefore, high maternal GH and IGF-1 levels are not contraindications for pregnancy.89,90,95 The development of macrosomia in these cases is a result of maternal diabetes mellitus induced by GH, rather than the GH directly.89,95

Due to the known insulin resistance and sodium-retaining effects of GH, impaired glucose tolerance, diabetes mellitus, and hypertension are common in patients with acromegaly.88,89,96,97 In addition, pregnancy itself is an insulin-resistant state.97 Therefore, compared with the general population, pregnant women with active acromegaly have an increased risk of developing those complications.81 In a retrospective multicenter study of 59 pregnancies in 46 women with acromegaly, gestational diabetes was diagnosed in 4 of the 59 pregnancies (6.8%).81 There is also an increased incidence of hypertension, preeclampsia, and coronary artery disease in pregnant women with acromegaly.81

Cheng et al. described 13 new cases and reviewed an additional 34 cases from the literature, and they concluded that pregnancy can proceed in treated acromegalic women without significant complications or teratogenicity.86

Jallad83 reviewed 32 pregnancies in women with acromegaly and found that active or uncontrolled acromegaly may be associated with an increased risk of not only gestational diabetes, but also pregnancy-induced hypertension.83 The altered IGF-axis in acromegaly also may be implicated in impaired glucose homeostasis.

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Volume 2

Robin Kjerstin Ohls, in Fetal and Neonatal Physiology (Fourth Edition), 2011

Fetomaternal Red Blood Cell Transfer

Maternal and fetal circulating cells may, at various times, cross the placental barrier. Fetal contamination of the maternal circulation can occur before delivery, as evidenced by studies of maternal blood group immunization. Approximately 50% to 75% of pregnancies are associated with some degree of fetomaternal transfer of blood. This event is uncommon in the first trimester (3%). Volumes of fetal transplacental transfer are relatively small, usually on the order of 0.01 to 0.1 mL, but on occasion they may be much greater. Approximately 1 pregnancy in 400 is associated with fetal transplacental bleeding of 30 mL or greater, and 1 pregnancy in 2000 is associated with a potential fetal transplacental hemorrhage of 100 mL or more.94 The overall risk for occurrence of Rh immunization in an Rh-incompatible pregnancy is 16% if the fetus is Rh-positive and ABO-compatible with its mother. This risk is 1.5% if the fetus is Rh-positive and ABO-incompatible. Fetal transfer of cells to the mother occurs during abortions as well (an approximately 2% incidence of such transfer with spontaneous abortion and a 4%+ to 5% rate if induced).95 Because fetal hemoglobin is resistant to acid elution, cells containing fetal hemoglobin can be distinguished from cells containing hemoglobin A. The Kleihauer-Betke stain of peripheral maternal blood uses this characteristic of fetal hemoglobin to detect fetal cells in the maternal circulation,96 although results with blood smears from mothers with diseases that result in increased fetal hemoglobin synthesis (such as maternal sickle cell disease, maternal thalassemia, and maternal hereditary persistence of fetal hemoglobin) are not reliable. Diagnosis of fetomaternal hemorrhage also may be missed when both mother and infant are ABO-incompatible. In such instances, the fetal cells are rapidly cleared from the maternal circulation by maternal anti-A or anti-B antibodies.

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Additional Biologic Therapeutics

Erin E. Grinich, Eric L. Simpson, in Comprehensive Dermatologic Drug Therapy (Fourth Edition), 2021

Special Populations

Omalizumab is traditional pregnancy category B. As an IgG antibody, omalizumab is able to cross the placental barrier. There are no studies of omalizumab in human pregnancy; however, reproductive studies in cynomolgus monkeys receiving 10 times the maximum recommended human dose (MRHD) did not reveal any maternal toxicity, teratogenicity, or embryotoxicity.27 Cynomolgus monkeys were also exposed to omalizumab during pregnancy and for 1 month of breastfeeding. After 1 month of breastfeeding, neonatal drug serum levels ranged from 11% to 94% of maternal serum levels.43

The Xolair Pregnancy Registry (EXPECT) is a postmarketing evaluation system following pregnant women exposed to omalizumab for asthma. In 2012, EXPECT reported that the prevalence of major congenital abnormalities was consistent between omalizumab (4.4%) and the general population (2.7%–4.2%) as well as the general population with asthma (2.7%–9.1%).89

There are no human breastfeeding studies for omalizumab; however, endogenous IgG is excreted into breast milk so infants may be exposed to omalizumab while breastfeeding. Breastfeeding studies in cynomolgus monkeys found omalizumab in a concentration of 1.5% of maternal serum levels. It remains unclear what affect this exposure may have on an infant (see Box 31.4).43

Study of omalizumab in geriatric patients (>65 years of age) is limited to 37 CIU patients and 134 asthma patients. There are no age-related responses seen in trials; however, the geriatric sample size is insufficient to fully elicit possible differences.27

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