Which of the following substances can cross the placenta between the mother and the embryo or fetus?

Placental Transfer of Hormones

The placenta forms the materno-fetal interface, delivering nutrients and oxygen to the fetus and acting as a selective barrier. The placenta demonstrates remarkable capacity to adapt to adverse environments and lessen their impact on the fetus. Placental transfer of hormones decreases with increasing molecular weight, and those larger than 0.7 to 1.2 kDa have little or no access to the fetal compartment.2 Maternal hormones therefore play a very limited role in the fetal endocrine milieu. Hormones that do cross the placenta may be metabolized en route (Fig. 23.1), including steroid hormones (cortisol), thyroid hormones (T3, T4), estradiol, and catecholamines.3–6

The concentration of maternal cortisol is almost 10-fold higher than that in the fetus. Placental cells contain an active 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) that catalyzes conversion of maternal cortisol to inactive cortisone.7 Synthetic glucocorticoids, such as dexamethasone or betamethasone, can bypass this protective mechanism resulting in exposure of the fetus to steroid hormones. While this is used acutely for its beneficial effects on fetal lung maturation in cases of threatened preterm delivery, chronic use may produce adverse effects on blood pressure, blood glucose, and memory, as demonstrated in rodent models,8–10 as well as impacting negatively on placental and fetal growth.11 Clinical use of single or multiple courses of glucocorticoid treatment in the obstetric management of threatened preterm delivery continues, but treatment for other proposed indications lacking robust evidence (e.g., use in pregnancy to reduce virilization of a fetus with congenital adrenal hyperplasia [CAH]) should take place only in a research setting with careful auditing.12,13

Estrogens modulate many intrauterine processes throughout gestation, and the balance between estrogens and progesterone inutero is thought to be critical to the maintenance of pregnancy, fetal maturation, and the onset of parturition. The placenta produces vast amounts of estrogens in the form of estradiol, estrone, estriol, and estetrol. The estrogen products released from the placenta depend on the nature of the substrate available. Estradiol is the primary estrogen circulating at term. In addition, significant levels of estriol and estetrol are also found in the maternal circulation, and they increase particularly late in gestation. These hydroxylated forms of estrogen are produced in the placenta, using substrates from the combined efforts of the fetal adrenal gland and liver. Though the primary site of estrogen biosynthesis is the placenta, the placenta lacks the cytochrome P450 enzyme CYP17 and accordingly is unable to synthesize estrogens de novo.14 Placental estrogen biosynthesis relies on a supply of C19 androgens, mainly dehydroepiandrosterone (DHEA) and its sulfoconjugate, DHEA sulfate (DHEAS), derived principally from the fetal and maternal adrenal cortex.14–16 By term, estradiol and estrone concentrations are 100-fold higher than those of nonpregnant women, and estriol concentrations are 1000-fold higher.16 The developing fetus is protected from excessive estrogen exposure by conversion of active estradiol to inactive estrone by placental 17β hydroxysteroid dehydrogenase.5

Flow-Limited and Diffusion-Limited Transfer

Placental transfer can be limited by the diffusion across the placental barrier (“diffusion-limited” transport) and/or by the rate of uteroplacental and umbilical blood flows (“flow-limited” transport). For example, the transfer of nutrients, which in most cases is mediated by transporters, binding proteins and/or receptors expressed in the syncytiotrophoblast plasma membranes or cytosol, is predominantly diffusion-limited. In contrast, placental transfer of oxygen is blood flow limited because it is a small molecule with high lipid solubility, which rapidly diffuses across the syncytiotrophoblast and fetal capillary endothelium. This is the reason why short-term reductions in placental blood flows affect the transfer of oxygen more than nutrient transport.

Placental Transfer and Metabolism

Our understanding of placental transfer and metabolism is rapidly improving (seeChapter 4).19 Early research was often limited to measuring drug concentration in the umbilical vessels and maternal vein at delivery. Results were variable and difficult to interpret, especially for drugs such as anesthetic agents that are administered shortly before delivery. Umbilical blood samples are obtained at variable times after drug exposure, well before steady-state conditions are achieved. The theory of a placental barrier was proposed because maternal and fetal concentrations were often different. However, differences in concentration of binding proteins are mainly responsible for the fetal-maternal distribution of drugs at steady state.20 The fetal concentration of albumin is slightly greater than that in the mother, but α1-acid glycoprotein concentration is only one-third of the maternal value at term. Umbilical-to-maternal blood ratios of total drug may be misleading because it is the free drug that equilibrates across the placenta. Maternal-to-fetal ratios of drugs do not provide information on the rate of drug transfer or the amount of drug that has already been transferred to the fetus.

Drug transfer across the placenta was previously thought to occur mainly by diffusion. This would favor the movement of lipophilic drugs, and placental perfusion would be an important factor affecting transfer. Fetal pH is lower than maternal pH, so that weak bases become more ionized in the fetus, thus limiting their transfer back across the placenta. Normally, the difference in pH is only 0.1 and this “ion trapping” is irrelevant, but fetal acidosis can significantly increase the fetal concentration of drugs such as local anesthetics.

It is now known that the placenta contains many drug transporters that can modify fetal drug exposure.14,16,19,21,22 In the treatment of sustained fetal tachyarrhythmia, placental P-glycoprotein, an adenosine triphosphate–dependent drug efflux pump, will reduce net transfer of substrates such as digoxin and verapamil from the mother. Although placental transport of immunoglobulin makes it possible to immunize the mother to protect the newborn, this transport also raises concerns when immunoglobulin tumor necrosis factor antagonists are used to treat maternal diseases.

The placenta contains many active enzymes responsible for Phase I and Phase II biotransformation.21 Clearance of substrates by UGT in full-term placentas may be sufficient to contribute to overall maternal metabolism.

Placental Transfer Studies

Placental transfer studies provide information on placental transfer of drugs by assessing the radioactivity in fetal tissue and maternal blood. There are many morphological differences and similarities in yolk sac and chorioallantoic placenta between rats, rabbits, and humans (Garbis-Berkvens and Peters, 1987; Foote and Carney, 2000). Therefore, it is unlikely that routine placental transfer studies, in which fetal exposure is determined after closure of the hard palate, would be adequate to correlate embryo–fetal exposure to an NCE with a developmental effect. In spite of the marked differences between placentas of animals, there is not much difference in placental transfer of most chemicals (Mihaly and Morgan, 1984). The relative distribution of a drug between the embryo–fetal and maternal unit is dependent not only on the physicochemical properties, but also on the physiological parameters and gestational age. Hence, placental transfer studies conducted only on one accession during gestation can provide distributional evidence only for that particular period of gestation. Consideration should also be given to the drug protein binding as it is the unbound free drug that crosses the placenta and is available for distribution.

Placental Transfer

To reach the fetal tissues and organs, the molecules that have entered the placenta via the maternal circulation have to first cross the placental barrier. The placental villous barrier or membrane is made up of the trophoblast, which covers the villous tissue externally and is in direct contact with the maternal blood in the intervillous space, the villous mesenchymal tissue, and the endothelium of the fetal capillaries (seeChapter 1).

Important anatomic changes take place between the first and second trimesters of pregnancy. During most of the first trimester, the entire gestational sac is covered with villous tissue and the entry of maternal blood inside the placenta is limited by the presence of trophoblastic plugs blocking the mouths of the uteroplacental arteries in the area destined to become the definitive placenta. On the fetal side, the villous capillaries are small in numbers and size and located more centrally inside the villi at a much greater distance from the trophoblastic layer than later in pregnancy. During that period of gestation, the placental transfer route is described as histiotrophic via the uterine glands, extraembyonic coelom, and the secondary yolk sac. The placenta becomes truly hemochorial only from the end of the first trimester. The villous membrane becomes progressively thinner, facilitating maternal-fetal exchanges in both directions with advancing gestation.

For the most part, placental drug transfers have been studied using animal models, essentially rodents, or in vitro using third-trimester ex vivo isolated dual-side perfused human cotyledons. Both models have obvious limitations, in particular, regarding transfers during the first trimester of human pregnancy, which is the gestational period when the human fetus is at highest risk for teratogenic effects. Placental drug pharmacokinetics can be indirectly studied in vivo using coelocentesis (the aspiration of coelomic fluid) in the first trimester or cord blood samples at delivery.

Overall, it is assumed that all drugs will in some manner cross into the placenta, especially those that are lipid soluble; water-soluble drugs and metabolites of drugs pass less readily. Only free drug will pass into the placenta, so any portion of drug bound by protein will not cross the placenta. Substances cross mainly from the maternal to the fetal circulation by passive diffusion (Fig. 7.2).9 Thus passive diffusion across the villous barrier is the predominant method of the fetus's exposure to drugs and environmental agents, with low-molecular-weight lipid-soluble substances and non-protein-bound drugs passing easily. Compounds greater than 600 Da—such as insulin, heparin, or drugs bound by proteins—do not pass easily into the placenta. Drug concentrations in the fetus may exceed maternal concentrations, with weakly basic drugs passing more easily. Passive drug transfer is flow dependent and membrane limited. As the flow volume in the placental circulations increases and the thickness of the villous barrier decreases, respectively, with advancing gestation, fetal exposure to drugs and environmental agents is greatest in the last trimester but the effect on fetal organs is the lowest.

Second-generation effects

Molecular Weight of Drugs

Placental transfer cannot be predicted solely on the basis of lipid solubility, drug ionization, and protein binding. Most investigators agree that for drugs with an MW >500 to 600 D, passive transport across the human placenta is limited, although peptides such as oxytocin (MW 1007 D) do cross the placental barrier.2,4 Accordingly, the high MW of erythropoietin (30 to 34 D) is believed to be the reason for its poor placental transfer in the placental perfusion model, and similar conclusions are made for example for insulin, heparin, or low-molecular-weight heparins.25,138,139

When different oral hypoglycemic agents were compared with regard to maternal-fetal transport in the recirculating single-cotyledon human placenta model, glyburide (MW 494 D) did not cross the human placenta in significant amounts. The glyburide-antipyrine transport ratio (0.11 : 0.21) was much lower than the tolbutamide-antipyrine transport ratio (0.74 : 1.05) (Figure 20-7).140 The investigators found a highly significant relationship between the mean drug antipyrine transport ratios obtained in their experiment (tolbutamide MW 270 D < chlorpropamide MW 277 D < glipizide MW 446 D, and < glyburide MW 494 D) and the independent variables (MW, log partition coefficient, and selected dissociation constants [R2 = 0.91; p = .0001]). This relationship was described by the following equation: (6)

[20-6]Td/Ta=−4.90+0,5log(Pd)+1.26pKa−0.0073 MWd

where Td = placental transport of the drug, Ta = placental transport of antipyrine, and MWd = MW of the drug.

The MW was the most important variable in this regression (F = 61,75; p < .001) and determined the cumulative percentage of transport of the drugs tested.140 Neither the log partition coefficient nor the dissociation constant individually provided significant associations by simple regression with either the drug-antipyrine ratio or the cumulative percentage of transport of these drugs. Furthermore, the high plasma protein binding of glyburide (99%) did not account for this finding, as discussed by Koren.141 However, more recently, the same group reported on in vivo paired maternal/umbilical cord blood samples at delivery in women with gestational diabetes mellitus, treated with glyburide. The mean maternal serum glyburide level at birth was 15.4 ng/mL, and the mean umbilical cord level was 7.5 ng/mL (fetal/maternal ratio = 0.49). However, extensive variability was observed, only partly explained by the maternal glyburide concentration.142 To further illustrate the clinical relevance of placental transfer, we refer to a case report on fetal macrosomia and neonatal hyperinsulinemic hypoglycemia associated with transplacental transfer of this sulfonylurea (high-dose glyburide, 85 mg/day) in a mother with neonatal diabetes.143

In vitro heparin does not cross the human term placenta.144 No biologic activity and very low fractions of radioactivity used for labeling were found in the fetal circulation in the human perfused placental cotyledon model for unfractionated heparin, low-molecular-weight heparin, and dermatan sulfate.145 These data are in line with in vivo observations in newborns whose mothers had been treated with unfractionated heparin or low-molecular-weight heparin.146,147 A similar case can be built for hydroxyethyl starch.148

Second-generation effects

Fetotoxicity

Transplacental transfer of nalbuphine was measured in eight mothers who underwent cesarean section and were given nalbuphine 200 micrograms/kg intravenously along with thiopental and suxamethonium. The umbilical cord/maternal vein ratio was 1.4:1 at delivery, which occurred at 2–10 minutes after nalbuphine injection. Mean Apgar scores at 1 minute were 6.6 and 8.5 at 5 minutes and did not correlate with either the serum nalbuphine concentration or the time between injection of nalbuphine and delivery [20].

Three neonates, whose mothers who had received nalbuphine during labor, developed apnea and cyanosis, which required ventilation within 3 minutes of birth [21,22].

Bradycardia and bradypnea have been reported in babies whose mothers were given nalbuphine a few hours before delivery [11,23].

Fetal sinusoidal rate pattern has been attributed to nalbuphine [24].

Congenital Varicella

Transplacental transmission of varicella following maternal chickenpox infection carries low risk of birth defects. The incidence of congenital varicella syndrome after maternal varicella during the first two trimesters is less than 1%.

Intrahepatic and intracranial calcifications are the most common imaging findings. Although rare, intrauterine encephalitis with atrophy and porencephaly have been reported. Calcifications may be seen in many organs, such as liver, heart, and kidney. Polyhydramnios due to neurologic impairment of swallowing, limb hypoplasia, and diaphragmatic paralysis are other imaging findings. Autonomic nervous system dysfunction may cause neurogenic bladder, hydroureter, esophageal dilatation with aspiration pneumonia. Cutaneous lesions in dermatomal distribution may also be seen.