Treating the placenta: an evolving therapeutic concept

6.1 Introduction

Generally, from the perspective of clinical pharmacology, one thinks of the placenta as the route of passage from mother to fetus or the reverse [ ], with or without metabolism. With few exceptions, it is generally not thought of as the target for therapy. However, we believe that as our understanding of placental function grows and as the science and application of obstetric-based clinical pharmacology broadens, the placenta may become an important therapeutic target for the mother, the fetus, or both [ ]. Clinically important diseases where such a strategy is employed today include the prevention of vertical HIV-1 virus transmission from mother to fetus and in the treatment of malaria where the placenta serves as an important reservoir for the malaria parasite. In this chapter, we critically review what is known about placental functions and its modulations throughout gestation and how placental processes can and might be manipulated for therapeutic gain.

Two recent reviews have explored drug development from the perspective of placental dysfunction (Sibley, 2017 #4) or from the perspective of prevention of abnormal fetal brain development from hypoxia [ ]. Sibley started his review with the premise that obstetrical challenges (e.g., fetal growth retardation, preeclampsia, preterm labor, preterm premature rupture of membranes, late spontaneous abortion, and placental abruption.) were a consequence of placental dysfunction. From that perspective, he illustrated how a contemporary drug development program could be developed for multiple compounds including sildenafil citrate, adenovirus vector with VEGF, pomegranate juice, tempol, resveratrol, melatonin, sofalcone, proton pump inhibitors, statins, and metformin. Phillips et al. proposed that placental secretions in response to hypoxia might play a role in brain development resulting in adult onset diseases. Using a nanoparticle-bound antioxidant, they demonstrated reduced oxidative stress in the placenta and reduced the reduction in birth weight. The treatment target in the Phillips et al. research was the placenta with an indirect impact on the pup/fetus. Both studies emphasize the potential benefit of treating the placenta.

6.2 The placenta as the therapeutic target: the past

An early example of targeting placental function for therapeutic purposes that was both unsuccessful as well as resulting in unexpected tragic consequences is the experience with diethylstilbestrol (DES). The DES experience highlights the importance of the need for a good understanding of the disease process, drug pharmacokinetics and pharmacodynamics, and acute, chronic, and generational toxicity before undertaking widespread drug-based manipulation of the maternal, placental, and/or fetal compartments [ ]. DES is a synthetic estrogen structurally similar to estradiol with potent estrogen-like activity that is rarely used today. From the 1940s to ∼1971, DES was commonly used for prevention of spontaneous abortions. An innovative randomized controlled clinical trial conducted at the Chicago Lying-In Hospital demonstrated that DES was unable to prevent pregnancy loss, and may have actually led to missed abortion [ ]. Unknown at the time but recently described, DES beneficial clinical effects are most likely a result of the drug's positive effects on placentation and trophoblast stem cell differentiation [ ] (see also [ ]; Sibley, 2017 #4 for discussion of placental treatments). Unfortunately, maternal use of DES results in a high incidence of developmental toxicity on the reproductive tracts of males and females and the subsequent development of vaginal clear cell adenocarcinoma in women of childbearing age [ ]. Many environmental chemicals and pollutants either as the intact compound or metabolite can also have similar or unique devastating adverse consequences on the mother, the placenta, and/or the fetus [ ] complicating our assessment of individual compounds during pregnancy. These and many other tragic experiences underscore the importance of careful study of mother–fetal benefit–risk profiles of drugs intended to treat the placenta.

6.2.1 Placental function

The placenta provides a link between the mother and fetus, metabolizing and transferring nutrients for growth and development of the fetus as well as for its own growth and development. Metabolic waste products generated in the fetus or placenta are eliminated by transfer into the maternal circulation. A unique function of the placenta is its role as an endocrine organ producing steroid and protein hormones. These characteristics must be considered in thinking about treating the placenta to enhance therapeutic success in placental, fetal, or maternal disease. A detailed description of placental anatomy, physiology, and gestational maturation is addressed in Chapter 5 . However, for completeness, we provide a brief overview of those anatomic and physiologic functions important to understanding therapeutic targeting of placental function for maternal and fetal health.

Briefly, fetal and maternal circulations are separated by placental tissue that changes throughout pregnancy; anatomically, the surface area over which maternal–fetal exchange occurs increases and the distance between maternal and fetal blood decreases. Morphologically, the syncytiotrophoblast layer is reduced in thickness and the cytotrophoblast becomes discontinuous as gestation progresses. Changes in the villous structure are also observed, with an increasing number of microvilli facilitating exchange between mother and fetus. These villi and the syncytiotrophoblast layer permit the maternal and fetal circulations to be close to each other, without contact while providing a transport barrier between the two circulations [ , , ].

In human placenta, the syncytiotrophoblast arises from the fusion of cytotrophoblast, forming a syncytium over the surface of the placenta facing the maternal blood. The plasma membranes of the syncytiotrophoblast are polarized; the brush border membrane is in direct contact with maternal blood and the basal membrane facing the fetal circulation. The brush border membrane possesses a microvillus structure that effectively amplifies the surface area, whereas the basal membrane lacks this structure.

Anatomic differences between species in the number of trophoblast layers and connection between maternal and fetal tissues result in species-specific variation in placental function that influences data gathered during the preclinical stages of drug development. The human placenta is unique in its villous structure. Factors such as diffusion, electrical potential across the placenta, magnitude of maternal and fetal blood flows, and differences in metabolism, transport proteins, and other mechanisms for exchange between maternal and fetal circulations should be considered as the placental transfer and metabolism of drugs varies dramatically among differing species. Discordant results for maternal–fetal drug disposition between humans and many animal species are often noted due to these anatomical differences in placental morphology and function [ ]. The thalidomide tragedy was the most important event to dispel the erroneous belief that the placenta was a barrier and spawned regulation for controlled, animal-based preclinical teratology studies [ ]. These anatomical and physiological differences can also lead to false implications for teratogenic effect(s). The widely used drugs diazepam and salicylates were shown to induce teratogenic effects in animals with no increased risk of any such effects in humans.

The previously widely used and therapeutically effective drug Benedictine (doxylamine plus pyridoxine) was shown in animal studies to cause cardiac and limb defects leading to enormous litigation and ultimately withdrawal from the US market though no increase in human teratogenic effects have been described [ ], and this drug combination remains the most effective intervention for treating pregnancy-associated nausea and vomiting (see Chapter 12 ). These misleading and sometimes erroneous findings are directly attributable to the interspecies differences that exist in placental structure and function. Despite these disparities and the need for better mechanisms for screening possible placental toxins or teratogens, animal screening remains the best process today [ ], although structure activity analysis is rapidly gaining credence (Wu, 2013 #11).

Drugs for treatment of placental disease should be concentrated within the placenta with little access to, and toxicity for, mother or fetus. Drugs developed for treatment of the mother should have minimal transport to fetal circulation and minimal impact on placental and fetal health. Drugs for treatment of fetal diseases should have unhindered access to the fetal circulation with minimal adverse impact on mother or placenta [ , ].

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