General commentary on drug therapy and drug risks in pregnancy

1.1

Introduction

Most prescribers and users of drugs are familiar with the precautions given concerning drug use during the first trimester of pregnancy. These warnings were introduced after the thalidomide disaster in the early 1960s. However, limiting the exercise of caution to the first 3 months of pregnancy is both shortsighted and effectively impossible – firstly, because chemicals can affect any stage of pre- or postnatal development; and secondly, because when a woman first learns that she is pregnant, the process of organogenesis has already long since begun (for example, the neural tube has closed). Hence, the unborn could already be inadvertently exposed to maternal drug treatment during the early embryonic period ( Figure 1.1 ).

This book is intended for practicing clinicians, who prescribe medicinal products, evaluate environmental or occupational exposures in women who are or may become pregnant. Understanding the risks of drug use in pregnancy has lagged behind the advances in other areas of pharmacotherapy. Epidemiologic difficulties in establishing causality and the ethical barriers to randomized clinical trials with pregnant women are the major reasons for our collective deficiencies. Nevertheless, since the recognition of prenatal vulnerability in the early 1960s, much has been accomplished to identify potential developmental toxicants such as medicinal products and to regulate human exposure to them. The adverse developmental effects of pharmaceutical products are now recognized to include not only malformations, but also growth restriction, fetal death and functional defects in the newborn.

The evaluation of human case reports and epidemiological investigations provide the primary sources of information. However, for many drugs and certainly new drugs (even more so in the case of chemicals) experience with human exposure is scarce, and animal experiments, in vitro tests, or information on related congeners provide the only basis for risk assessment. Registration authorities in different continents have mandated that medications potentially used in pregnant women must now be followed via pregnancy registries.

This book presents the current state of knowledge about the use of drugs during pregnancy. In each chapter, the information is presented separately for two different aspects of the problem: firstly, seeking a drug appropriate for prescription during pregnancy; and secondly, assessing the risk of a drug when exposure during pregnancy has already occurred.

1.2

Development and health

The care of pregnant women presents one of the paradoxes of modern medicine. Women usually require little medical intervention during a (uneventful) pregnancy. Conversely, those at high risk of damage to their own health, or that of their unborn, require the assistance of appropriate medical technology, including drugs. Accordingly, there are two classes of pregnant women; the larger group requires support but little intervention, while the other requires the full range of diagnostic and therapeutic measures applied in any other branch of medicine ( ). Maternal illness demands treatment tolerated by the unborn. However, a normal pregnancy needs to avoid harmful drugs – both prescribed and over-the-counter, and drugs of abuse, including smoking and alcohol – as well as occupational and environmental exposure to potentially harmful chemicals. Obviously, sufficient and well-balanced nutrition is also essential. Currently, this set of positive preventive measures is by no means broadly guaranteed in either developing or industrial countries. When such primary preventive measures are neglected, complications of pregnancy and developmental disorders can result. Furthermore, nutritional deficiencies and toxic effects during prenatal life predispose the future adult to some diseases, such as schizophrenia ( ), fertility disorders ( ), metabolic imbalances ( ), hypertension, non-insulin-dependent diabetes, and cardiovascular illnesses, as demonstrated by and based upon epidemiological and experimental data. Studies of programming in fetal life are now on the agenda for medical research.

1.3

Reproductive stages

The different stages of reproduction are, in fact, highlights of a continuum. These stages concern a specific developmental time-span, each with its own sensitivity to a given toxic agent.

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  Primordial germ cells are present in the embryo at about 1 month after the first day of the last menstruation. They originate from the yolksac-entoderm outside the embryo, and migrate into the undifferentiated primordia of gonads located at the medio-ventral surface of the urogenital ridges. They subsequently differentiate into oogonia and oocytes, or into spermatogonia. Toxic effects on primordial germ cells may cause infertility or mutagenic harm.

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  Oocytes in postnatal life are at an arrested stage of the meiotic division. This division is reinitiated much later following birth, shortly before ovulation, and is finalized after fertilization with the expulsion of the polar bodies. Thus, all-female germ cells develop prenatally and no germ cells are formed after birth. Moreover, during a female lifespan approximately 400 oocytes undergo ovulation. All these facts make it possible to state that an 8-week pregnant mother of an unborn female is already prepared to be a grandmother! This implies that the oocytes are not only older than the female but also that they are being exposed to substances from prenatal time forward. As we have seen in Section 1.2 , fetal programming during early stages of pregnancy might induce diseases in later adult life; such programming for toxicity might also be possibly focused upon oocytes.

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  The embryonal spermatogenic epithelium, on the contrary, divides slowly by repeated mitoses, and these cells do not differentiate into spermatocytes and do not undergo meiosis in the prenatal period. Gonocytes exist in the neonatal testis and represent a transient population of male germ-line stem cells. It has been demonstrated that stem cell self-renewal and progeny production are probably controlled by the neighboring differentiated cells and extracellular matrix known as niches. The onset of meiosis in the male begins at puberty. Spermatogenesis continues throughout (reproductive) life. Even after chemotherapeutic treatment for example with anticancer drugs or radiation with destruction of spermatogonia, repopulation of the epithelium is possible with even a complete functional restitution. This is in contrast with oogonia after such chemotherapeutic treatment. When the complexity of sexual development and female and male gametogenesis is considered, it becomes apparent that pre- and postnatal drug exposures are special toxicological problems having different outcomes. The specificity of the male and female developmental processes also accounts for unique reactions to toxic agents, such as drugs, in both sexes.

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  After fertilization of the oocyte by one of the spermatozoa in the oviduct, there is the stage of cell division and transport of the blastocyst into the endocrine-prepared uterine cavity. After implantation, the bilaminar stage is formed and embryogenesis begins with beating heart and the functioning yolksac as a nutritional and excretion organ, followed by contact with the mother by the placenta. The next 7 weeks are a period of finely balanced cellular events, including proliferation, migration, association and differentiation, and programmed cell death, precisely arranged to produce tissues and organs from the genetic information present in each conceptus.

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  During this period of organogenesis , rapid cell multiplication is the rule. Complex processes of cell migration, pattern formation and the penetration of one cell group by another characterize these later stages.

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  Final morphological and functional development occurs at different times during fetogenesis , and is completed after birth.

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  Postnatal adaptation characterizes the passage from intra- into extra-uterine life with tremendous changes in, for example, circulatory and respiratory physiology (see also Table 1.1 ).

  Table 1.1

  Reproductive stages: organs and functions potentially affected by toxicants

  Reproductive stage	Female	Male	Possible endpoints
  Germ cell formation	Oogenesis (occurs during fetal development of mother) Gene replication Cell division Egg maturation Hormonal influence on ovary Ovulation	Spermatogenesis Gene replication Cell division	Sterility, subfecundity, damaged sperm or eggs, chromosomal aberrations, menstrual effects, age at menopause, hormone imbalances, changes in sex ratio
  		Sperm maturation Sertoli cell influence Hormonal influence on testes
  Fertilization	Oviduct contractility secretions Hormonal influence on secretory and muscle cells Uterus contractility secretions Nervous system behavior libido	Accessory glands Sperm motility and nutrition	Impotence, sterility, subfecundity, chromosomal aberrations, changes in sex ratio, reduced sperm function
  		Hormonal influence on glands Nervous system erection ejaculation behavior libido	Impotence, sterility, subfecundity, chromosomal aberrations, changes in sex ratio, reduced sperm function
  Implantation	Changes in uterine lining and secretions Hormonal influence on secretory cells		Spontaneous abortion, embryonic resorption, subfecundity, stillbirths, low birth weight
  Embryogenesis	Uterus Yolksac placenta formation Embryo cell division, tissue differentiation, hormone production, growth		Spontaneous abortion, other fetal losses, birth defects, chromosomal abnormalities, change in sex ratio, stillbirths, low birth weight
  Organogenesis	Placenta nutrient transfer hormone production protection from toxic agents Embryo organ development and differentiation growth		Birth defects, spontaneous abortion, fetal defects, death,retarded growth and development, functional disorders (e.g. autism), transplacental carcinogenesis
  Perinatal	Fetus growth and development Uterus Contractility Hormonal effects on uterine muscle cells Maternal nutrition		Premature births, births defects (particularly nervous system), stillbirths,neonatal death, toxic syndromes or withdrawal symptoms in neonates
  Postnatal	Infant survival Lactation		Mental retardation, infant mortality, retarded development, metabolic and functional disorders, developmental disabilities (e.g. cerebral palsy and epilepsy)

1.4

Reproductive and developmental toxicology

Reproductive toxicology is the subject area dealing with the causes, mechanisms, effects and prevention of disturbances throughout the entire reproductive cycle, including fertility induced by chemicals. Teratology (derived from the Greek word τερας which originally meant star ; later meanings were wonder , divine intervention and, finally, terrible vision , magic , inexplicability , monster ) is the science concerned with birth defects of a structural nature (dysmorphology). However, the terminology is not strict, since literature also recognizes “functional” teratogenic effects, such as fetal alcohol effects in the absence of alcohol-related birth defects and dysmorphology.

To understand the different definitions in this domain of toxicity the following explanations are helpful. Reproductive toxicology represents the harmful effects by agents on the progeny and/or impairment of male and female reproductive functions. Developmental toxicity involves any adverse effect induced prior to attainment of adult life. It includes the effects induced or manifested in the embryonic or fetal period, and those induced or manifested postnatally. Embryo/fetotoxicity involves any toxic effect on the conceptus resulting from prenatal exposure, including structural and functional abnormalities, and of postnatal manifestations of such effects. Teratogenicity is a manifestation of developmental toxicity, representing a particular case of embryo/fetotoxicity, by the induction or the increase of the frequency of structural disorders in the progeny.

The rediscovery of Mendel’s laws about a century ago, and the knowledge that some congenital abnormalities were passed from parents to children, led to attempts to explain abnormalities in children based on genetic theory. However, noticed that piglets born to sows fed a vitamin A-deficient diet were born without eyes. He rightly concluded that a nutritional deficiency leads to a marked disturbance of the internal factors, which control the mechanism of eye development. During a rubella epidemic in 1941, the Australian ophthalmologist, Gregg, observed that embryos exposed to the rubella virus often displayed abnormalities, such as cataracts, cardiac defects, deafness and mental retardation ( ). Soon after it was discovered that the protozoon Toxoplasma , a unicellular parasite, could induce abnormalities such as hydrocephaly and vision disturbances in the unborn. These observations proved undeniably that the placenta is not an absolute barrier against external influences.

Furthermore, from the early 1960s maternal exposure to the mild sedative thalidomide , marketed since 1957 in Germany appeared to be causing characteristic reduction deformities of the limbs, ranging from hypoplasia of one or more digits to the total absence of all limbs. An example of the thalidomide embryopathy is phocomelia: the structures of the hand and feet may be reduced to a single small digit, or may appear virtually normal but protrude directly from the trunk, like the flippers of a seal (phoca). Nowadays there exists some confusion and discussion about the discovery of thalidomide as human teratogen. The book “Dark Remedy: the Impact of Thalidomide and its Survival as a Vital Medicine” by explains in detail the events in 1961 and 1962. H.R. Wiedemann reported the first series of children with thalidomide-induced malformations in the 16 September 1961 Issue of the Med. Welt (in German). W.G. McBride placed a question in a 15-line Letter to the Editor published in the 16 December 1961 issue of the Lancet stating “... In recent month I have observed that the incidence of multiple severe abnormalities in babies delivered of women who were given the drug thalidomide ... bony development seems to be affected ... have any of your readers seen similar abnormalities who have taken this drug during pregnancy?” Following this letter, the Lancet editor inserted a statement indicating that the 2 December 1961 issue carried a statement from the Distillers Company Ltd. referring to “reports from two overseas sources possibly associating thalidomide with harmful effects on the foetus ... the company decided to withdraw from the market all its preparations containing thalidomide.” On 6 January confirmed in a Letter to the Lancet : “I have seen 52 malformed infants whose mothers had taken “Contergan” (thalidomide) in early pregnancy ... since I discussed the aetiological role of “Contergan” ... at a conference with the producer on Nov. 18, 1961, I have received letters ... reporting 115 additional cases...”.

This discovery of , and independently led to a worldwide interest in clinical teratology. In the Unites States Francis Kelsey, working at the FDA and being dissatisfied with the application for marketing of the product, prevented a catastrophe of unimaginable proportion ( ). Fifty years after the thalidomide disaster, the risk of drug-induced developmental disorders can be better delimited. To date there has been no sudden confrontation by a medicinal product provoking, as in the case of thalidomide, such devastating disorders. Drugs that nevertheless caused birth defects, such as retinoids, were known and expected, based upon animal experiments, to cause these conditions. Moreover, in general terms the prevalence of birth defects (3–4%) has not increased in the last half century, although substantially more substances have been marketed during these years. It should though be noted that it was not until the 1990s that autism was associated with thalidomide exposure very early in development before limb malformations would be induced ( ).

Contrary to the assessment of drug-induced disorders and drugs of abuse, it is more difficult to indicate a risk from occupational chemical and physical exposure. In such situations, an individual risk assessment is nearly impossible since the information necessary for a pertinent evaluation is lacking, although Occupational Exposure Limits (OELs) or Threshold Limit Values (TLVs) and occupational precautions are important considerations (see Chapter 2.23 ).

An essential aim of public health is prevention. Primary prevention of developmental disorders can be defined as an intervention to prevent the origin of a developmental disorder – for example, by rubella vaccination, or by correction of an aberrant lifestyle such as alcohol use. Moreover, primary prevention of developmental disorders can be achieved when a chemical substance is identified as a reproductive toxicant and either is not approved for marketing, or is approved with specific pregnancy labeling, restricted use or removed from the market. This is in contrast to secondary prevention of developmental disorders, which means the prevention of the birth of a child with a developmental defect – usually by termination of pregnancy. In this context, tertiary prevention of a developmental disorder indicates an early detection of a metabolic disorder so that, for example, in the case of phenylketonuria (PKU) as an intervention a special diet low in phenylanaline is indicated to prevent mental retardation (phenylpyruvic oligophrenia).

When thalidomide was recognized as being the causal factor of phocomelia, the removal of the drug from the market resulted in the disappearance of the embryopathy. However, it took at least 5 years before the association was made between the introduction of the teratogen and the extremely rare type of deformities. This event was also accompanied by a transient drastic avoidance of general drug intake by pregnant women.

Healthcare professionals and pregnant women must continue to develop a more critical approach to the use of drugs and exposure to chemicals, not only during pregnancy but also before pregnancy – or, even better, during the entire fertile period. Such a critical approach should result in avoiding many unnecessary and unknown risks.

These remarks imply that health professionals, couples planning to have children, and pregnant women must be informed about drugs proven to be safe, and the risks of wanted or unwanted exposures to chemicals as medications, environmental, including infections or occupational exposures.

1.5

Basic principles of drug-induced reproductive and developmental toxicology

Drugs that have the capacity to induce reproductive toxicity often can be identified before being marketed, based upon the outcome of laboratory animal experiments. The final conclusions can only become available through epidemiological studies after the product has been on the market for some time. The determination of whether a given medicinal product has the potentiality or capability to induce developmental disorders is essentially governed by four established fundamental principles ( ). It can be stated that an embryo- and fetotoxic response depends upon exposure to: (1) a specific substance in a particular dose, (2) a genetically susceptible species, (3) a conceptus in a susceptible stage of development, and (4) by the mode of action of reproductive toxic drugs.