Author: Pēteris Apinis, physician. Opinion piece
Currently, the world, including Latvia, is rethinking attitudes towards gender equality, often with exaggerations. Many participants in discussions use the topic of discrimination against women only because at a given time and place there is no other opportunity to draw attention to their own words, spoken aloud or written. Where arguments or reasoning are lacking, politicians or inter-ministerial working groups step in. Yet on a global scale, the story of complex and very significant discrimination against women and its impact on their health and well-being has very important aspects that it is time to focus on, both in Latvia and around the world.
I would like to draw attention to the fact, that we have no research on the effects of medication on pregnant and breastfeeding women. To put it bluntly, we lack information on the effectiveness and safety of medicines for pregnant and breastfeeding women.
In an ideal world, pregnant and breastfeeding women would be able to obtain evidence-based prescriptions for medicines and then make their own informed decisions that optimise their perinatal and postnatal health, as well as that of their children.
Like everyone else, both pregnant and breastfeeding women get sick; they have to take medication. However, because clinical trials are regularly and systematically – almost NEVER – conducted with pregnant and breastfeeding women, neither their doctors nor they themselves have sufficient data to make informed decisions about the dosage, safety, and effectiveness of medications.
This puts the doctor and the patient faced with two false choices:
– to use a treatment (drug, combination of drugs) that puts the woman and her baby at uncertain risk of harm, but has a certain outcome in treating the disease;
– refuse a treatment, that may cause harm because of an untreated disease.
World policymakers, the World Health Organisation, experienced clinicians see and understand that the time has come for the ethical and responsible participation of pregnant women and women nursing infants in clinical trials – to generate evidence to help make clinical decisions – about how to treat pregnant women or women breastfeeding infants.
In fact, pregnant and breastfeeding women were excluded from clinical trials because of potential legal liability, while attempts to include such women in trials would have involved reputational risk to the researcher, higher costs, and trial complexity.
The tragedy of thalidomide
To illustrate the complexity of the problem, I would like to give an example. In the history of medicine, this is known as the thalidomide tragedy (often referred to as the “contergan scandal” – the name under which thalidomide was marketed in Germany).
Thalidomide was developed in the early 1950s by the Swiss pharmaceutical company CIBA and later by Chemi Grunenthal in the form of “contergan” tablets. The drug was initially widely advertised as a sedative, allowing patients to fall into a deep sleep, waking up the next morning without hangover symptoms, with thalidomide having a low risk of drug dependence compared to the barbiturates popular in the last century. The drug was subjected to baseline testing by researchers, as was common in the last century, and thalidomide was believed to have no toxic effects on humans. Unlike the current level of research, thalidomide was not analysed for potentially dangerous teratogenic effects (those that, when exposed to a human or animal embryo, cause malformations or abnormal growths that do not conform to the body’s natural structure).
In the second half of the 1950s, thalidomide became popular among pregnant women due to its reduction of nausea and vomiting, antiemetic and analgesic effects. The drug’s widespread use among pregnant women was facilitated by the fact that it could be purchased without a prescription and was affordable.
After thalidomide became widely used in Japan, Australia, and Europe, doctors noticed a link between mothers who took thalidomide and birth mutations in their children. Doctors Vidukind Lenze and William McBride proved a link between thalidomide use by expectant mothers and congenital mutations. In total, at least 10 000 children worldwide have been shown to have been born with phocomelia as a result of thalidomide use. Phocomelia is a congenital malformation in which the arms and legs attached to the child’s body are absent or very underdeveloped. In addition, the teratogenicity of thalidomide was manifested in ear deformities, facial paralysis, visceral lesions, eye defects and congenital heart defects. Thalidomide was later shown to be associated with increased abortion rates as well.
In 1961, thalidomide was withdrawn from sale in most countries.
Today, thalidomide is known for its effectiveness in treating malignant and inflammatory diseases. After the tragedy, thalidomide research increased manifold. Thalidomide was found to act through two types of mechanisms: anti-angiogenesis and anti-inflammatory effects. These properties brought the drug back to pharmacies and hospitals as a treatment for various diseases.
Thalidomide was approved in 2006 for the treatment of plasma cell myeloma, a type of bone marrow cancer. Since thalidomide has anti-angiogenic properties, it prevents metastasis, growth and hypervascularity of the cancerous tumour.
Thalidomide is also currently used to treat leprosy. Since 1961, the drug is no longer used in pregnant women and, if possible, in young women who are potentially having a baby.
In response to the thalidomide tragedy, the pharmaceutical industry has undergone significant changes, with many measures taken to increase the scrutiny of drugs before they are put on the market. Thalidomide has led to a worldwide set of requirements to test all medicines for possible toxicity. This set of requirements varies from country to country but is generally very stringent. These requirements are largely driven by the US Food and Drug Administration (FDA), which modernised the drug approval process in 1962 and effectively excluded pregnant and breastfeeding women from any studies of new drugs. Sixty years later, pregnant women are still virtually excluded from participating in clinical trials.
Although I only mentioned thalidomide in the title, I would also like to touch on valproic acid, or sodium valproate, in the description. Valproic acid is used to control seizures in the treatment of epilepsy, as well as in the treatment of bipolar disorder and migraine.
Taking valproic acid during pregnancy increases the likelihood that the baby will be born with serious birth defects. According to the literature, the risk of birth defects is higher when taking high doses of valproic acid or when seizures are treated with more than one drug. If valproic acid is used in the first trimester of pregnancy, the baby may have heart defects, cleft upper lip, or a neural tube defect (a hole in the baby’s spine or skull). The most common neural tube defect associated with taking valproic acid is spina bifida (a hole in the spine). The chance of developing a neural tube defect while taking valproic acid is between 1% and 2%.
If valproic acid is already known to cause such serious birth defects, why do pregnant women continue to take this drug?
The fact is, that when pregnant women stop taking the drug, their seizures often return and their bipolar disorder worsens. In addition, having a seizure during pregnancy is harmful to the baby. Epileptic seizures can cause periods, when the baby is not getting enough oxygen, which can lead to developmental problems. Seizures can also be life-threatening for both the pregnant woman and the baby. The baby is often injured during a seizure.
Pregnant women with bipolar disorder who stop taking their medication during pregnancy may be more likely to experience symptoms of depression or mania, which are dangerous for both the pregnant woman and the baby.
A less studied and less well described factor is learning and behavioural problems in children who received valproic acid during pregnancy. Children have developmental delays, poor language and memory skills, and poorer social and adaptive behavioural skills.
Information about the negative effects of valproic acid on the foetus is largely responsible for the general fear of taking any medication during pregnancy.
Not all drugs cause severe birth defects, but experience shows that adverse reactions after birth do occur. For example, it is known that if a pregnant woman regularly takes certain drugs that affect the central nervous system, such as opioids, antipsychotics and anticonvulsants, the newborn is very likely to develop neonatal adaptation syndrome, manifested as irritability, sleep disturbances or drowsiness.
About medications for pregnant and breastfeeding women
Any discussion about the use of drugs and medications for pregnant and breastfeeding women is conducted quietly. A small number of colleagues feel that these discussions should not go beyond the professional audience. At the same time, there are lively discussions on social media about the safety of medicines during pregnancy, and these discussions are not without misconceptions.
When treating pregnant women, medication safety is of paramount importance because any effects of medications (chemicals) on the developing foetus are not immediately apparent, and the damage done can have lifelong negative consequences for the child.
The use of medication during pregnancy is the norm, not the exception. According to a study in France, 90% of pregnant women are prescribed medication and use medication. When I interviewed my colleagues – gynaecologists and general practitioners – I had the impression that this percentage may be lower in Latvia.
In everyday clinical practice, it is impossible to avoid prescribing medicines to pregnant women, and at the same time, medicines without pregnancy warnings are almost completely absent. If there is no alternative, one should choose a preparation from the set of effective medicines, which, according to current data, is the safest for the unborn child and the mother. The pregnant woman should be informed of the discrepancy between the drug information and the treatment decision, both to ensure compliance and to avoid unwarranted assumptions of causality in the event of an accidental congenital disease or pregnancy complication.
No medicine can guarantee 100% safety for a pregnant woman, as there is no information available to physicians on the use of these medicines in pregnant women to this extent.
Any risk assessment of a medicine can only establish a probability and compare that probability of risk with another probability – that an untreated disease will harm the mother and baby.
The fact that it is not easy for either a doctor or a pharmacist to prescribe a medication to a pregnant woman can be seen in the example of paracetamol. In recent years, some studies have reported an association between paracetamol use during pregnancy and childhood disorders such as attention deficit hyperactivity disorder, delayed speech development, cryptorchidism and asthma. However, these findings should be interpreted with caution given the methodological shortcomings of these studies, as their statistically significant results are based on relatively small numbers of affected children. Nevertheless, paracetamol remains the drug of first choice and is recommended in standard doses during pregnancy.
The public perception that over-the-counter drugs and nutritional fortifiers are less harmful than ‘strong’ medicines often leads pregnant women to follow the advice of the pharmacist, but also presents the pharmacist with a difficult choice: there is no research, let alone global experience, on the most likely nutraceutical to treat or prevent illness in pregnant women.
The real problem, observed mainly in Western Europe and other developed countries, is irrational actions in assessing the risk to the foetus when taking medicines during pregnancy – these irrational actions consist of refusing treatment or even terminating a desired pregnancy after taking a supposedly “risky” drug.
For most indications (diseases, symptoms), the physician has a medication to administer with sufficient clinical experience to support its safety. Drugs are considered “acceptable” in pregnancy if there is currently no credible evidence of teratogenic effects in humans, but the state of the evidence base is not yet sufficient to make a conclusive statement. Drugs with known teratogenic or fetotoxic effects are labelled as “contraindicated”. The risk to a pregnant woman exposed to such drugs should be assessed individually and a risk management strategy determined. In order to assess as accurately as possible the risks that each medicine may pose and to dispel misconceptions for both new and long-standing medicines, pharmacovigilance authorities in each country carefully collect and collate data on the effects and side effects of medicines during pregnancy.
The safety of medicines during pregnancy always concerns two people: the mother and the foetus.
The unborn child who receives a medicine with every medication is at the most vulnerable stage of life. Unlike children or adults, side effects affecting the fetus cannot be seen and diagnosed early enough to prevent potential lifelong harm. In any case, a quality ultrasound under the supervision of an experienced gynaecologist-ultrasonologist is considered the gold standard for ruling out serious fetal malformations.
Let’s assume (as I’m sure is the case in most cases) that both doctor and patient make an effort to carefully read the information about each medication the doctor prescribes and the patient receives. This information is available in online databases, in medicine books, and in the leaflet on the packaging. Information on the use of medicines during pregnancy in this literature in particular is usually not specific enough and is sometimes misleading. Both the leaflet and the description usually emphasise that the medicine crosses the placenta, but controlled studies are lacking. Such controlled studies are unlikely to be useful because almost all therapeutic agents cross the placenta and enter the fetal bloodstream, and the assessment of drug safety in pregnant women is ethically based largely on observational data. Although at least two systems of drug administration during pregnancy have been developed in the literature and are well understood by European physicians, they have many shortcomings.
It should be noted that serious fetal or neonatal malformations occur in 1-3% of cases, but only a small proportion (2-4%) of all birth defects can be definitely attributed to a chemical or physical cause, one of which is maternal pharmacotherapy. However, data from German researchers show, that alcohol consumption is at least 5-10 times more likely to cause such problems, so that in Germany alcohol causes many times more harm to the foetus each year than all medications combined. Since Latvian women and pregnant women consume more alcohol than women in Germany,
it must be assumed that alcohol causes even more malformations in Latvia.
More than 40% of pregnancies are unplanned (data from various European countries). To prevent the use of unsafe drugs in early pregnancy, all women of childbearing age should only be prescribed drugs that are compatible with pregnancy. In other words, women with chronic diseases should be treated with pregnancy-compatible medicines, even if pregnancy is not planned. The exception should be the treatment of malignant tumours and the intensification or withdrawal of treatment for serious diseases such as Systemic lupus erythematosus, Crohn’s disease, etc.
Pregnancy is usually recognised by the test already when the mother’s body is rapidly entering a very sensitive period of embryogenesis, so it is important to take measures in advance to protect the embryo from inappropriate drugs throughout its life.
Untimely treatment of serious diseases poses a threat not only to the pregnant woman, but also to the development of her future child.
Primarily, it is necessary to choose the drugs whose safety is most reliable, and in the second place – to observe the rule: “If the mother is healthy, her child is healthy too”. Effective treatment of a serious illness with a drug that is suspected to be incompatible with pregnancy (e.g. with a warning in the drug description) should not be stopped abruptly when the patient becomes pregnant, as this may jeopardise the success of the treatment and put the pregnancy at risk because of the adverse effects of the mother’s illness on the unborn child.
In cases of life-threatening disease (e.g. cancer, urgent cardiac crisis), optimising the effectiveness of maternal treatment overrides the need to avoid potential teratogenic risk. In such cases, optimising maternal treatment is also vital for the survival of the unborn child.
This article focuses on the health and treatment of both pregnant and breastfeeding women. So far, the author has mainly focused on the medical treatment of pregnant women. Pregnant and lactating women have different physiological characteristics and very different risk profiles that also need to be considered. 90% of drugs are excreted into human milk in very low concentrations, so mothers can safely breastfeed while taking these drugs. Virtually no drug in a single dose poses a risk to the breastfed infant – except, in the author’s opinion, for some cytostatics and radionuclides.
However, repeated or prolonged administration of a drug through breast milk may lead to accumulation of the drug in the infant and possibly adverse reactions. This is mainly the case with centrally acting drugs: opioids, psychiatric and anticonvulsants. Unfortunately, the use of synthetic narcotic opioids and other synthetic drugs by breastfeeding women has increased in Europe. These substances, even through milk, cause significant cognitive impairment in the newborn.
Infants under 2 months of age are more sensitive to any (prolonged) administration of maternal drugs; this is especially true for premature infants. However, because premature and sick infants benefit most from breast milk, maternal medication should not be considered a reason for premature weaning in this sensitive population.
Prescribing drugs during pregnancy does not imply drugs with clinical trials in place; such trials are in short supply
Hundreds of drugs appear on the world market each year, but few are approved for specific use during pregnancy and breastfeeding. To my knowledge, in the last 40 years, only atoziban has been developed and approved for use in pregnancy.
Unfortunately, there has been little or no research on pregnant and breastfeeding women in the last 60 years. Excluding pregnant and breastfeeding women from clinical trials because of liability risks harms these populations as well as their fetuses and the children of breastfeeding women.
In order to develop drugs specifically for pregnant or nursing women, the industry must conduct research, but before doing so, it must agree on safeguards and rules for conducting that research.
As I said at the beginning of this article, global pharmaceutical and medical policy is currently trying to hide behind the words “informed consent”, placing the responsibility for the use of medicines on the patient herself, her doctor and the clinical pharmacist.
It is not easy to weigh the benefits and risks when two lives are at stake. Patients and their doctors are still forced to make treatment decisions in the information vacuum that has allowed thalidomide to cause such widespread harm. It is time for society to recognise the harms caused by the lack of information and take action to ensure that pregnant women and babies are included in future clinical trials.
What should a pregnant patient do if her doctor or pharmacist is unsure if a medicine is safe for use during pregnancy?
Many women don’t know which sources of information to trust. Truth be told, sometimes I don’t know either, because there are no conclusive studies of medicines for pregnant women. There are often contradictions between sources, but more often than not, the information on the use of medications during pregnancy is written in such scientifically bureaucratic language that it is difficult to understand for someone who doesn’t work in pharmacology on a daily basis.
To give you an example: very often, both in written information and on social media, there is an opinion that some drugs can be taken fearlessly in the third trimester. But it is in the third trimester that the brain and central nervous system of the foetus are developing rapidly. The cerebellum is the fastest growing part of the brain in the third trimester. Therefore, it is with the presence of chemicals (pesticides, household chemicals) that world science links the increase in the number of autistic disorders in children. True, in this case, we can not exclude the possibility of exposure to drugs during the third trimester of pregnancy.
Over the past decades there has been tremendous progress in science, the development of therapies and clinical care. However, pregnant and lactating women and their babies have been neglected and have not enjoyed the benefits available to others. The time has come to provide pregnant and lactating women with the same opportunities.
Sooner or later, pregnant women will have to participate in clinical trials, and clinical trial methods are very diverse, and one can choose those that do not expose the mother and foetus to undue risk wherever possible.
On the other hand, clinical trials on breastfeeding women can be conducted without exposing the infants to any drug, since breastfeeding women may not feed their babies this milk. Despite this minimal risk of harm, breastfeeding women are rarely included in clinical trials.
The Declaration of Helsinki – on medical research and ethical standards – will be reviewed and updated in June 2024
Currently, both in Latvia and in Europe, the allegations that pharmaceutical companies (Latvian social media users unite global pharmaceutical giants, including Covid-19 vaccine manufacturers, Latvian generics factories, which are tiny laboratories compared to large global pharmaceutical companies, wholesalers and pharmacies) are simply artificially raising drug prices through research are completely unfounded, Modern medical science is a complex mechanism based on a very high level of research. The level and requirements for this research are defined by the Declaration of Helsinki, adopted by the World Medical Association (WMA) in 1964, which has been amended seven times since then, most recently at the General Assembly in October 2013. The next amendment to the Declaration will be made in less than two months, as the world’s science and research process is rapidly evolving and requires increasingly stringent regulation. Since 2016, the Declaration of Helsinki has been complemented by the Taipei Declaration on the Ethical Aspects of Databases and Biobanks.
The Declaration of Helsinki is one of the three most important global medical documents. These three global documents are the Declaration of Geneva, most often referred to as the modern version of the Hippocratic Oath, the Declaration of Helsinki on Research Involving Human Subjects, and the WMA International Code of Medical Ethics, which is actually also a supplement to the Declaration of Helsinki and addresses the professional responsibilities of physicians to patients, to other physicians and health care professionals, to themselves and to society at large.
There is no higher standard in the world than that which governs the treatment of a human being who gives up his or her body for research. And meeting that standard is not only a matter of ethics, but also of money – drug research is very, very expensive.
I recommend that everyone read the Declaration of Helsinki in the original on the World Medical Association website (wma.net). The Declaration of Helsinki is mainly meant for physicians.
The main idea of the Declaration of Helsinki is that medical progress is based on research, including research involving human subjects. The main purpose of medical research is to understand the causes, development and consequences of diseases and to improve preventive, diagnostic and therapeutic measures – methods, procedures and treatments. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights. While the primary purpose of medical research is to produce new knowledge, this goal should never override the rights and interests of individual research subjects.
According to the Declaration of Helsinki, the responsibility for the protection of research subjects rests with the physician or other health professionals, and the physician has a duty to protect the life, health, dignity, integrity, right to self-determination, privacy and confidentiality of personal information of research subjects.
It should be noted that the provisions of the Declaration of Helsinki are binding on all countries of the world and no national or international ethical, legal or regulatory requirements can diminish or override any of the standards for the protection of human subjects set out in the Declaration of Helsinki, namely that medical research should be conducted in a manner that minimises potential harm to human subjects and the environment.
No research in the world is without risk. For this reason, medical research should only be conducted by persons with appropriate ethical and scientific education, training and qualifications.
Physicians who combine medical research with medical care should involve their patients in research only to the extent justified by its preventive, diagnostic or therapeutic value. The researcher must monitor, assess and document risks at all times.
However, if anyone is harmed as a result of the research, they must be adequately compensated.
Some groups and individuals are particularly vulnerable and may be at increased risk of harm or additional harm. It is only justified to carry out medical research on a vulnerable group if the research meets the health needs or priorities of that group and if the research cannot be carried out on a vulnerable group. To some extent, this is where the Declaration of Helsinki resists research on pregnant and breastfeeding women.
The design and conduct of every study involving human subjects should be clearly described and justified in the research protocol. Importantly, the protocol should include information about funding, sponsors, institutional affiliation, potential conflicts of interest, incentives for subjects, and information about treatment or compensation provisions for subjects who are harmed as a result of participation in the study.
The research protocol must be submitted to the appropriate research ethics committee for review, comment, recommendation, and approval before the study begins.
The committee must have the authority to observe the study. At the end of the study, the researcher must submit a final report to the committee summarising the results and conclusions of the study.
An additional burden on the researchers is the need to take all precautions to protect the privacy of the subjects and the confidentiality of their personal information.
In medical research involving human subjects capable of giving informed consent, each potential subject must be adequately informed about the purpose of the research, methods, sources of funding, possible conflicts of interest, institutional affiliation of the researcher, expected benefits and possible risks of the research, as well as possible inconveniences that may arise after the research, and other relevant aspects of the research. The potential subject must be informed of the right to refuse to participate in the study or to withdraw consent to participate in the study at any time without penalty. Once the researcher is satisfied that the potential subject has understood the information,
the physician must obtain voluntary informed consent in writing from the potential subject.
The physician must fully inform the patient about what aspects of his/her treatment are relevant to the study. A patient’s refusal to participate in the study or a patient’s decision to withdraw from the study should never adversely affect the patient-physician relationship.
When conducting medical research using identifiable human materials or data, such as research using materials or data stored in biobanks or similar repositories, physicians must obtain informed consent for their collection, storage and re-use. In exceptional situations where it is impractical to obtain consent, such research may only be conducted after review and approval by a research ethics committee.
The Declaration of Helsinki also strictly defines the use of placebos.
In addition, researchers, authors, sponsors, editors and publishers have ethical obligations regarding the publication and dissemination of research results. Researchers are obliged to make the results of human research publicly available and are responsible for the completeness and accuracy of their reports. All parties must comply with accepted ethical reporting standards. Both negative and inconclusive as well as positive results must be published or otherwise made publicly available.
A modern world is unthinkable without strong ethical standards, accurate documentation, and thoughtful publications. Social media-only medicine means pointless adverts by nutritional enrichers claiming that this pill will cure everything. Medicine today is about finding step-by-step cures for the most complex diseases, and this is an expensive process. Latvian pharmaceutical and biomedical science is still a part of world science, and it is thanks to the research of Latvian scientists that medicines are becoming more and more effective, better and at the same time more expensive.
Medicines only work if they are used, and only if they are used to treat a precise disease in a precise dose and at a precise time for a precise patient.
Also read: BNN INTERVIEW | Apinis: on shortage of money for medicine; Pavļuts’ and Covid-19 debts; the need to improve healthcare
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