Today we are embarking on a journey in the area of information on drug prescriptionin pregnancy with particular attention to the assessment of the embryo-foetal risk profile. This is the first in a series of articles to be published in the coming months.
In this first contribution, special emphasis is placed on the most prescribed drugs based on the 2018 OsMed report and the associated risk profile assessment. In subsequent articles, a number of classes of drugs, starting with antihypertensives, will be explored in more detail.
Many drugs are used during pregnancy
A considerable number of women take drugs during pregnancy, for pregnancy-related diseases or for the presence of acute or pre-existing chronic diseases. National and international studies show the wide use of drugs during pregnancy with percentages that, excluding vitamins and minerals, in many cases exceed 80%1,2 and with use prevalences that remain high in the different trimesters of pregnancy.2-5
Some drugs are used to treat pregnancy-related conditions such as vomiting or preeclampsia; others are prescribed for the treatment of acute, infectious or algic forms, or for chronic disorders such as hypertension, diabetes and epilepsy.
Exposure to medication contributes very little to the complex of risk factors for fetal malformations. To date, some thirty or so potentially teratogenic drugs have been identified in humans.6 On the other hand, the fetotoxic risk from drugs should not be forgotten, particularly for the second and third trimester of pregnancy.
Teratogenic risk The drugs can cause congenital malformations if administered during the first trimester of pregnancy, particularly at risk is the period between the third and eleventh week of gestation, due to the occurrence of the phase of differentiation and embryonic proliferation with high susceptibility to external agents.
Fetotoxic risk Possible alteration of the growth and functional development of the fetus or possible toxic effect on fetal tissues during the second and third trimester of pregnancy.
[Both definitions were taken and modified from "Italian National Guidelines System. Guidelines for physiological pregnancy. 2010]
Which medications can be prescribed during pregnancy with the lowest predictable risk for embryo foetal development? In general, a drug may be used during pregnancy if there is evidence of efficacy in support of its use, minimal adverse effects in current use and wide use during pregnancy, if there are no reports of teratogenicity in experimental animals, and if at least one epidemiological study of its negative use during pregnancy is available.6
It is therefore important, also from a pharmacovigilance perspective, to have information flows that allow to monitor over time the prescriptive trends of the drugs used by women of childbearing age and pregnant women.
AIFA presents annually the National Report on the use of drugs in Italy, edited by the National observatory on the use of Medicines (OsMed), which analyzes the different information flows available, in order to describe the pharmaceutical assistance provided both in the local area and in hospitals, charged to the National Health Service and through the private purchase of the citizen. In the 20187 edition, AIFA dedicated a specific chapter to the so-called fragile populations, such as children, the elderly and pregnant women. For the latter, a working group was set up with some Italian Regions to integrate the various available flows and provide a description of the use of drugs not only in the gestational period but also pre-conception and post-pregnancy.
Using data from the CeDAP (Certificate of Birth Assistance) flow, women aged between 15 and 49 years who gave birth in the period between 1 October 2014 and 30 September 2017, resident at the time of delivery in Emilia-Romagna, Lazio and Puglia, were evaluated. For the period considered, 221,066 pregnant women received at least one prescription during pregnancy (80.4% of the selected population). In addition, 36.5% of women giving birth during the period under consideration received at least one prescription in the trimester preceding pregnancy and 50.7% in the trimester following delivery.
The most prescribed drugs during pregnancy fell into the therapeutic category of blood and hematopoietic organs (55.9%), followed by antimicrobials for systemic use (41.5%), drugs of the genito-urinary system and sex hormones (25.5%), systemic hormonal preparations, excluding sex hormones (14.9%), drugs of the gastrointestinal tract and metabolism (13.5%) and those of the respiratory system (10.5%). The OsMed Report also cites the first 30 most prescribed drugs during pregnancy (see Table 1).
Table 1. Top 30 most prescribed drugs in pregnancy and distribution per trimester7
|In pregnancy||I trimester||II trimester||III trimester|
|5||amoxicillin and clavulanic acid||33,689||12.3||11,27||4.1||13,418||4.9||12,91||4.7|
|25||ferrous glycine sulfate||3,231||1.2||363||0.1||1,626||0.6||2,173||0.8|
|26||immunoglobulin anti-d (rh)||3,178||1.2||220||0.1||1,016||0.4||2,104||0.8|
The classification of teratogenic risk
Over the years, a number of Institutions have been involved in the classification of teratogenic risk from drugs: the US Food and Drug Administration, the Australian Drug Evaluation Committee, the Swedish Farmaceutiska Specialiteter i Sverige, the German Bundesverband der Pharmazeutischen Industrie and the WGR.
These are essentially systems for categorizing drugs useful, synthesizing the risk of drugs in pregnancy but not always, unfortunately, completely consistent with each other. These tools, although simple and immediate, have limits: in fact, the risk category is not always contraindicated in pregnancy, because it is essential to evaluate the prescriptive indication in order to establish it. Moreover, a drug can be teratogenic or fetotoxic in a certain gestational period but not necessarily in another.
One of the most used classifications is the Australian one, developed by the Australian Drug Evaluation Committee (ADEC), a body of the Australian public Therapeutic Goods Administration (TGA). The classification was developed by a team of experts who considered the drugs on the Australian market and assigned them the category indicated on the basis of available evidence in relation to teratogenic risk.
Category A includes drugs taken by a large sample of pregnant women without an increased frequency of malformations, unwanted or toxic effects to the fetus (e.g. salbutamol, progesterone).
Category B includes medications taken during pregnancy by a more limited number of women who have not been shown to cause malformations in the fetus. In particular in subcategory B1 animal studies do not show an increased fetal risk (e.g. azithromycin), in B2 animal studies are non-existent or insufficient and those available do not show any risk to the fetus (e.g. phosphomycin), in B3 animal studies show a teratogenic effect, whose significance in humans remains doubtful (e.g. beclomethasone). Category C includes drugs that cause, or are suspected to cause, potentially reversible, non-malformative effects in the foetus or infant (e.g. enoxaparin). Category D includes drugs responsible for malformations or fetal-neonatal toxicity. Category X includes drugs with such a high risk of fetal harm that they should not be used during pregnancy (e.g. tretinoin).
Reprotox is a database of reproductive teratology and toxicology constantly updated by the Reproductive Toxicology Center, a US non-profit foundation. The usefulness of this database lies above all in its completeness and updating with respect to the texts and classifications mentioned and in its ease of use: for each drug, in vitro studies are reported in the laboratory animal and in humans and their effects on male and female fertility, pregnancy and breastfeeding. All reported data are constantly updated and reviewed by a team of experts. This tool is extremely useful for the teratologist, but may be difficult to interpret for the less experienced reader, who may find himself confused by the list in the literature, not interpreted by the clinical teratologist.
On the other hand, the texts cited, respectively the Manual of Teratology produced by the U.S. authors10 and that of the authors of the German Center of Teratology11, are both very useful, as they contain numerous monographs on the use of drugs in pregnancy and lactation, summarizing clinical studies and also reporting the evaluation of the expert teratologist, which is helpful for the reader without specific expertise. The texts report the drugs present in their respective markets, so it is advisable to consult both sources.
Table 2 shows the most commonly prescribed drugs during pregnancy with the relevant risk profile assessment starting from the classification developed by the Therapeutic Goods Administration (TGA)8, the Reprotox9 reproductive toxicology and teratology database, and some of the most authoritative reference texts such as that of Briggs10 and that of Schaeffer11.
Table 2 shows the risk profile of the most commonly prescribed drugs in pregnancy, most of which are associated with a risk assessment that is not increased and compatible with use in the gestational period.
Table 2. Comparison of the risk profile of the most prescribed drugs during pregnancy
|Progesterone||Natural substance that does not increase the risk. Reported association with hypospadias||Compatible. Some studies have shown cases of hypospadias||Compatible. Indicated in the threat of abortion/pretermination|
|Azithromycin||Based on experimental studies and limited human exposure data no increase in risk||Compatible. No embryo foetal risk||Used when the resistance spectrum requires it or in case of penicillin allergy. Does not increase the risk of embryo-foetal|
|Amoxicillin and clavulanic acid||Most studies do not show an increase in risk||Compatible. Crosses the placenta. Does not increase the risk in pregnancy. Reported association with necrotizing enterocolitis for exposure before childbirth||Antibiotic of choice in pregnancy.|
Reported association with necrotizing enterocolitis for exposure before childbirth
|Levotiroxine sodium||Not associated with increased risk of congenital abnormalities||Compatible with pregnancy||Compatible. Not teratogenic or fetotoxic effects at therapeutic doses|
|Fosfomycin||In relation to experimental studies and limited human exposure data, the risk is not increased||Compatible. Used in all trimesters without harm to the fetus||Indicated if antibiotics of choice cannot be used during pregnancy. No teratogenic and fetotoxic risk in humans|
|Amoxicillin||Most studies do not show an increase in risk||Compatible. Not increased risk in pregnancy||Antibiotic of choice in pregnancy|
|Beclomethasone||Inhalation therapy of choice for asthma during pregnancy. Reported increased risk of cleft lip palate and intrauterine growth retardation with intravenous therapy.||Inhalation therapy of choice during pregnancy for the treatment of chronic asthma||Treatment of choice during pregnancy by inhalation. Fetotoxic effects for high dose intravenous use|
|Enoxaparin||Doesn't cross the placenta, doesn't increase the risk||Compatible. Doesn't cross the placenta. No increased risk to the fetus. Drug of choice for thromboprophylaxis||Compatible. Used for thromboprophylaxis|
|Hydroxy Progesterone Caproate||No increased risk reported||Compatible||Compatible. Indicated in the threat of abortion/delivery before term|
|Acetylsalicylic acid||In the animal increased risk for high dose exposures. In humans increased risk of abortion for exposures in the first trimester; risk of premature closure of the Botallo duct and abnormal bleeding for exposures in the second and third trimesters. Use at low doses (60-100 mg/day) is not contraindicated||Low dose compatible. Human data suggest increased risk for full doses in first and third trimesters||Avoid analgesic or anti-inflammatory doses in the third trimester. Prolonged use beyond the 28th week may result in premature closure of the Botallo duct. Low dose therapy can be used|
|Betametasone||Increased risk of cleft lip palate for exposure in the first trimester and reduced fetal growth for prolonged exposures reported. Indicated for induction of fetal lung maturity||Compatible. Reported association with oral-facial schisis in the first trimester||Indicated for induction of fetal pulmonary maturity|
|Alginic acid||Not specific studies. In a study of 130 cases not reported an increased risk||-||Studies show efficacy and safety in second and third trimesters|
|Prednisone||Increased risk of cleft lip palate risk reported in first trimester and reduced fetal growth for prolonged exposures in second and third trimesters||Minimal increase of cleft lip palate risk for use in first trimester reported||Increased risk of cleft lip palate in first trimester and reduced fetal growth for prolonged exposures in second and third trimesters reported|
|Cefixima||Limited data in humans do not show an increase in risk||Limited data in humans do not show an embryo-foetal risk||Free of teratogenic effects at therapeutic doses|
|Ampicillin||No increase in risk||Compatible. Not increased risk||Antibiotic of choice in pregnancy|
|Estradiol||Report genital abnormalities for high-dose use in the animal. No increased risk for therapeutic doses in humans||Contraindicated||Not recommended for treatment during pregnancy. Accidental use does not increase embryo- foetal risk|
|Magaldrate||In the absence of reproductive toxicology studies, the extensive use does not suggest an increased risk||-||Compatible|
|Nadroparin calcium||Not associated with increased fetal-neonatal risk||Compatible. Not increased risk||Compatible. Used for thromboprophylaxis|
|Clarithromycin||Increased risk in the animal even at low dosages. No increased risk in humans||Compatible. Animal data indicate increased risk. No increased risk in humans||Do not increase the risk of malformations or fetotoxicity. Used when the microbial resistance requires it or in case of penicillin allergy|
|Ketoprofen||Do not increase the risk in the animal. The use in advanced pregnancy is associated with the risk of premature closure of the Botallo duct||Use in the third trimester of pregnancy is associated with the risk of premature closure of the Botallo duct||Contraindicated from the 28th week of pregnancy for the risk of premature closure of the Botallo duct|
|Salbutamol||It interferes with embryonic development in the animal. Does not increase the risk in humans||Compatible. Not associated with increased malformative and fetotoxic risk||Compatible. Inhalation therapy of choice for asthma during pregnancy|
|Nifedipine||In the animal it can interfere with embryonic development. No increased risk for use in second amd third trimesters||Not increased teratogenic risk. Used in second amd third trimesters for the treatment of hypertension||No evidence of increased risk of malformations due to exposure during the first trimester. After methyldopa is the drug of choice in pregnancy|
|Pantoprazole||Studies in animals and limited data in humans do not show an increased risk||Studies in animals and limited data in humans do not suggest an increased risk||Available studies do not indicate an increased risk|
|Methyldopa||No increase in risk||Compatible. No evidence of embryofoetal risk and abnormalities in the neurocognitive development||Drug of choice for hypertension during pregnancy|
|Fluconazole||There is a reported association between prolonged high-dose therapy and Antley-Bixler syndrome. No increased risk for therapeutic doses used in vaginal candidiasis||Limited human studies. Teratogenic risk in the first trimester at doses ≥400 mg/day, with malformations compatible with Antley-Bixler syndrome. No increased risk for therapeutic doses||If systemic treatment is required, it is recommended after the first trimester. High doses are associated with malformations characteristic of Antley-Bixler syndrome. Exposure in the first trimester for vaginal candidiasis seems not to increase the risk|
|Fluconazolo 150 mg vaginal (singola dose)|
On the other hand, among the 30 most prescribed drugs in pregnancy are drugs for which an increased risk of embryo-foetal damage is reported or suggested. The use of these molecules is associated with the treatment of acute, chronic or pregnancy-related conditions, starting from a careful assessment of the possible risks and benefits of the therapy identified for the specific indication. At the same time, this use suggests the need to manage some treatments with greater appropriateness, for example in the preconceptional period in view of pregnancy, especially for pre-existing chronic diseases.
The monitoring of information flows, also in terms of precise assessment of the embryo-fetal risk profile, can therefore represent a useful contribution to pharmacovigilance activities, aimed at identifying, assessing and preventing possible critical issues related to the use of drugs, in support of an overall assessment of the benefit/risk ratio of treatments.
Mariangela Marrone1, Elena Cesari2, Roberto Leone3, Renata Bortolus1
1 Master’s Degree "Pharmacovigilance and drug regulatory disciplines", University of Verona
2 Vittore Buzzi Children’s Hospital, University of Milan
3 Sezione di Farmacologia, Dipartimento di Diagnostica e Sanità Pubblica, University of Verona
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