EUROCAT Northern Netherlands Use of teratogenic medication during pregnancy
Use of teratogenic medication during pregnancy
The use of teratogenic medication during pregnancy and congenital anomalies of the offspring in the Northern Netherlands, 1981-2020

Update: March 2022

 

Background

Medication use during pregnancy might be necessary, for example in patients with epilepsy. However, prescribed medications are not always safe during pregnancy. There are several classification systems for the safety of medication during pregnancy. Nowadays in Europe and the United States, descriptive text is used, instead of the formerly used letter classification A t/m D and X. For drugs that might lead to congenital anomalies in the offspring, the Dutch Teratology Information Service (TIS) uses:

  1. Teratogen effect, outweigh benefit and risk, if necessary: monitor on adverse effects
  2. Teratogen effect, do not use (temporarily)

For some of the medications in the second group, teratogen effect, do not use (temporarily), a Pregnancy Prevention Program (PPP) has been set up.

Eurocat collects data since 1981 about possible risk factors for congenital anomalies. Parents fill in a questionnaire, which results in information about the use of medication by the mother during pregnancy, of the father during periconception, as well as information about chronic diseases, special health issues during pregnancy and lifestyle factors. Additional data about prescribed medications is collected from pharmacies. For this report we yearly investigate the Eurocat database to find out if and how many teratogenic medications were used by the mothers, and investigate which anomalies have occurred in the exposed offspring.

Method

From the Eurocat database, all cases born between 1981 and 2020 were selected. We identified all cases that were exposed in utero to a medication described with ‘teratogen effect’ according to the TIS classification, or having a Pregnancy Prevention Program (PPP).

Mothers who used medication from category 1 (table 1), category 2 (table 2), or with a PPP (table 3) were counted.
A mother could occur in more than one medication group. Frequency tables are given for medication use in every medication group. Cases exposed to medications used in the second or third trimester only from categories 1 and 2 were excluded. All exposures to medications with a PPP were counted.
The Fisher’s exact test (two sided) was used for associations on the level of the main groups of congenital anomalies of the offspring and teratogenic medication of the mother (SPSS Statistics, version 23). Associations with a p-value less than .05 were considered significant. Medications with a count less than 5 were excluded from the test. Cases with multiple congenital anomalies are counted for in more than one anomaly group.

Table 1. Medication from category 1: ‘Teratogen effect, outweigh benefit and risk,
monitor on adverse effects’

Medication name Group
Valproic acid*, carbamazepine, phenytoin, topiramate Antiepileptics, other
Phenobarbital , primidone Antiepileptics, barbiturate class
Carbimazole, propylthiouracil,thiamazole Thyreostatics
Lithium Bipolar disorder treatment

*additional advice TIS: ‘Try to avoid the use of Valproic acid in pregnancy’.

Table 2. Medication from category 2: ‘ Teratogen effect, do not use (temporarily)’

Medication name Group
(dihydro)ergotamine Antimigraine
Acenocoumarol, warfarin, fenprocoumon Anticoagulation
ACE-inhibitors Cardiovascular treatment
ATII-antagonists Cardiovascular treatment
Tetracycline antibacterials Antibiotics
Aminoglycoside antibacterials Antibiotics
Kinine Antimalaria
Nandrolone Anabolic steroid
Cyproterone, danazol, tamoxifen Antihormones
Methotrexate Antirheumatics
Fluorouracil Cytostatics


Table 3. Medication with a Pregnancy Prevention Program

Medication name Group
Isotretinoin Antiacne
Acitretinoin Antipsoriasis
Thalidomide Antileprosy/antitumor
Lenalidomide, pomalidomide Multiple myeloma
Alitretinoin Severe eczema
Ambrisentan, bosentan, macitentan (*) Pulmonary arterial hypertension
Vismodegib Basal cell carcinoma
Mycofenolic acid Immunosuppressant

(*) PPP due to maternal risks due to underlying illness

Results

In the period 1981-2020, 19,019 cases are registered at Eurocat. We discarded cases with a known cause, for example chromosomal anomalies, and cases with no information about medication use, leaving 11,344 cases.

Medication of category 1 and 2 was counted 308 times in total. Medication with a PPP was counted only once. For each group we counted the following numbers (table 4).

Table 4. Number of cases exposed to medication from category 1 and 2, or with a PPP Eurocat database 1981-2020

Medication name   N
Category 1 Total count 88
Valproic acid, Carbamazepine, Phenytoin, Topiramate,
Phenobarbital, Primidone (all antiepileptics)
  72*
Valproic acid   42
Carbamazepine, Phenytoin, Topiramate   31
Phenobarbital, Primidone   4
Carbimazole, Propylthiouracil, Thiamazole   10
Lithium   6
     
Category 2 Total count 218
Tetracycline antibacterials   184
Acenocoumarol, Warfarin, Fenprocoumon   18
(dihydro)Ergotamine   5
ACE-inhibitors   8
Methotrexate   1
Angiotensin II-antagonists   4
Aminoglycoside antibacterials   0
Kinine   0
Nandrolone   0
Cyproterone, Danazol, Tamoxifen   0
Fluorouracil   0
     
Pregnancy Prevention Program Total count 1
Isotretinoin   1
Acitretinoin   0
Thalidomide   0
Lenalidomide, Pomalidomide   0
Alitretinoin   0
Ambrisentan, Bosentan, Macitentan   0
Vismodegib   0
Mycofenolic acid   0

*Some mothers used a barbiturate as well as another antiepileptic.


Congenital anomalies in the main groups were counted 12,304 times in total. For each main anomaly group we counted the following numbers (table 5).

Table 5. Main congenital anomaly groups, Eurocat database 1981-2020

Main anomaly group N
Total count 12537
Anomalies of the nervous system 904
Eye anomalies 233
Ear anomalies 73
Congenital heart defects 3033
Congenital malformations of the respiratory system 255
Oro-facial clefts 1016
Congenital malformations of the digestive system 1384
Genital anomalies 895
Congenital malformations of the urinary system 1380
Limb anomalies 3175
Abdominal wall defects 189



For each group of teratogenic medication, we compared exposed cases from a specific anomaly group with all other  cases not exposed to this specific teratogenic medication. Total number of cases is 11,344. As mentioned before, a mother could occur in more than one medication group and cases with multiple congenital anomalies  cover more than one anomaly group. The result of significant associations are shown in table 6.

Table 6. Number of Category 1 and 2 medication associated with specific main congenital anomaly groups, Eurocat database 1981-2020

  Anomalies of the nervous system
Exposed to medication category 1:      
  n expected
count
p-value
Valproic acid, Carbamazepine, Phenytoin, Topiramate, Phenobarbital, Primidone (n=72) 16 5,7 < .001
Valproic acid (n=41) 11 3,3 < .001
       
Exposed to medication category 2:      
ACE-inhibitors (n=6) 3 .6 .021
       
  Anomalies of the respiratory system
Exposed to medication category 1:      
Carbimazole, Propylthiouracil, Thiamazole (n=10) 2 .2 .021

 

We found an –well known from literature- association between the use of antiepileptics and anomalies of the nervous system (16, expected count 5,7, p<.001). In more than half of the cases (42 out of 72), valproic acid was used. We therefore also found an association between valproic acid only and anomalies of the nervous system (11, expected count 3,3, p<.001).

ACE-inhibitors were also associated with the nervous system anomalies (3, expected count .6, p=.021).

In the small group of thyreostatics (carbimazole, propylthiouracil and thiamazole), we found an association with anomalies of the respiratory system (2, expected count .2, p=.020). Both cases have lung hypoplasia.

The largest group is formed by the tetracycline antibacterials. We found no statistically significant associations in this group. Apart from the above mentioned associations, we found no significant signals in category 1 and 2 medications.

Only one case was exposed to a medication that nowadays has a PPP. The mother used isotretinoin in the year 2000 and the child suffered from a mild urinary tract anomaly.

New in this report

We found a total of 220 new cases with maternal medication use in 2020.  Only six new cases concerned medication with a possible teratogen effect. Within the group of tetracycline antibacterials, we count three new cases with maternal use of these antibiotics. In this medication group, no significant associations with congenital anomalies were found.

Also in the group of ACE-inhibitors, we found two new cases. The case doesn’t have an anomaly of the nervous system. The association found within this last group is therefore less  significant, compared to the last year report.

Comments

Our yearly check on the use of medications with a possible teratogen effect, results in more or less stable outcome of known cases. After 2000, no more cases exposed to a medication that nowadays has a PPP, were found in our region.