Table 2.
Results of literature review relating to 13 validated signals
| Signal | Evidence to support signal | Medication uses and literature relating to their teratogenicity in humans |
|---|---|---|
| A02AD01
Ordinary salt combinations Cleft lip with or without cleft palate |
C*, * | Ordinary salts are combinations and complexes of aluminium, calcium and magnesium compounds used as antacids. There is no evidence relating specifically to the teratogenicity of the ordinary salt combinations. One case‐control study explores the teratogenicity of combinations and complexes of aluminium, calcium and magnesium. No increase in all CAs combined among those treated with aluminium magnesium hydrocarbonate (OR 1.5, 95% CI 0.3–8.9) or aluminium magnesium hydroxide (OR 0.6, 95% CI 0.2–2.4) was reported 103. |
| A03FA
Propulsives (metoclopramide, cisapride, domperidone, bromopride, alizapride, clebopride and itopride) Total anomalous pulmonary venous return |
C | Propulsives enhance gastrointestinal motility and are used to treat nausea and vomiting. Cohort studies have found no increase in the risk of all CAs combined 90, 91, 92, 93, 94, hypospadias or orofacial clefts 95 following exposure to the propulsives. There was no evidence of an association between transposition of the great vessels, ventricular septal defect (VSD), atrial septal defect (ASD), Tetralogy of Fallot, pulmonary valve stenosis or coarctation of the aorta 96 and first trimester exposure to metoclopramide (A03FA01). A retrospective cohort study found no significant association between first trimester exposure to metoclopramide and ‘other anomalies of the circulatory system’, a group which includes total anomalous pulmonary venous return 97. However, the number of cases involved in this group was small and it is unclear what proportion, if any, had total anomalous pulmonary venous return. No studies have looked specifically at the risk of total anomalous pulmonary venous return. |
| A06AC
Bulk‐forming laxatives (ispaghula (psylla seeds), ethulose, sterculia, linseed, methylcellulose, triticum (wheat fibre), polycarbophil calcium, ispaghula combinations, sterculia combinations and linseed combinations) Anencephalus and similar anomalies |
C*, * | Bulk‐forming laxatives are used to treat constipation. The single cohort study exploring the teratogenciity of ispaghula (A06AC01) found no significant difference in the rate of all CAs combined between those who were exposed in the first trimester and those who were not 104. |
| A07DA
Antipropulsives (diphenoxylate, opium, loperamide, difenoxin, loperamide oxide, morphine combinations and loperamide combinations) Syndactyly |
B | Antipropulsives are used to treat diarrhoea. Two cohort studies explore the teratogenicity of loperamide (A07DA03) and found no increase in all CAs combined 105. An association was found between loperamide exposure and hypospadias (RR 3.2, 95% CI 1.3–6.6, n = 7) but multiple comparisons mean that this may have been due to chance 71. |
| C02DB
Hydrazinophthalazine derivatives (dihydralazine, hydralazine, endralazine, cadralazine) Atrial septal defect (ASD) |
C*, * | Hydrazinophthalazine derivatives act on arteriolar smooth muscle and are used to treat hypertension. A single case‐control study found no significant association between dihydralazine (C02DB01) exposure, before and throughout pregnancy, and all CAs combined 82. |
| G03AB03/G03AA07
Levonorgestrel and ethinylestradiol Gastroschisis |
A | Levonorgestrel and ethinylestradiol is a combined oral contraceptive containing both an oestrogen and a progestogen. Evidence specifically relating to levonorgestrel and ethinylestradiol is limited to one large case‐control study where 6/133 (4.5%) CA case and 8/129 (6.2%) non‐malformed control infants were exposed to levonorgestrel and ethinylestradiol 106. Exposure to oral contraceptives in early pregnancy does not increase the risk of all CAs combined 107, 108, neural tube defects (NTD) 109, 110, 111, CHD 108 or orofacial cleft 112. The evidence relating to gastroschisis is conflicting with some articles showing a significant association (68% of gastroschisis cases exposed vs. 26% of malformed controls 40; OR 1.8, 95% CI 1.3–2.7, n = 40 41) and others showing none 42, 43. The same is true for genital anomalies 44, 45, 113, 114, 115, 116. One case‐control study describes an increased risk of urinary tract anomalies following first trimester exposure to oral contraceptives 117. |
| G03DA
Pregnen (4) derivatives (gestonorone, medroxyprogesterone, hydroxyprogesterone and progesterone) Complete absence of a limb |
A | Pregnen (4) derivatives are progestogens, compounds with biological activity similar to progesterone, used in hormone replacement therapy, infertility and to treat menstrual problems. Cohort and case‐control studies found no significant increase in all CAs combined with any of the pregnen (4) derivatives 118, 119, 120, 121, 122, 123, 124. A cohort study found that medroxyprogesterone (G03DA02) increases the rate of CHDs, gastro‐intestinal defects, CAs of the integument, chromosome defects and all other defects. These findings may be due to chance as multiple comparisons were made and the range of defects including chromosomal defects is not plausible 125. A number of case‐control studies have found a significant association between hypospadias and both hydroxyprogesterone (G03DA03) and progesterone (G03DA04) 46, 126, 127. However, other studies have found no association 44, 47, 128 and recall bias is a concern 48. In the 1960s and 1970s a number of studies were published linking ‘sex hormones’ with an increased incidence of nongenital congenital malformations such as CHDs and limb reduction defects 49, 50, 51, 52, 53, 54, 55. However, the evidence supporting the link between progestogens and contraceptive agents with nongenital malformations was contradictory, poor methodologically and the study material lacked uniformity 121, 129, 130. By 1993 the controversy surrounding this issue meant that there had been 20 review articles written on this subject, none of which concluded that sex hormones produced nongenital organ teratogenesis 56, 57. |
| G03DB
Pregnadien derivatives (dydrogesterone, megestrol, medrogestone, nomegestrol, demegestone, chlormadinone, promegestone and dienogest) Hypospadias |
A | Pregnadien derivatives are also progestogens and are used as per the pregnadien derivatives. A review of case reports and three very small trials found no increase in all CAs combined with dydrogesterone (G03DB01) 131, 132, 133, 134. The broader medication group, the progestogens, have been associated with hypospadias 45, 47, 58 but these findings have not been consistent 44, 46, 48, 59. |
| G03GB
Synthetic ovulation stimulants (cyclofemil, clomiphene and epimestrol) Hypospadias |
A | Synthetic ovulation stimulants are used in infertility treatment. Across cohort and case‐control studies there is no evidence that exposure to clomiphene citrate (G03GB02) in the periconceptional period increases the rate of all CAs combined. There is conflicting evidence of an association with NTDs 135, 136, 137. Clomiphene has been associated with coarctation of the aorta 66, 138, anencephaly, Dandy Walker malformation, septal heart defects, muscular ventricular septal defects, esophageal atresia, cloacal exstrophy, craniosynostosis and omphalocele but multiple comparisons and small numbers of cases make these findings tentative 66. An association between periconceptional clomiphene exposure and the more severe, proximal forms of hypospadias 44, 60, 61, 62, but not all forms of hypospadias combined 63, 64, has been described. |
| L02AE
Gonadotropin‐releasing hormone analogues (GnRHa) (buserelin, leuprorelin, goserelin, triptorelin and histrelin) Laterality |
C*, * | Gonadotropin‐releasing hormone analogues are used in infertility treatment. Evidence relating to the teratogenicity of the GnRHa's is limited to case reports/series 86, 87, 88, 89. There is no evidence for a pattern of anomalies but the numbers reported are small and there is potential for reporting bias. |
| J05AF
Nucleoside and nucleotide reverse transcriptase inhibitors (Ns/NtRTIs) (zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil, adefovir dipivoxil, emtricitabine, entecavir, telbivudine, clevudine) Congenital heart defects (CHD) |
A | The Ns/NtRTIs are used to treat HIV/AIDS and chronic hepatitis. Case‐control, cohort studies and a manufacturer maintained pregnancy registry explore the teratogenicity of individual Ns/NtRTIs and the group as a whole. There is no evidence that first trimester exposure to any of the individual Ns/NtRTIs, or the group as a whole, increases the rate of all CAs combined 139, 140, 141, 142, 143. First trimester exposure to zidovudine (J05AF01) has been found to increase the risk of CHD 143, 144, but this has not been a consistent finding 145, 146. A significant association between first trimester exposure to ARV regimes containing at least one Ns/NtRTI and CHD is reported 147. There is no evidence relating to the risk of PVS as a specific CHD. Small numbers of cases have also suggested an increased risk of central nervous system (CNS) anomalies 146 and hypospadias 148 following first trimester exposure to zidovudine and head and neck defects following first trimester exposure to didanosine (J05AF02) 143. |
| J05AF30
Combinations of nucleoside and nucleotide reverse transcriptase inhibitors Pulmonary valve stenosis (PVS) |
A | |
| N02CC
Selective serotonin agonists (sumatriptan, naratriptan, rizatriptan, almotriptan, eletriptan and frovatriptan) Congenital constriction bands or amniotic bands |
C | Selective serotonin agonists, also called triptans, are used to treat migraines. Cohort studies and a manufacturer maintained pregnancy registry explore the teratogenicity of these medications, sumatriptan (N02CC01) in particular. First trimester exposure to sumatriptan does not significantly increase the rate of all CAs combined 72, 73, 74, 75, 76, 77. Eletriptan (N02CC06) was found to significantly increase the rate of all CAs combined but this was based on 14 exposures and may have been a chance finding 78. None of the other triptans 75, 77, 79, or the triptans as a group appear to increase the rate of all CAs combined 76, 80, 81. |
A: teratogenicity leading to signal CA described in literature;
B: teratogenicity leading to other CA described in literature;
C: no evidence of teratogenicity.
*
Published evidence minimal