The Microbiologist had a recent call from a worried colleague who had been contacted by an even more worried patient. The patient had just found out she was pregnant but was unaware of this while she was taking Doxycycline as malaria prophylaxis whilst on holiday. She had been on the internet and read that Doxycycline should never be given in pregnancy as it can do all sorts of horrible things to babies. The patient’s doctor had double checked in the British National Formulary (BNF) and sure enough Doxycycline was contraindicated in pregnancy. The Microbiologist confirmed what the BNF said; however exactly how big was the risk? The Microbiologist realised he didn’t actually know… time to start looking at the evidence and get back to the patient’s doctor as soon as possible.
Throughout my medical career I have been told never to give any tetracyclines, including Doxycycline, to pregnant women or children under 12 years of age. The reason given for this is that tetracyclines cause congenital abnormalities and problems with teeth and bone development in children and the developing fetus, as well as liver problems in the mother during pregnancy. But is this true? What is the evidence? Are there any circumstances where using Doxycycline is justified in these patients?
Throughout my medical career I have been told never to give any tetracyclines, including Doxycycline, to pregnant women or children under 12 years of age. The reason given for this is that tetracyclines cause congenital abnormalities and problems with teeth and bone development in children and the developing fetus, as well as liver problems in the mother during pregnancy. But is this true? What is the evidence? Are there any circumstances where using Doxycycline is justified in these patients?
The tetracyclines were developed between 1948 and 1953 but Doxycycline was developed later in 1967. There is plenty of evidence that the early tetracyclines like Oxytetracycline and Tetracycline could cause congenital abnormalities and problems with teeth and bones as well as liver damage. Therefore a “class effect” has been assumed for all subsequent tetracyclines, including Doxycycline, even though up until recently there has been no attempt to look at the evidence as to whether this is true or not.
There has now been an excellent systematic review of Doxycycline in pregnancy and early childhood published by authors from Thailand and the UK which has looked at the available literature and drawn some surprising conclusions. I would definitely recommend reading the paper; it is a great piece of work. The reference is at the end of the blog.
So what does the evidence, presented in this review, tell us about the risks of using Doxycycline in pregnancy and children?
Does Doxycycline cause congenital abnormalities?
Tetracyclines are teratogenic; use in pregnancy is associated with neural tube defects, cleft palate and other congenital abnormalities. THEY SHOULD NOT BE USED. However for Doxycycline there is no evidence that it is teratogenic and an increasing body of evidence to suggest that it is not teratogenic.
A massive survey of congenital abnormalities from Hungary has shown no significant increased risk from taking Doxycycline. In this study 18,500 babies with congenital abnormalities were compared to 32,800 babies without congenital abnormalities. There was similar exposure in utero to Doxycycline in both groups (56 and 63 respectively). The conclusion of this study was that the “known” teratogenic risk of Doxycycline in pregnancy is exaggerated. The result is the avoidance of using Doxycycline when in fact it might be the best treatment option, as well as causing anxiety in mothers who have been inadvertently exposed.
Another large study, this time from the USA, looked at a group of 1,843 mothers given Doxycycline whilst unaware they were pregnant. It showed the congenital abnormality rate of 2.5% was actually lower than the 2.9% rate where mothers were exposed to other antibiotics. Animal studies have also failed to show any teratogenic risk from Doxycycline in pregnancy.
From these studies it appears that Doxycycline poses no additional risk of congenital abnormalities compared to other antibiotics.
Does Doxycycline cause tooth discolouration or bone abnormalities?
Tetracycline interferes with calcium orthophosphate metabolism in developing bones and teeth by chelating (binding) the calcium to produce a brown molecule that is irreversibly incorporated into the tooth and permanently discolours the tooth. This effect is seen in 3-6% of cases of exposure. The brown molecule does not damage the strength of the tooth; the effect is cosmetic only. Deciduous tooth development begins at about 6-12 weeks in utero and adult tooth development begins in babies at about 3-4 months of age and finishes by 8 years of age, at which stage no tooth discolouration can occur. Tetracycline in utero can only stain deciduous teeth not adult teeth.
Tetracycline can restrict bone growth in premature babies and during the second and third trimester by up to 40%. This may sound alarming however this restriction is reversible on stopping the tetracycline and catch up growth occurs rapidly with no permanent damage to the bone.
Doxycycline is much less able to chelate calcium than tetracycline and therefore it might be expected that Doxycycline is therefore less likely to cause tooth discolouration or restriction of bone growth. This has been backed up by 2 case-control studies and a blinded, randomised, controlled study of the use of Doxycycline in children under 8 years which showed no difference between cases or controls in terms of tooth staining. Animal studies have also shown the same results.
Does Doxycycline increase the risk of liver damage?
Perhaps the best evidence for whether Doxycycline causes liver damage comes from a study of 3,377 cases of hepatotoxicity in the USA where the patient had been exposed to Tetracycline or Doxycycline. The study showed a 3-4 fold higher risk of developing liver failure in patients exposed to Tetracycline whereas there was no increased risk in those exposed to Doxycycline.
There is no evidence that Doxycycline increases the risk of liver damage. In fact the BNF does now state that Doxycycline is safer than other tetracyclines with regards to the risk of hepatotoxicity.
Conclusions
So the recent systematic review (Ref.1) of the available literature on whether Doxycycline is safe to use in pregnancy or in young children has concluded:
So what do I think? Am I brave enough to routinely recommend the use of Doxycycline in pregnancy or young children? …no I don’t think I am.
The evidence for the safety of Doxycycline in pregnancy and young children is compelling. However the BNF still says that this antibiotic SHOULD NOT be given in these patients and as this is likely to be used as an argument in any medicolegal case that resulted from the use of Doxycycline in pregnancy or children… then at present it’s hard to go against it. However, if I was in a position where the risk of not using Doxycycline outweighed the risk of using it… then I would use it… but I would talk to the patient or their guardian first, explain the risks using the above evidence, and get written informed consent from the patient or their guardian.
For our patient inadvertently exposed to Doxycycline in pregnancy, the Microbiologist rang the patient’s doctor and explained the above evidence. Whilst everyone was reassured that the risk to the baby was probably non-existent it was agreed to refer the mother early to the Obstetrician for close follow up just in case something went wrong. It was an anxious time but eventually the mother gave birth to a healthy baby boy and when his teeth came through… they also were normal; so finally everyone involved could relax.
Reference
There has now been an excellent systematic review of Doxycycline in pregnancy and early childhood published by authors from Thailand and the UK which has looked at the available literature and drawn some surprising conclusions. I would definitely recommend reading the paper; it is a great piece of work. The reference is at the end of the blog.
So what does the evidence, presented in this review, tell us about the risks of using Doxycycline in pregnancy and children?
Does Doxycycline cause congenital abnormalities?
Tetracyclines are teratogenic; use in pregnancy is associated with neural tube defects, cleft palate and other congenital abnormalities. THEY SHOULD NOT BE USED. However for Doxycycline there is no evidence that it is teratogenic and an increasing body of evidence to suggest that it is not teratogenic.
A massive survey of congenital abnormalities from Hungary has shown no significant increased risk from taking Doxycycline. In this study 18,500 babies with congenital abnormalities were compared to 32,800 babies without congenital abnormalities. There was similar exposure in utero to Doxycycline in both groups (56 and 63 respectively). The conclusion of this study was that the “known” teratogenic risk of Doxycycline in pregnancy is exaggerated. The result is the avoidance of using Doxycycline when in fact it might be the best treatment option, as well as causing anxiety in mothers who have been inadvertently exposed.
Another large study, this time from the USA, looked at a group of 1,843 mothers given Doxycycline whilst unaware they were pregnant. It showed the congenital abnormality rate of 2.5% was actually lower than the 2.9% rate where mothers were exposed to other antibiotics. Animal studies have also failed to show any teratogenic risk from Doxycycline in pregnancy.
From these studies it appears that Doxycycline poses no additional risk of congenital abnormalities compared to other antibiotics.
Does Doxycycline cause tooth discolouration or bone abnormalities?
Tetracycline interferes with calcium orthophosphate metabolism in developing bones and teeth by chelating (binding) the calcium to produce a brown molecule that is irreversibly incorporated into the tooth and permanently discolours the tooth. This effect is seen in 3-6% of cases of exposure. The brown molecule does not damage the strength of the tooth; the effect is cosmetic only. Deciduous tooth development begins at about 6-12 weeks in utero and adult tooth development begins in babies at about 3-4 months of age and finishes by 8 years of age, at which stage no tooth discolouration can occur. Tetracycline in utero can only stain deciduous teeth not adult teeth.
Tetracycline can restrict bone growth in premature babies and during the second and third trimester by up to 40%. This may sound alarming however this restriction is reversible on stopping the tetracycline and catch up growth occurs rapidly with no permanent damage to the bone.
Doxycycline is much less able to chelate calcium than tetracycline and therefore it might be expected that Doxycycline is therefore less likely to cause tooth discolouration or restriction of bone growth. This has been backed up by 2 case-control studies and a blinded, randomised, controlled study of the use of Doxycycline in children under 8 years which showed no difference between cases or controls in terms of tooth staining. Animal studies have also shown the same results.
Does Doxycycline increase the risk of liver damage?
Perhaps the best evidence for whether Doxycycline causes liver damage comes from a study of 3,377 cases of hepatotoxicity in the USA where the patient had been exposed to Tetracycline or Doxycycline. The study showed a 3-4 fold higher risk of developing liver failure in patients exposed to Tetracycline whereas there was no increased risk in those exposed to Doxycycline.
There is no evidence that Doxycycline increases the risk of liver damage. In fact the BNF does now state that Doxycycline is safer than other tetracyclines with regards to the risk of hepatotoxicity.
Conclusions
So the recent systematic review (Ref.1) of the available literature on whether Doxycycline is safe to use in pregnancy or in young children has concluded:
- “Doxycycline is not dangerous and its classification is misleading”
- There is evidence that Doxycycline DOES NOT cause congenital abnormalities, tooth staining, bone defects or liver damage, unlike other tetracyclines
- “Doxycycline is safe in early pregnancy, possibly throughout pregnancy and for children at the current dosage regimes”
- “The restraints on Doxycycline could be lifted for targeted or empiric treatment during the first half of pregnancy and for children under 8 years of age”
So what do I think? Am I brave enough to routinely recommend the use of Doxycycline in pregnancy or young children? …no I don’t think I am.
The evidence for the safety of Doxycycline in pregnancy and young children is compelling. However the BNF still says that this antibiotic SHOULD NOT be given in these patients and as this is likely to be used as an argument in any medicolegal case that resulted from the use of Doxycycline in pregnancy or children… then at present it’s hard to go against it. However, if I was in a position where the risk of not using Doxycycline outweighed the risk of using it… then I would use it… but I would talk to the patient or their guardian first, explain the risks using the above evidence, and get written informed consent from the patient or their guardian.
For our patient inadvertently exposed to Doxycycline in pregnancy, the Microbiologist rang the patient’s doctor and explained the above evidence. Whilst everyone was reassured that the risk to the baby was probably non-existent it was agreed to refer the mother early to the Obstetrician for close follow up just in case something went wrong. It was an anxious time but eventually the mother gave birth to a healthy baby boy and when his teeth came through… they also were normal; so finally everyone involved could relax.
Reference
- Revisiting doxycycline in pregnancy and early childhood – time to rebuild its reputation. Cross R, Ling C, Day N et al. Expert Opinion on Drug Safety 2016, 15: 3; 367-382
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