Revisiting doxycycline in pregnancy and early childhood – time to rebuild its reputation?

Figures & data

Table 1. Current treatment recommendations in pregnant and non-pregnant patients when doxycycline is ‘drug of choice’.

Infectious disease	Causative organism	Adult non-pregnant	Pregnant women
Rocky mountain spotted fever (RMSF)	Rickettsia rickettsii	Orally or i.v. doxycycline is the DOC for the treatment of RMSF in both adults and children, except for pregnant women. A dose of 100 mg for 7 days or for 2 days after temperature has subsided. Some recommend an initial one time loading dose of 200 mg.[15–17]	Chloramphenicol is preferred: 50 mg/kg per day in four divided doses p.o. for 7 days.[15]
Genito-urinary and non-genitourinary disease^a	Mycoplasma spp. Ureaplasma urealyticum	M. hominis, unlike other Mycoplasma and Ureaplasma spp., is not susceptible to macrolides, use doxycycline 100 mg IV/p.o. b.i.d. x 7–10 days.[18–21] M. pneumoniae: Doxycycline 100 mg IV/p.o. b.i.d. x 7–10 days.[21] Ureaplasma spp. are typically susceptible in vitro to the tetracyclines e.g. doxycycline.[19] Tetracycline resistant M. hominis and ureaplasma spp. reported.	M. hominis: preferably clindamycin.[22] U. urealyticum clarithromycin or moxifloxacin.[22,23] M. genitalium: azithromycin.[23] M. pneumoniae: azithromycin 500 mg p.o. day one and then 250 mg p.o. x 4 days or levofloxacin 750 mg p.o./IV x 5 days.[21]
Human ehrlichiosis (HME) and anaplasmosis (HGA)	Ehrlichia chaffeensis, Anaplasma phagocytophilum	Recommendations are based on clinical case series and in vitro data. Both tetracycline (mostly doxycycline) and chloramphenicol appear to be effective clinically.[24] E. chaffeensis is susceptible only to doxycycline.[25]	No guidelines exist for the treatment of ehrlichiosis in pregnancy. Experts believe that doxycycline is warranted in the treatment of life-threatening HME or HGA during pregnancy.[26] Doxycycline has been used successfully and safely in a few cases in pregnant women with HME or HGA.[27,28] Rifampin has been effective in small numbers of pregnant women with HGA.[29]
Chlamydia trachomatis infection	Chlamydia trachomatis	CDC recommends: 1 g azithromycin orally as single dose, or 100 mg doxycycline orally (b.d.) for 7 days for uncomplicated genito-urinary infection. Alternate regimens include erythromycin 500 mg orally four times a day (q.i.d.) or ofloxacin 300 mg orally (b.d.) for 7 days.[30,31]	Azithromycin 1 g orally given as a single dose or amoxicillin 500 mg orally three times daily for 7 days or erythromycin 500 mg orally four times a day (q.i.d.) if either of these is not tolerated.
Brucellosis	Brucella spp. B. melitensis, B. abortus, B. suis, and B. canis	Doxycycline plus aminoglycoside.[32] Adults and children aged >8 are recommended 100 mg doxycycline p.o. bid x 6 weeks and gentamicin 5 mg/kg IV once daily x 7 days or rifampin 600–900 mg p.o. once daily x 6 weeks to replace gentamicin.[33]	World Health Organization (WHO) calls for the use of rifampicin monotherapy.[34] Sanford guide suggests trimethoprim-sulfamethoxazole (TMP-SMX). 5 mg/kg of TMP component p.o. b.i.d. plus Rifampin 600–900 mg p.o. q24 h for 4 weeks.[33]
Lyme disease	Borrelia species: B. burgdorferi (in US) and B. afzelii, B. garinii (Europe, Asia)	Equal efficacy: doxycycline, amoxicillin, cefuroxime axetil early Lyme disease. Doxycycline is drug of choice as it treats a potential coinfecting agent, Anaplasma phagocytophilum. Of the oral agents commonly used to treat Lyme disease, doxycycline has the best penetration into the central nervous system.	Early Lyme disease 500 mg of amoxicillin three times a day for 14–21 days.[35–37]
Anthrax	Individuals exposed to aerosolised Bacillus anthracis	Ciprofloxacin 500 mg every 12 h in adults or doxycycline 100 mg every 12 h in adults. Recommended PEP duration is 60 days; coverage of incubation period and protection until sufficient vaccine-induced immunity.[38] Treatment with doxycycline + clindamycin, or azithromycin + rifampicin, according to guidelines.	Ciprofloxacin 500 mg orally every 12 h is considered the first-line drug for PEP, or clindamycin 600 mg every 8 h or doxycycyline 100 mg every 12 h.[13]
Q fever	Coxiella burnetii	Doxycycline 100 mg p.o. b.i.d. for 2–3 weeks.[39]	TMP-SMX (Trimethoprim-sulphamethoxazole) DS Table 1 p.o. b.i.d. for duration of pregnancy to prevent premature labour.[39]
Cholera	Vibrio cholerae	Doxycycline 300 mg p.o. as a single dose (plus rehydration solution).[40]	Azithromycin 1 gm p.o. single dose.[40]
Malaria	Plasmodium falciparum, Plasmodium vivax	Treatment: artesunate followed by doxycycline 100 mg po twice daily/ seven days or clindamycin 20 mg base/kg/day orally divided three times daily for 7 days.[41] Prevention: doxycycline.[42]	For uncomplicated P. falciparum: artemether-lumefantrine 4 tablets (80 mg/480 mg) single dose, then 4 tablets after 8 h and then after every 12 h for 2 days.[43] or Quinine sulphate 10 mg/kg p.o.t. i.d. x3 days (7 days SE Asia) + clindamycin 20 mg/kg/day divided b.i.d. x 7 days.[43] Prophylaxis for chloroquine-resistant malaria: mefloquine 250 mg 1 tablet p.o. once weekly, 2–3 weeks before, during and 4 weeks after travel to at-risk area.[42,44]

Tetracyclines, contraindicated as risk of fetal bone and teeth malformations and hepatotoxicity in the mother except: (a) third trimester because of ‘Gray syndrome’ in premature infants and newborns; (b) life threatening situations with multiorgan failure, as doxycycline is thought to be superior to chloramphenicol and protecting the life of the mother is of primary importance; (c) when chloramphenicol cannot be obtained. The risks and benefits of the choice of antibiotic must be discussed with the patient and determined on a case by case basis. If used, doxycycline is the preferred tetracycline.[26,45]

^aInfections that have been linked to M. hominis include: Pelvic inflammatory disease (PID), chorioamnionitis, postpartum and postabortal fever, pyelonephritis, central nervous system infections, septicemia, wound infections, joint infections, upper and lower respiratory tract infections, endocarditis, neonatal bacteremia and meningitis, neonatal abscesses.

Ureaplasma spp. have been linked to: chorioamnionitis, postpartum and post-abortal fever, congenital pneumonia, neonatal bacteremia, neonatal abscesses.

Figure 1. Studies selection process flow chart for this systematic review.

Table 2. Summary and comparison of reported adverse effects for tetracycline versus doxycycline.

	Tetracycline		Doxycycline		Difference in proportion
Adverse effect	Exposure with AE	Exposure without AE	Exposure with AE	Exposure without AE	p-value (RD; 95% CI)	Comments	References
Irreversible tooth-staining	928	313	1	38	p < 0.0001 (0.72; 0.67–0.78)	Doxycycline given to premature infants aged 4–55 days, 2 mg/kg for 6–17 days. 1/25 with slight spotted discoloration of upper incisors.	[3,6,9,46–60]
Reversible bone growth inhibition	25	0	NA	NA	^#	Mean fibula growth inhibition of up to 40% length during tetracycline treatment, rapid compensatory growth rate and return to normal upon discontinuation of drug.	[61]
Teratogenicity	16	214	56	1949	p = 0.001 (0.04; 0.07–0.75)	Doxycycline: no evidence for increased teratogenicity observed, OR was equal to or smaller than controls. Oxytetracycline with higher teratogenic risk: OR (95% CI): neural tube defects (9.7, 2.0–47.1), cleft palate (17.2, 3.5–83.5), MCAs (12.9, 3.8–44.3).	[62–65]
Hepatotoxicity	77*	0	0	62**	^$	Doxycycline recipients and matched controls had similar incidences of hepatotoxicity compared to tetracycline in 3377 cases. *Tetracycline: Current use OR (95% CI) 3.7, 1.19–11.45 Past use OR (95% CI) 2.72, 1.26–5.85 **Doxycycline: Current use OR (95% CI) 1.49, 0.61–3.62 Past use OR (95% CI) 1.74, 0.99–3.06	[2,4,5,7,8,10–12]
Nephrotoxicity	7	0	0	0	^$	All patients had concomitant liver involvement.	[10,66]
Total SAEs	1053	527	57	2049		No doxycycline-associated SAEs in n = 2049, except for one case with slight discoloration of upper incisors.

AE = adverse effect; RD = risk difference; OR = odds ratio; MCA = major congenital anomaly; NA = not available; # comparison not possible; $ comparison not valid (studies not congruent); data of patients with hepatotoxicity under tetracycline* or doxycycline** use, respectively. Statistically increased risk of hepatotoxicity was described with tetracycline, but not doxycycline (current use OR 3.70, 95% CI 1.19–11.45; past use OR 2.72, 95% CI 1.26–5.85), ref [67]. Comparisons of proportions were calculated for ‘Irreversible tooth-staining’ and ‘Teratogenicity’ only, as studies were not congruent for other endpoints.

Table 3. A comparison of antibiotics reviewed in the Hungarian Congenital Anomaly Registry.

Antibiotic taken during pregnancy (all trimesters)	Offspring with MCAs	Offspring with no MCAs	Statistical analysis OR (95% CI)	References
Doxycycline	56/18,515 (0.3%)	63/32,804 (0.19%)	1.6 (1.1–2.3)	[64]
Erythromycin	113/22,865 (0.5%)	172/38,151 (0.5%)	1.1 (0.9–1.4)	[80]
Chloramphenicol	52/22,865 (0.23%)	51/38,151 (0.13%)	1.7 (1.2–2.5)	[81]
Ampicillin	1643/22,865 (7.2%)	2632/38,151 (6.9%)	1.0 (0.7–1.2)	[82]
Oxytetracycline	216/22,865 (0.9%)	214/38,151 (0.6%)	1.7 (1.4–2.1)	[62]

The Hungarian Congenital Anomaly Registry was established in 1980 and has the largest case–control data set of major congenital anomalies (MCA) in the world. The total number of participants enrolled was at least 51,319 pregnant women. Of all 18,515 women who had an infant with a MCA, 0.3% had received doxycycline. Of the 32,804 women who had offspring with no MCA, 0.19% had inadvertently taken doxycycline (the majority during the first and second months of gestation 44.5%). Case–control pair analysis showed no significant increase in doxycycline treatment in second and third months of pregnancy in any group of MCA.

MCA: major congenital anomaly; OR: odds ratio.

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