. Author manuscript; available in PMC: 2016 Jan 12.

Published in final edited form as: Obstet Gynecol. 2013 Oct;122(4):885–900. doi: 10.1097/AOG.0b013e3182a5fdfd

Table II.

Safety of Safety data for PEP antibiotics

Author	Antibiotic	Study Design	Quality Rating^a	Gestational Age at Exposure	Maternal Outcome	Neonatal Outcome
Cooper (2008)	Ciprofloxacin (n=588)	Retrospective cohort using Tennessee Medicaid data 1985–2000 Outcome: major congenital malformations ascertained by: 1) birth certificates, 2) hospital discharge data, 3) death certificates, 4) hospital records	II-2	2 categories of exposure: 1) < 4 months, 2) entire PG	Not reported	Rate of congenital malformations among exposed - 2.9%, unexposed - 3%. Multivariable analysis: Exposure in 1^st 4 months: Relative Risk =0.64, (95% CI 0.31–1.30} Exposure any time during pregnancy: Relative Risk= 0.97 {95% CI 0.58–1.63}
Eric (2007)	Ciprofloxacin (n=9) Also included norfloxacin (n=1)	Case series in Serbia, 2001; Outcome: major and minor malformations ascertained by 1) detailed examination by pediatrician of newborns at birth, 2) pathophysiological exam of fetuses	III	1^st trimester	Not reported	1 newborn had a choroid plexus cyst
Wogelius (2005)	Ciprofloxacin (n=130 all fluoroquinolones)	Database cohort in 4 Danish counties of all female residents with >20 week live birth or stillbirth; Outcome: stillbirth, perinatal death, preterm birth (PTB), low birth weight (LBW), congenital malformations	II-2	(130) 1^st trimester or within 30 days before (87) during entire pregnancy	Not reported	Prevalence rate (PRR) of congenital malformations 0.7 (95% CI 0.30–2.0); 1^st trimester exposed- 3.1%, unexposed 4.2%, PTB exposed 6.9%, unexposed 5 % LBW exposed 1.2% unexposed 1.9%
Loebstein (1998)	Ciprofloxacin (n=105) Total exposed to quinolones (n=−200) Also included: norfloxacin n=93, ofloxacin n=2, Controls exposed to other antibiotics (n= 200)	Prospective cohort from 4 teratogen information systems; Outcomes: congenital anomalies, developmental outcomes (based on post –delivery maternal/physician interview and Denver Developmental Scale)	II-2	(136) 1st trimester (34) 2nd trimester (30) 3rd trimester	No association between quinolone exposure and major pregnancy outcomes with the exception of lower birth rates among quinolone-exposed women (attributed to higher rates of therapeutic abortion)	No association between quinolone exposure during organogenesis and congenital malformations Relative Risk O.85 (95% CI 0.21–3.49) No difference in developmental milestones between those exposed to quinolones and those unexposed
Wilton (1998)	Ciprofloxacin (n=9)	Meta-analysis of cohort studies identified through Prescription Pricing Authority, United Kingdom; Outcomes: pregnancy outcome and congenital anomalies ascertained by physician questionnaire	III	(9) 1st trimester	5 live births including 1 preterm birth, 1 ectopic pregnancy, 1 spontaneous abortion, 2 elective terminations	No congenital anomalies among 5 live births with first trimester exposures.
Schaefer (1996)	Ciprofloxacin (n=70) Other quinolones included: Norfloxacin (n=318_, oflaxacin (n=93), pefloxacin (n=57). 2 quinolone (n=8)	Prospective cohort of pregnant women contacting the European Teratogen Information System, 1986–1994; Outcomes reported by mother or physician questionnaire and data from manufacturer (Bayer) registry	II-3	Ciprofloxacin only: 43 exposures during 1st trimester	Ciprofloxacin only: 42 normal births, 2 preterm births, 1 IUGR, 3 “postnatal disorder”; 15 elective terminations, 6 spontaneous abortions	Among women exposed in 1st trimester to Ciprofloxacin - 4.7% congenital anomalies among live births exposed during 1^st trimester (2/43)
Koul (1995)	Ciprofloxacin (n=8)	Case series of women treated with ciprofloxacin for multi-drug resistant enteric fever, India Outcome: developmental delays and cartilage damage ascertained by clinical follow up:	III	(1) 1^st trimester (6) in 2nd trimester (2) at 35 weeks	All full term pregnancies with healthy newborns and normal Apgar scores	No developmental delays or cartilage damage in 7 children followed up to 5 years. Normal growth in 6 month old exposed in 1^st trimester
Berkovitch (1994)	Ciprofloxacin (n=10)) Norfloxacin (n=28); 38 matched women unexposed to fluoroquinolones but receiving other antibiotics	Prospective cohort of pregnant women who consulted Motherisk from 1989–1992, Outcome: Perinatal complications, birth weight, birth defects, and developmental milestones ascertained by follow-up interview with mother after delivery and at mean age of 27 months and confirmation with physician	II-2	(35) 1st trimester	No difference in major outcomes of pregnancy. Fetal distress and cesarean section more common in quinolone group (p=.005). Exposed newborns had higher average birth weight (p=.05),	No malformations in exposed group 1 ventricular septal defect in unexposed group. No differences in major developmental milestones measured by Denver Developmental Scale at 11–63 months
Bomford (1993)	Ciprofloxacin (n=103)	Case series created by manufacturer (Bayer) from reports of ciprofloxacin use in during pregnancy from health professionals requesting information Outcome: pregnancy outcome and congenital anomalies ascertained by case reporting from health professional	III	(87) 1^st trimester (2) in 1^st and second trimester (4) in 2^nd trimester (4) in 3^rd trimester (6) unspecified	63 healthy live births; 18 therapeutic abortions, 10 SAB, 4 IUFD	8 congenital anomalies identified in association with receiving ciprofloxacin: Rubinstein-Taybi syndrome, deformation of the right ear causing hearing loss, ventricular hypoplasia (brain), severe cognitive impairment, spasticity, blindness, hypospadias, aplasiar femur, indentation of left ear, amelia of the forearm, hip dysplasia, femur- ulna complex
Cooper (2008)	Doxycycline (n=1843)	Retrospective cohort using Tennessee Medicaid data 1985–2000 Outcome: major congenital malformations ascertained by: 1) birth certificates, 2) hospital discharge data, 3) death certificates, 4) hospital records	II-2	2 categories of exposure: 1) < 4 months, 2) entire PG Pregnancy	Not Reported	Rate of congenital malformations Exposed - 2.5% Unexposed - 3%. Multivariable analysis: Exposure in 1^st 4 months: Relative Risk =0.85 (95% CI 0.59–1.23} Exposure any time during pregnancy: Relative Risk= 0.84 {95% CI 0.59–1.19}
Eric (2007)	Doxycycline (n=41)	Case series in Serbia, 2001; Outcome: major and minor malformations ascertained by 1) detailed examination by pediatrician of newborns at birth, 2) pathophysiological exam of fetuses	III	1st trimester	Not reported	1 malformation: diastasis of rectus abdominal muscle
Kazy/Czeizel (2007)	Doxycycline (n=78)	Retrospective cohort from Hungarian Case Control surveillance of Congenital Anomalies 1980–1996 Outcome: fetal growth retardation ascertained through registry data	III	(27) 1st month (20) in 2nd and 3rd month (20) in 2nd trimester (11) in 3rd trimester	No significant difference in: 1) mean gestational age, p=0.08 2) mean birth weight, p=0.70 Preterm births: Exposed 3.8% Unexposed 9.2% Odds ratio =0.4 (95% CI 0.1–0.4) No difference in low birth weight: Exposed 6.4% Unexposed 5.9% Odds ratio 1.2 (95% CI 0.5– 1.8)
Czeizel (1997)	Doxycycline (n=63)	Retrospective cohort from Hungarian Case Control Surveillance of Congenital Anomalies 1980–1996 Outcome: congenital abnormalities ascertained through 1) registry data 2) questionnaires to parents, 3) prenatal log books	II-2	1^st trimester (31) 2^nd trimester (12) 3^rd trimester (4) Unknown (9)	Not reported	All 10 anomalies: Odds ratio= 1.6 (95% CI 1.1–2.3) Specific anomalies Entire Pregnancy: Cleft lip and/or palate Odds Ratio= 3.9 (95% CI 1.9–8.2) Esophageal atresia = Odds Ratio 5.8 (95% CI 1.4–24.1); 2– 3 months: Neural tube defects Odds ratio= 4.5 (95% CI 1.0–20.1)
Horne (1980)	Doxycycline (n=54)	Prospective cohort of pregnant women divided into 3 groups: Doxycycline 1^st trimester and 2^nd trimester if culture positive Doxycycline 1^st trimester only Controls – routine care Outcome: Pregnancy outcome and abnormalities ascertained by clinical follow up and by maternal report at 1 year of age	III-3	(50) 1^st trimester only (3) 1^st and 2^nd trimester (1) unknown	Percentage of fetal loss : 15% Group A, 25% Group B and 25% Group C. Percentage of normal, full term deliveries : 83% Group A, 75% Group B and 75% Group C	No fetal anomalies reported among 43 infants 1 year old infants (mothers exposed in the 1^st and 2^nd trimester)
Eric (2012	Amoxicillin (n=128) Amoxicillin- clauvulanate (n=50)	Prospective cohort of 6992 pregnant women in maternity hospitals in Croatia	II-2	1^st trimester (40) 2^nd trimester (30) 3^rd trimester (47) Unspecified (85)	Not reported	6 fetuses with malformations: Urogenital system, short lingual frenulum (1), hypospadias, talipes valgus, micrognathia, right ear flap
Molgaard-Nielsen (2012)	Amoxicillin (n=9 cases)	Prospective cohort of 806, 011 livebirths in Denmark from 1996–2008 Outcome: orofacial clefts by exposure to antibiotics	II-2	1^st trimester (9) 2^nd month (2) 3^rd month (1)	Not reported	All antibiotics: POR Cleft lip with or without palate =1.08 {95% CI 0.89–1.30} POR Cleft Lip alone=1.14 {95% CI 0.86–1.51}
Cooper (2008)	Amoxicillin (n=14534)	Retrospective cohort using Tennessee Medicaid data 1985–2000 Outcome: major congenital malformations ascertained by: 1) birth certificates, 2) hospital discharge data, 3) death certificates, 4) hospital records	II-2	2 categories of exposure: 1) < 4 months, 2) entire PG	Not reported	Rate of congenital malformations Exposed - 3% Unexposed - 3%. Multivariable analysis: Exposure in 1^st 4 months: Relative Risk =1.09 (95% CI 0.86–1.37} Exposure any time during pregnancy: Relative Risk= 0.99 {95% CI 0.80–1.23}
Eric (2008)	Amoxicillin (n=81) Amoxicillin- clauvulanate (n=12)	Case series in Serbia, 2001; Outcome: major and minor malformations ascertained by 1) detailed examination by pediatrician of newborns at birth, 2) pathophysiological exam of fetuses	III	Amoxicillin: (32) 1st trimester (27) 2nd trimester, (43) 3rd trimester; 12 used Augmentin: (8) 1st trimester (3) 2nd trimester (4) 3rd trimester		Malformations: Amoxicillin (4 exposed in all trimesters): short lingual frenulum, hypospadias, talipes valgus, micrognathia Augmentin (1 exposed in 1^st trimester): malformed ear flap
Puho (2007)	Amoxicillin (n=7)	Retrospective cohort Hungarian Congenital Abnormality Registry 1980–1996. Outcomes: cleft lip/ palate and posterior cleft palate associated with amoxicillin exposure ascertained by : prenatal log book, maternal questionnaires, home visits	II-2	2 categories of exposure: 1) 2nd – 3rd month 2) entire pregnancy		Cleft lip/palate Prevalence odds ratio 2nd –3^rd month of exposure to controls= 15.9 (CI 4.9–51.2) Prevalence odds ratio to malformed infants =5.4 (95% CI 1.9–5,4)
Rahangdale (2006)	Amoxicillin (n=25)	Retrospective cohort of patients treated for Chlamydia at Kaiser facilities July 1999–Dec 2000 compared to other antibiotics Outcome: congenital anomalies ascertained by medical record abstraction	III	Entire pregnancy		1 infant with dysmorphic features in Amoxicillin group
Berkovitch (2004)	Amoxicillin- clauvulanate (n=191) Amoxicillin (n=191)	Prospective cohort of women who contacted Israeli Information Service 1999–2000. Outcome: obstetrical outcomes and major anomalies ascertained by questionnaire and follow up telephone interview, medical record review	II-2	1st trimester	Spontaneous abortion: Amoxicillin: 7.3% Augmentin: 6.3% Preterm delivery: Amoxicillin: 3.8% Augmentin: 3% Low birth weight: Amoxicillin: 4.4% Augmentin: 3.6% Cesearean delivery: Amoxicillin : 21% Augmentin: 12.3%	Rate of major anomalies Augmentin - 1.9% Amoxicillin - 3% Major anomalies Augmentin: clubfoot, unilateral hydronephrosis, ventricular septal defect/pulmonic stenosis; Amoxicillin: ventricular septal defect, congenital hip dislocation, tracheo-esophageal fistula
Jepsen (2003)	Amoxicillin (n=401)	Retrospective cohort of pregnant women in Denmark delivering after 28 weeks from Birth Registry and linked to Pharmacy database. 1991– 2000. Outcome: birth weight, preterm delivery, spontaneous abortions and congenital malformation ascertained by Birth registry and Hospital Discharge Registry	II-2	2 categories of exposure: Anytime during PG (147) 1st trimester	Preterm delivery: Exposed 1st trimester- 6.1% Exposed anytime 5% Controls 6.3% Odds Ratio =0.78 (95% CI 0.49–1.22) Low birth weight Exposed 1st trimester - 1.4% Exposed anytime 1.3% Controls 1.9% Adjusted odds ratio= 0.63 (95% 0.28–1.67) Spontaneous abortions Cases- 1.2% Controls 1.3% Adjusted odds ratio=0.92 (95% CI 0.69–1.23)	Rate of congenital anomalies 1st trimester - 4.8% Anytime in PG - 4.0%, Controls = 4.1% Adjusted Odds ratio= 1.16 (95% CI=.54–2.5)
Czeizel (2001)	Amoxicillin- clauvulanate (n=52)	Retrospective cohort from Hungarian Case Control Surveillance of Congenital Anomalies 1991–1996 Outcome: congenital abnormalities ascertained through 1) registry data 2) questionnaires to parents, 3) prenatal log books	II-2	1^st trimester (20)) 2^nd trimester (12) 3^rd trimester (20) (56 controls)	No differences in major pregnancy outcomes Threatened abortion : 36.5% cases 19.6% controls	Rate of congenital malformations Entire Pregnancy Odds ratio = 2.6 (95% CI 1.1–6.0) for cardiovascular anomalies Specific Defects: Ventricular Septal Defect (7), Atrial Septal Defect (6) 2^nd–3^rd month Odds ratio=3.4 (95% CI 0.3–33) Entire pregnancy Odds Ratio for hypospadias = 4.3 (95% CI 1.2–15.4) 2^nd–3^rd month Odds Ratio for hypospadias =7.0 (95% CI 0.4–135.5)
Ou (2001)	Amoxicillin (plus erythromycin or clindamycin) (n=23)	Case series Taiwan 1993– 1999 of women treated with threatened abortion with antibiotics Outcome: pregnancy outcome and neonatal anomalies ascertained by clinical follow up	III	1st trimester	(22) term deliveries (1) 1st trimester fetal demise	No neonatal anomalies reported
Cavenee (1993)	Amoxicillin/Probenicid (n=71)	Case series Pregnant women treated at Parkland hospital for Gonorrhea 3 treatments Groups: Ceftriaxone Amoxicillin Spectinomycin Outcomes; infant delivery, congenital anomalies ascertained by medical records	III	2 categories of exposure: Less than 14 weeks (n=14) greater than 14 weeks (n=57)		Exposed 1st trimester - 1 major malformation: unexplained asymmetric Intrauterine growth restriction with microcephaly Exposed < 14 weeks: 4 minor malformations Exposed >14 weeks: 10 minor malformations Overall: 1% risk of major malformations, 20% risk of minor malformations
Pedler (1985)	Augmentin (n=39)	Prospective randomized clinical trial of pregnant women with bacteruria England	I	Entire pregnancy (10) in 1st trimester		No anomalies in the Augmentin group

Studies were reviewed and evaluated for quality according to the method outlined by the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists: I Evidence obtained from at least one properly designed randomized controlled trial. II-1 Evidence obtained from well-designed controlled trials without randomization II-2 Evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group. II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments also could be regarded as this type of evidence. III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. This grading schema was modified to include downgrading by one level for studies with major design flaws.