Table 1.

Direct evidence for adverse outcomes with use of LNG, UPA and Yuzpe ECPs among women with certain medical conditions or characteristics.

Author, year, county, funding source	Study design	Population, intervention	Type(s) of EC	Primary and secondary outcomes	AEs	Strengths	Weaknesses	Quality
LNG
Pregnant women
Zhang L, 2009, China [10] China National Science and Technology Ministry, Shanghai Population and Family Planning commission grants	Prospective cohort	332 pregnant women exposed to LNG EC in conception cycle (0.75 mg-9 mg), 272 infants 332 pregnant women without LNG exposure recruited from outpatients, matched for DOB and LMP, 298 babies	LNG (dosage range: .75–9 mg; 84.4% took 1.5 mg)	Congenital malformations, perinatal complications and delivery circumstances	First trimester miscarriage: LNG+: 31 (10.3%), 4 malformations LNG−: 28 (8.6%, p=0.47), 4 malformations (not significant) Second trimester terminations due to fetal malformation:LNG+: congenital polycystic kidney LNG−: sacrococcygeal tumor, Achondroplasia No differences in fetal development at 1st or 2nd ultrasound. No differences in rates of birth defects LNG+:1.5% LNG−: 1.3% (RR 1.10, 95% CI, 0.28, 4.37) 3 newborn malformations in LNG+ group: hip dislocation, small incomplete cleft lip and facial hemangioma 2 newborn malformations in LNG group: cleidocranial dysplasia and girl with anus fistula No difference in rate of pathologic pregnancy outcome between groups (previa, abruption, velamentous cord, GDM, PIH, ICP, PROM, oligohydramnios, fetal distress, dystocia or total pregnancy complications) One IUFD, one PTL at 35 weeks with TTN in study group In comparison group, one CS at 37 weeks with resolutive tachypnea	No other teratogenic exposure within 3 months for either group; other potential confounders assessed and found similar between groups Exposure and outcome ascertainment well defined Examined dosages of LNG used Low attrition in both groups (< 2%)	No power calculation Small sample size for rare events No infant follow-up after delivery	II-2, fair
De Santis, 2005, Italy [9] Source of funding not reported	Retrospective cohort	Exposed: Pregnant women contacting teratology information service after EC failure in first trimester (n=36) Unexposed: Pregnant women calling about nonteratogenic drugs (n=80) n=10 cases exposed to other drugs n=2 cases exposed to other known teratogenic drugs (valproic acid and phenobarbitone in 1 epileptic patient, and methimazole treatment in 1 hyperthyroid patient). N=25 exposed neonates N=60 nonexposed neonates	Exposure: LNG: n=25 or Yuzpe (EE+LNG): n=11	Rate of congenital anomalies, abortion rate, ectopic pregnancies, gestational age at birth, birth weight and length, prepartum or peripartum complications.	Prenatal exposure among cases range 10 days to 45 days of pregnancy (unknown if by LMP or date of conception) Pregnancy outcomes: No increased risk of (p reported as not statistically significant): Spontaneous abortion: EC+: 6/36, 17% EC−: 3/80, 4% Stillbirth: EC+: 0/36, 0% EC−: 1/80, 1% No ectopic pregnancies in either group No maternal complications in either group Neonatal outcomes (n=25 exposed neonates): Congenital anomalies EC+: 1 (Rubella-related malformation) EC−: 1 (planus hemangioma on the arm) Neonatal complications: EC+: 2 (1 case of gastroesophageal reflux requiring medical treatment, 1 case of nasolacrimal duct obstruction, surgically drained) EC−: 0 No increased risk malformations No difference in length or weight No congenital abnormalities observed in 2 infants exposed to ECP + other teratogen.	Assessed potential confounders, including other medications used Timing by day of exposure collected	LNG and Yuzpe examined together Small sample size No power calculation Unclear if outcomes ascertained by patient report or medical record	II-2, poor
BF women
Polakow-Farkash, 2013, Israel [7] Source of funding not reported	Prospective cohort	Exposed: BF women contacting teratology information service who used EC (n=71 mothers, and n=72 infants) Unexposed: BF women calling about ethynodiol diacetate or desogestrel and breastfed infants (n=72) Questionnaires administered at 6 months and 12 years	LNG (dose not specified)	Effects of LNG during BF on infants, mothers or milk volume	No reported adverse effects of LNG during lactation on feeding or behavior of infant Transient irritability in 2 control infants; one control infant diagnosed with hypertrichosis n=1 infant in LNG group had weight < 5th percentile at 1 year n=1 infant in control group had slow development at 1 year No difference in subjective estimation of milk volume (7% vs. 6%, p=0.74) 75% BF women discontinued for less than 8h after LNG 2/71 women in LNG group did not reinitiate BF. Side effects in LNG group mothers:Vaginal bleeding: n=11 Dizziness: n=1	Only included those with follow-up Women informed to take LNG after BF and resume BF Assessed potential confounders and similar between groups (infants significantly older among study group at initial encounter and at follow-up)	No power calculation for primary outcome Wide range of follow-up questionnaire between 6 months to 2 years after initial consultation Outcomes by self-report and potential for recall bias with long follow-up time Potential for selection bias, as women experiencing problems may have been more likely to call in. Comparison group was also exposed to progestin-only contraception (lower dose and different progestins, but on a regular basis)	II-2, poor
Shaaban, 2013, Egypt [8] Mini-grant from Department of Public Health, Assiut University and Johns Hopkins Bloomberg School of Public Health joint project	Open-label RCT	Women intending to use LAM for 6 months and breastfeed for 1 year after singleton live birth were randomly assigned to: LAM-only group or LAM + EC counseling + advance provision of one packet of EC group (n=579 per arm) to use with loss of LAM prerequisites All received postpartum contraceptive counseling Excluded women planning to use other method of contraception shortly after delivery and those taking medications for chronic diseases. Followed to 6 months postpartum.	0.75-mg LNG q12h × 2 doses	Start of regular contraception, use of EC, side effects, pregnancy	No difference in duration of lactation, resumption of menstruation or pattern of BF 44.2% women in EC arm used ECPs Of these, 30% complained of nausea, 2.9% complained of vomiting. Mothers who used EC did not report changes over time in quantity of milk or infant health.	Large sample size Potential confounders assessed and groups appear similar at baseline 100% follow-up at 6 months	Randomization allocation not described Not designed to detect differences in BF outcomes by LNG exposure Infant outcomes not reported	I, fair
Repeated ECP use
Zhang, 2015, China [4] Shanghai Scientific and Technical Committee Grants	Matched case-control	Cases: Women with ectopic pregnancy according to ACOG diagnostic criteria identified in the inpatient department of gynecology (n=2411) Controls: Women with intrauterine pregnancies matched 1:1 by age +/− 5 years, marital status and gestational age identified from prenatal clinic and family planning clinic (n=2419)	LNG use within the last year (single or double doses) Nonuse	Ectopic pregnancy IUP	Adjusted OR (95% CI) for ectopic pregnancy vs. IUP: Not used: Reference 1–2 times: 1.17 (0.99–1.38) 3–4 times: 0.93 (0.74–1.17) ≥ 5 times: 0.85 (0.66–1.11) p for trend 0.67	Matched analysis Large sample size Case and control identification described Several adjustments made for potential confounders	Identification of risk factors including LNG ECP use by self-report	II-2, fair

q12h: every 12 h; GDM: gestational diabetes mellitus; PIH: pregnancy-induced hypertension; ICP: intrahepatic cholestasis of pregnancy; PROM: premature rupture of membranes; IUFD: intrauterine fetal demise; PTL: preterm labor; TTN: transient tachypnea of the newborn; CS: caesarean section; ACOG: American College of Obstetricians and Gynecologists.