Comprehensive review of telbivudine in pregnant women with chronic hepatitis B

Table 1 Food and drug administration pregnancy categories for hepatitis B virus antiviral therapy[15]

Pregnancy category	definition	HBV therapy categorization
A	Adequate and well controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters)	None
B	Animal reproduction studies have failed to demonstrate a risk to the fetus, and there are no adequate and well-controlled studies in pregnant women or animal studies that have shown an adverse effect, but adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester	Telbivudine; Tenofovir
C	Animal reproduction studies have shown an adverse effect on the fetus, and there are no adequate and well controlled studies in humans, but potential benefits might warrant use of the drug in pregnant women despite potential risks	Lamivudine; Entecavir; Adefovir
D	There is positive evidence of human fetus risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits might warrant use of the drug in pregnant women despite potential risks	None
X	Studies in animals or humans have demonstrated fetus abnormalities, and/or there is positive evidence of human fetus risk based on adverse reaction data from investigational or marketing experience, and the risks involved in use of the drug in pregnant women clearly outweigh potential benefits	Interferon

Table 2 Reproductive and developmental toxicity with telbivudine

Study type	Route of administration	Species	No. of animals	Doses (mg/kg per day)	Treatment	Reference
Rat studies
Fertility, reproduction,	Oral gavage	Sprague Dawley rats	25 males	0, 100, 500, 1000	Males: -28 AC to DG 17	Study 1314-001
developmental			25 females		Females: -15 AC to DG 17
Fertility	Oral gavage	Sprague Dawley rats	25 males	0, 1000, 2000	Males: -28 AC to DG 13	Study 1314-005
			25 females
Fertility	Oral gavage	Sprague Dawley rats	25 males	0, 2000	Females: -15 AC to DG 7	Study 1314-006
			25 females
Peri/postnatal	Oral gavage	Sprague Dawley rats	25 females	0, 100, 250, 1000	Females: DG 7 to DL 20	Study 1314-003
Rabbit study
Developmental	Oral gavage	New Zealand White rabbits	20 females	0, 50, 250, 1000	Females: DG 6-18	Study 1314-002

AC: Ante coitum; DG: Gestation day; DL: Lactation day.

Table 3 Non-overlapping literature references of telbivudine exposure during pregnancy

Ref.	Original language	Study design	LdT starting trimester during pregnancy	No. of pregnancy with exposure to LdT	Maternal HBV DNA (at inclusion)
Chen et al[46]	Chinese	Prospective	1st trimester	43	≥ 1 × 107 copies/mL
Han et al[47]	English	Prospective	2nd and 3rd trimesters	362	> 1.0 × 106 copies/mL
Jiang et al[53]	Chinese	Prospective	3rd trimesters	28	> 103 copies/mL (at inclusion)
Liu et al[38]	Chinese	Prospective	3rd trimester	5	≥ 1 × 107 copies/mL (before treatment)
Liu et al[28]	English	Prospective	1st trimester	89	> 1 × 105 copies/mL
Liu et al[21]	English	Prospective	1st, 2nd or 3rd trimesters	82	≥ 106 IU/mL
Mohan et al[54]	English	Prospective	1st trimester	1	4.0433 × 104 copies/mL
Peng et al[39]	Chinese	Prospective	3rd trimester	40	≥ 1 × 106 copies/mL
Wu et al[27]	English	Prospective	2nd or 3rd trimester	279	> 106 IU/mL
Yu et al[44]	English	Prospective	1st, 2nd or 3rd trimester	233	> 1.0 × 106 copies/mL
Zeng et al[40]	Chinese	Prospective	3rd trimester	22	≥ 105 copies/mL
Zeng et al[22]	English	Prospective	1st or 3rd trimester	54	Not reported
Zhao et al[55]	Chinese	Prospective	3rd trimester	30	Not reported
Zhang et al[41]	Chinese	Prospective	3rd trimester	31	> 1 × 107 copies/mL
Zhang et al[42]	Chinese	Prospective	3rd trimester	60	≥ l × 106 copies/mL
Zhang et al[26]	English	Prospective	3rd trimester	257	> 6 log10 copies/mL
Zhou et al[43]	Chinese	Prospective	3rd trimester	36	≥ 1 × 107 copies/mL
Zhou et al[45]	Chinese	Prospective	1st trimester	73	≥ 1 × 107 copies/mL

Table 4 Summary of prevalence rates of birth defects, abortion and perinatal transmission rates with telbivudine exposure during pregnancy in literature studies

	Events (n)	Population (N)	Rate in telbivudine treated patients (n/N)	Non-antiviral treatment control in literature studies	Background rates in overall population (prevalence based on surveillance reports)
Birth defects: Live birth prevalence	6	1673	3.6/1000a	3.0/1000	14.5-60/10001
Birth defects: Birth prevalence	6	1673	3.6/1000a	3.0/1000	NA
Birth defects: Total prevalence	7	1674	4.2/1000b	3.0/1000	NA
Spontaneous abortion	7	1682	4.2/1000	NA	16/10002
Elective termination	1	1682	0.6/1000	NA	230/10003
MTCT	11	1572	0.70% (11/1572)d	11.9% (124/1041)	10%-15%4

¹EUROCAT data[48]; MACDP data[49]; Christianson et al[50] (2006); Dai et al[34] (2011);

²US CDC data[51];

³WHO data[52];

⁴Historical data from HBV-infected population without antiviral treatment[10-12].

^aP = 1.0000 vs non-antiviral treatment control in the same literature studies (Fisher’s exact test);

^bP = 0.7502 vs non-antiviral treatment control in the same literature studies (Fisher’s exact test);

^dP < 0.0001 vs non-antiviral treatment control in the same literature studies (Fisher’s exact test). NA: Not available; MTCT: Mother-to-child transmission.