Safety of hepatitis E vaccination for pregnancy: a post-hoc analysis of a randomized, double-blind, controlled phase 3 clinical trial

Figures & data

Figure 1. Study profile. HE: Hepatitis E. HPV: Human papillomavirus. All the women who received at least one dose of vaccine were followed up to 66 months. *By mistake, one participant in the HPV vaccine group was given the HE vaccine for dose 1, and two participants in the HE vaccine group were given the HPV vaccine for dose 3. These three participants were included in the HPV vaccine group for safety analysis, according to the protocol. ^†One woman with one pregnancy event in the HPV vaccine group was excluded from the analysis due to loss of follow-up and incomplete information on pregnancy outcome. ^‡Proximal exposure was defined as vaccination during pregnancy or the onset of pregnancy within 90 days post any dose. Abbreviations: HE, hepatitis E; HPV, human papillomavirus.

Table 1. Characteristics of HE or HPV vaccinees who became pregnant throughout the study.

Characteristic		HE vaccine group	HPV vaccine group	p-value
Pregnant women
	No.	1263	1259	–
	Median follow-up months (IQR)	68.5 (66.6,69.4)	68.2 (66.6,69.3)	0.5947
	No. of pregnancy (%)			0.8479
	1	905 (71.7)	918 (72.9)
	2	298 (23.6)	283 (22.5)
	3	53 (4.2)	53 (4.2)
	≥4	7 (0.6)	5 (0.4)
Pregnancy events
	No.	1684	1660	–
	Median maternal age (IQR)	28.0 (26.0, 30.0)	28.0 (26.0, 31.0)	0.1094
	Distribution of maternal age-No. (%)			0.0608
	<35	1505 (89.4)	1449 (87.3)
	≥35	179 (10.6)	211 (12.7)
	Site distribution-No. (%)			0.1087
	Liuzhou City	753 (44.7)	719 (43.3)
	Funing County	388 (23.0)	446 (26.9)
	Xinmi County	305 (18.1)	267 (16.1)
	Fengning County	131 (7.8)	130 (7.8)
	Yangcheng County	107 (6.4)	98 (5.9)
	Vaccination during pregnancy*-No. (%)			0.3040
	Yes	66 (3.9)	77 (4.6)
	No	1618 (96.1)	1583 (95.4)
	Median interval months between the onset of pregnancy and the last vaccination (IQR)^†	23.8 (10.8, 37.8)	22.7 (9.1 37.9)	0.2164
	Classification of vaccination exposure^‡ -No. (%)			0.4376
	Proximal	213 (12.6)	225 (13.6)
	Distal	1471 (87.4)	1435 (86.4)

*Only one woman in HE vaccine group received more than one vaccination (two doses, first and second) during the same pregnancy event, and her stage of gestational vaccine exposure was defined as the stage at the time of the first dose. The gestational stage of vaccine exposure was the first trimester for all pregnancy events with vaccination during pregnancy.

^† Data were calculated only for those events without vaccine exposure during pregnancy.

^‡ Proximal exposure was defined as vaccination during pregnancy or the onset of pregnancy within 90 days post any dose.

Abbreviations: HE, hepatitis E; HPV, human papillomavirus; No., number; IQR, interquartile range.

Table 2. Overall summary of pregnancy outcomes and complications.

		Non-advanced maternal age			Advanced maternal age
		HE vaccine group	HPV vaccine group	p-value	HE vaccine group	HPV vaccine group	p-value
Termination
	No. (%)	672/1505 (44.7)	691/1449 (47.7)	0.0979	118/179 (65.9)	133/211 (63.0)	0.5528
	Causes of termination-No. (%)
	Elective termination	583/1505(38.7)	597/1449(41.2)	0.1718	99/179(55.3)	118/211(55.9)	0.9027
	Spontaneous abortion	66/1505(4.4)	69/1449(4.8)	0.6242	13/179(7.3)	13/211(6.2)	0.6639
	Stillbirth	13/1505(0.9)	12/1449(0.8)	0.9158	3/179(1.7)	1/211(0.5)	0.3371
	Maternal complications	10/1505(0.7)	13/1449(0.9)	0.4719	3/179(1.7)	1/211(0.5)	0.3371
Delivery
	No. (%)	833/1505 (55.3)	758/1449 (52.3)	0.0979	61/179 (34.1)	78/211 (37.0)	0.5528
	Number of newborns*	836	761		62	79
	Gender of newborns-No. (%)			0.8669			0.7456
	Male	459 (54.9)	421 (55.3)		37 (59.7)	45 (57.0)
	Female	377 (45.1)	340 (44.7)		25 (40.3)	34 (43.0)
	Median gestational week of newborns (IQR)	39.4 (38.9,40.0)	39.6 (39.0,40.0)	0.8689	39.0 (38.0,40.0)	39.1 (38.4,40.0)	0.1328
	Median weight of newborns (IQR)	3.3 (3.0,3.6)	3.3 (3.1,3.7)	0.4556	3.5 (3.1,3.7)	3.4 (3.1,3.7)	0.5286
	Median Apgar score of newborns (IQR)	10 (9,10)	10 (9,10)	0.5600	10 (10,10)	10 (9,10)	0.2422
	Neonatal abnormality-No. (%)
	Abnormal weight	51/836 (6.1)	59/761 (7.8)	0.1928	10/62 (16.1)	10/79 (12.7)	0.5577
	Preterm birth	26/836 (3.1)	30/761 (3.9)	0.3666	6/62 (9.7)	5/79 (6.3)	0.5535
	Low Apgar score	10/836 (1.2)	6/761 (0.8)	0.4138	1/62 (1.6)	2/79 (2.5)	1.0000
	Congenital anomaly and other neonatal complications^†	2/836 (0.2)	1/761 (0.1)	1.0000	0	0	–
Pregnancy complications in focus		17/1505(1.1)	24/1449 (1.7)	0.2212	6/179 (3.4)	4/211 (1.9)	0.5529

*Four twin pregnancies occurred in both groups, resulting in a greater number of newborns than delivery events.

^† In the HE vaccine group, a female infant was diagnosed with congenital ureter stenosis of the right kidney and a male infant was diagnosed with heritable thalassaemia. In the HPV vaccine group, a male newborn presented with neonatal asphyxia at birth. These events were not considered to be related to vaccination by the data and safety monitoring board.

Abbreviations: HE, hepatitis E; HPV, human papillomavirus; No., number; IQR, interquartile range.

Table 3. Adverse events in women who were inadvertently vaccinated during pregnancy.

Classification of adverse events	HE vaccine group (N = 66)	HPV vaccine group (N = 74)	p-value^‡	Matched nonpregnant HE vaccinees (N = 132)	p-value^§
Serious adverse events after vaccinating during pregnancy *-No. (%)	3 (4.5)	9 (12.2)	0.1080	10 (7.6)	0.5499
Adverse reaction^†-No. (%)	21 (31.8)	26 (35.1)	0.6782	46 (34.8)	0.6710
Systemic symptom	17 (25.8)	19 (25.7)	0.9912	35 (26.5)	0.9091
Fever	12 (18.2)	15 (20.3)	0.7545	23 (17.4)	0.8952
Myalgia	1 (1.5)	2 (2.7)	1.0000	5 (3.8)	0.6657
Headache	2 (3.0)	1 (1.4)	0.6017	3 (2.3)	1.0000
Fatigue	3 (4.5)	0 (0.0)	0.1022	4 (3.0)	0.6880
Allergic reaction	1 (1.5)	0 (0.0)	0.4714	2 (1.5)	1.0000
Diarrhoea	1 (1.5)	1 (1.4)	1.0000	2 (1.5)	1.0000
Cough	0 (0.0)	0 (0.0)	-	4 (3.0)	0.3034
Nausea	0 (0.0)	1 (1.4)	1.0000	1 (0.8)	1.0000
Dizziness	0 (0.0)	0 (0.0)	-	1 (0.8)	1.0000
Abdominal pain	0 (0.0)	0 (0.0)	-	1 (0.8)	1.0000
Local symptom	9 (13.6)	12 (16.2)	0.6696	18 (13.6)	1.0000
Pain	4 (6.1)	10 (13.5)	0.1423	15 (11.4)	0.2324
Redness	1 (1.5)	2 (2.7)	1.0000	0 (0.0)	0.3333
Pruritus	4 (6.1)	1 (1.4)	0.1880	4 (3.0)	0.4446
Swelling	1 (1.5)	0 (0.0)	0.4714	2 (1.5)	1.0000
Induration	1 (1.5)	4 (5.4)	0.3701	2 (1.5)	1.0000

*Serious adverse events included only those that occurred after vaccinating during pregnancy. None of severe adverse events reported was related to the vaccine.

^† Adverse reaction: Adverse events related to vaccine. For the HE vaccine group and the HPV vaccine group, adverse reactions included only those that occurred within 30 days after the vaccine administered during pregnancy. For matched nonpregnant HE vaccinees, adverse events were included and analysed only for the matched doses with the pregnant women group.

^‡ p-value for the comparison between the HE vaccine group and the HPV vaccine group.

^§ p-value for the comparison between the HE vaccine group and the matched nonpregnant HE vaccinees.

Abbreviations: HE, hepatitis E; HPV, human papillomavirus; No., number.

Table 4. Association between exposure to vaccination and adverse pregnancy outcomes or pregnancy complications*.

	Proximal exposure				Distal exposure				Exposure at any time				OR^† (95% CI)	p-value^†
	HE vaccine group (n=213)	HPV vaccine group (n=225)	OR (95% CI)	p-value	HE vaccine group (n=1471)	HPV vaccine group (n=1435)	OR (95% CI)	p-value	HE vaccine group (n=1684)	HPV vaccine group (n=1660)	OR (95% CI)	p-value
Abnormal fetal loss	14 (6.6)	18 (8.0)	0.80 (0.38,1.70)	0.5668	94 (6.4)	91 (6.3)	1.02 (0.76,1.37)	0.9037	108 (6.4)	109 (6.6)	0.98 (0.74,1.29)	0.8935	1.17 (0.64,2.15)	0.6092
Spontaneous abortion	14 (6.6)	13 (5.8)	1.13 (0.51,2.53)	0.7604	65 (4.4)	69 (4.8)	0.92 (0.65,1.31)	0.6560	79 (4.7)	82 (4.9)	0.95 (0.69,1.31)	0.7585	1.67 (0.91,3.08)	0.0989
Stillbirth	0 (0.0)	1 (0.4)	NA	NA	16 (1.1)	12 (0.8)	1.31 (0.62,2.78)	0.4853	16 (1.0)	13 (0.8)	1.22 (0.58,2.55)	0.5948	NA	NA
Maternal complications	0 (0.0)	4 (1.8)	NA	NA	13 (0.9)	10 (0.7)	1.29 (0.56,2.98)	0.5478	13 (0.8)	14 (0.8)	0.93 (0.43,2.00)	0.8557	NA	NA
Neonatal abnormality	9 (4.2)	4 (1.8)	2.46 (0.74,8.18)	0.1429	80 (5.4)	86 (6.0)	0.91 (0.66,1.24)	0.5363	89 (5.3)	90 (5.4)	0.98 (0.72,1.32)	0.8880	0.82 (0.40,1.68)	0.5876
Abnormal weight	6 (2.8)	2 (0.9)	3.28 (0.64,16.82)	0.1542	54 (3.7)	66 (4.6)	0.79 (0.55,1.15)	0.2174	60 (3.6)	68 (4.1)	0.87 (0.61,1.24)	0.4394	0.81 (0.34,1.95)	0.6396
Preterm birth	1 (0.5)	2 (0.9)	0.52 (0.05,5.97)	0.6004	30 (2.0)	32 (2.2)	0.92 (0.55,1.55)	0.7637	31 (1.8)	34 (2.0)	0.91 (0.55,1.51)	0.7087	0.26 (0.03,1.95)	0.1905
Low Apgar score	1 (0.5)	2 (0.9)	0.52 (0.05,5.75)	0.5964	8 (0.5)	6 (0.4)	1.31 (0.45,3.77)	0.6196	9 (0.5)	8 (0.5)	1.11 (0.43,2.88)	0.8298	0.84 (0.11,6.58)	0.8711
Congenital anomaly and other neonatal complications	1 (0.5)	0 (0.0)	NA	NA	1 (0.1)	1 (0.1)	1.00 (0.06,16.70)	1.0000	2 (0.1)	1 (0.1)	1.97 (0.18,21.71)	0.5804	7.58 (0.78,73.66)	0.0807
Pregnancy complications in focus	3 (1.4)	5 (2.2)	0.65 (0.15,2.82)	0.5684	20 (1.4)	23 (1.6)	0.85 (0.46,1.59)	0.6191	23 (1.4)	28 (1.7)	0.82 (0.46,1.45)	0.4927	1.34 (0.37,4.86)	0.6592

*The reported measures of association are odds ratios estimated with the use of logistic regression model.

†Comparison of the risk between proximal and distal exposures was specifically drawn in the HE vaccine group.

Abbreviations: HE, hepatitis E; HPV, human papillomavirus; OR, odds ratio; NA, no answer; CI, confidence interval.