Abstract
This cohort study assesses the association of maternal hepatitis B virus (HBV) serostatus with pregnancy outcomes in women undergoing freeze-thaw embryo transfer (FET).
Introduction
Hepatitis B virus (HBV) infection poses a significant global public health challenge. In mainland China, the prevalence of hepatitis B surface antigen (HBsAg) among pregnant women was estimated at 6.27% from 2013 to 2020.1
Infection with HBV has been linked to a higher risk of miscarriage and preterm birth in natural pregnancies.2 However, its effects on assisted reproductive technology, especially freeze-thaw embryo transfer (FET), are uncertain.3 Previous research has not explored the association between HBV infection and pregnancy outcomes in FET. To fill this knowledge gap, we conducted a retrospective cohort study to examine the association of maternal HBV serostatus with pregnancy outcomes in women undergoing FET.
Methods
This retrospective cohort study was approved by the Ethics Committees of Chongqing Medical University and Chengdu Xinan Gynecology Hospital. A waiver of informed consent was granted because this study used deidentified data. The study followed the STROBE reporting guideline.
We investigated the association between HBV infection and pregnancy outcomes among women undergoing their first FET between January 1, 2018, and April 30, 2021, using data from Chengdu Xinan Gynecology Hospital and Chengdu Jinjiang Hospital for Women's and Children’s Health. The study focused on 3 groups: A (HBsAg positive and hepatitis Be antigen [HBeAg] negative), B (HBsAg positive and HBeAg positive), and C (HBsAg negative and HBeAg negative). Propensity score matching was used to address baseline differences among groups. The primary outcome was live birth, and secondary outcomes included biochemical pregnancy, clinical pregnancy, ectopic pregnancy, miscarriage (early and late), and preterm delivery of singleton (gestational age <37 weeks). Multivariate logistic regression was used to calculate each outcome’s adjusted odds ratios and 95% CIs. The eMethods in Supplement 1 contains the various covariates used in the regression analysis. Statistical analyses used SPSS, version 25.0 (IBM Corp), with 2-sided P < .05 indicating statistical significance.
Results
After propensity score matching, 642 women in group A vs 2565 in group C, 151 in group B vs 600 in group C, and 480 in group A vs 146 in group B were included in the analysis, with partial duplication among groups. The groups did not differ regarding age, body mass index, infertility type, or cause of infertility (Table 1). In the analyses of 3 matched groups (A vs C, B vs C, and A vs B) presented in Table 2, no statistically significant differences were observed for the primary pregnancy outcome of live birth (groups A vs C odds ratio [OR], 1.13 [95% CI, 0.95-1.34]; groups B vs C OR, 1.12 [95% CI, 0.78-1.60]; groups A vs B OR, 1.25 [95% CI, 0.86-1.82]) or the secondary outcomes. These findings remained nonsignificant even after adjusting for various factors.
Table 1. Comparison of Patient Characteristics and Reproduction-Related Clinical Parameters Among All Groupsa.
| Characteristic | Group A vs group C | Group B vs group C | Group A vs group B | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Group A (n = 642) | Group C (n = 2565) | P value | Group B (n = 151) | Group C (n = 600) | P value | Group A (n = 480) | Group B (n = 146) | P value | |
| Age, mean (SD), y | 31.53 (3.54) | 31.53 (3.61) | .38 | 29.69 (3.60) | 29.62 (3.57) | .79 | 30.55 (3.34) | 29.84 (3.52) | .03 |
| BMI, mean (SD) | 21.81 (2.96) | 21.79 (2.95) | .70 | 21.81 (2.75) | 21.81 (3.07) | .17 | 21.74 (3.00) | 21.84 (2.77) | .70 |
| Infertility type, No. (%) | |||||||||
| Primary infertility | 292 (45.48) | 1161 (45.26) | .92 | 81 (53.64) | 329 (54.83) | .79 | 243 (50.63) | 76 (52.05) | .76 |
| Secondary infertility | 350 (54.52) | 1404 (54.74) | 70 (46.36) | 271 (45.17) | 237 (49.38) | 70 (47.95) | |||
| Cause of infertility, No. (%) | |||||||||
| Tubal factor | 474 (73.83) | 1932 (75.32) | .44 | 114 (75.50) | 451 (75.17) | .93 | 366 (76.25) | 109 (74.66) | .69 |
| Ovulatory disorders | 10 (1.56) | 33 (1.29) | .60 | 3 (1.99) | 13 (1.99) | .89 | 3 (0.63) | 8 (5.48) | .76 |
| PCOS | 57 (8.88) | 203 (7.91) | .42 | 34 (22.52) | 133 (22.17) | .93 | 57 (11.88) | 29 (19.86) | .01 |
| EMs | 25 (3.89) | 99 (3.86) | .97 | 4 (2.65) | 15 (2.50) | .92 | 13 (2.71) | 4 (2.74) | .98 |
| Male factor | 123 (19.16) | 442 (17.23) | .25 | 25 (16.56) | 110 (18.33) | .61 | 85 (17.71) | 25 (17.12) | .87 |
| Unexplained | 15 (2.34) | 60 (2.34) | .10 | 1 (0.66) | 5 (0.83) | .83 | 5 (1.04) | 1 (0.68) | .70 |
| Duration of infertility, median (IQR), y | 3 (2-5) | 3 (2-5) | .62 | 3 (2-5) | 3 (2-5) | .32 | 3 (2-5) | 3 (2-5) | .88 |
| AMH level, median (IQR), ng/mL | 3.49 (1.81-5.74) | 3.52 (1.89-5.83) | .65 | 4.94 (2.74-7.69) | 5.13 (2.91-7.97) | .44 | 3.96 (2.13-6.25) | 4.69 (2.68-7.44) | .01 |
| FSH level, median (IQR), mIU/mL | 7.45 (6.35-8.83) | 7.48 (6.39-8.91) | .93 | 7.20 (6.16-8.50) | 7.15 (6.03-8.31) | .72 | 7.39 (6.29-8.68) | 7.21 (6.17-8.64) | .23 |
| LH level, median (IQR), mIU/mL | 4.57 (3.31-6.23) | 4.14 (3.08-5.82) | .001 | 4.43 (3.51-6.72) | 4.57 (3.31-6.70) | .69 | 4.51 (3.36-6.25) | 4.37 (3.44-6.30) | .52 |
| Estradiol level, median (IQR), pmol/L | 49 (37-66) | 48 (36-63) | .06 | 47 (37-63) | 50 (37-63) | .54 | 49 (37-65) | 46 (36-62) | .32 |
| Progesterone level, median (IQR), ng/mL | 0.61 (0.41-0.90) | 0.58 (0.39-0.86) | .15 | 0.66 (0.45-0.96) | 0.60 (0.43-0.88) | .23 | 0.62 (0.43-0.92) | 0.67 (0.45-1) | .39 |
| Endometrial thickness on the day of planning FET, median (IQR), mm | 9.00 (8.50-10.50) | 9.00 (8.50-10.50) | .75 | 9.50 (8.50-10.50) | 9.50 (8.50-10.25) | .87 | 9.00 (8.50-10.50) | 9.50 (8.50-10.50) | .65 |
| FET protocol, No. (%) | |||||||||
| Natural cycle | 43 (6.70) | 190 (7.41) | .92 | 8 (5.30) | 32 (5.33) | .96 | 30 (6.25) | 8 (5.48) | .85 |
| DRC | 59 (9.19) | 239 (9.32) | 10 (6.62) | 33 (5.50) | 41 (8.54) | 10 (6.85) | |||
| HRC | 481 (74.92) | 1892 (73.76) | 113 (74.83) | 458 (76.33) | 355 (73.96) | 109 (74.66) | |||
| OPC | 59 (9.19) | 244 (9.51) | 20 (13.25) | 77 (12.83) | 54 (11.25) | 19 (13.01) | |||
| No. of embryos transferred, No. (%) | |||||||||
| 1 | 204 (31.78) | 842 (32.83) | .61 | 39 (25.83) | 181 (30.17) | .30 | 144 (30.00) | 38 (26.03) | .36 |
| 2 | 438 (68.22) | 1723 (67.17) | 112 (74.17) | 419 (69.83) | 336 (70.00) | 108 (73.97) | |||
| Type of embryo transferred, No. (%) | |||||||||
| Blastocyst | 507 (78.97) | 2043 (79.65) | .70 | 124 (82.12) | 497 (82.83) | .84 | 392 (81.67) | 120 (82.19) | .89 |
| Cleavage | 135 (21.03) | 522 (20.35) | 27 (17.88) | 103 (17.17) | 88 (18.33) | 26 (17.81) | |||
| No. of good quality embryos transferred, No. (%) | |||||||||
| 0 | 171 (26.64) | 668 (26.04) | .94 | 36 (23.84) | 146 (24.33) | .89 | 119 (24.79) | 35 (23.97) | .97 |
| 1 | 215 (33.49) | 857 (33.41) | 54 (35.76) | 202 (33.67) | 169 (35.21) | 51 (34.93) | |||
| 2 | 256 (39.88) | 1040 (40.55) | 61 (40.40) | 252 (42.00) | 192 (40.00) | 60 (41.10) | |||
Abbreviations: AMH, antimüllerian hormone; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); DRC, downregulation cycle; EMs, endometriosis; FET, freeze-thaw embryo transfer; FSH, follicle-stimulating hormone; HRC, hormone replacement cycle; LH, luteinizing horomone; OPC, ovulation-promoting cycle; PCOS, polycystic ovary syndrome.
SI conversion factor: To convert to nmol/L, multiply by 3.18.
Group A indicates hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative; group B, HBsAg positive and HBeAg positive; and group C, HBsAg negative and HBeAg negative. The variables in the propensity score–matched model include age of women, body mass index, duration of infertility, type of infertility, basal sex hormone level (estradiol, progesterone, FSH, and LH), AMH level, endometrial preparation protocols, endometrial thickness, the number of good-quality embryos transferred, and the type of embryos transferred.
Table 2. Pregnancy Outcomes Among Groupsa .
| Outcome, No. (%) | Comparison group | Reference group | P value | Unadjusted analysis | Adjusted analysis | ||
|---|---|---|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | ||||
| Groups A (n = 642) vs C (n = 2565 [reference])b | |||||||
| Live birth | 323 (50.31) | 1212 (47.25) | .17 | 1.13 (0.95-1.34) | .17 | 1.13 (0.95-1.34) | .19 |
| Biochemical pregnancy | 447 (69.63) | 1708 (66.59) | .14 | 1.15 (0.95-1.39) | .14 | 1.14 (0.94-1.38) | .17 |
| Clinical pregnancy | 395 (61.53) | 1483 (57.82) | .09 | 1.17 (0.98-1.39) | .09 | 1.16 (0.97-1.39) | .10 |
| Ectopic pregnancy | 5 (0.78) | 22 (0.86) | .75 | 0.85 (0.32-2.26) | .75 | 0.85 (0.32-2.25) | .74 |
| Early miscarriage | 59 (9.19) | 224 (8.73) | .93 | 0.99 (0.72-1.35) | .93 | 1.00 (0.73-1.36) | .10 |
| Late miscarriage | 8 (1.25) | 27 (1.05) | .79 | 1.12 (0.50-2.47) | .79 | 1.07 (0.48-2.38) | .87 |
| Singleton preterm delivery | 44 (6.85) | 133 (5.19) | .12 | 1.35 (0.92-1.96) | .12 | 1.38 (0.94-2.01) | .10 |
| Groups B (n = 151) vs C (n = 600 [reference])c | |||||||
| Live birth | 85 (56.29) | 321 (53.50) | .54 | 1.12 (0.78-1.60) | .54 | 1.12 (0.78-1.60) | .54 |
| Biochemical pregnancy | 117 (77.48) | 432 (72.00) | .17 | 1.34 (0.88-2.04) | .18 | 1.33 (0.88-2.04) | .18 |
| Clinical pregnancy | 99 (65.56) | 383 (63.83) | .69 | 1.08 (0.74-1.57) | .69 | 1.08 (0.74-1.57) | .70 |
| Ectopic pregnancy | 1 (0.66) | 5 (0.83) | .81 | 0.77 (0.09-6.68) | .81 | 0.73 (0.08-6.33) | .77 |
| Early miscarriage | 12 (7.95) | 47 (7.83) | .97 | 0.99 (0.50-1.94) | .97 | 0.99 (0.50-1.94) | .97 |
| Late miscarriage | 1 (0.66) | 11 (1.83) | .29 | 0.35 (0.04-2.71) | .31 | 0.35 (0.04-2.73) | .32 |
| Singleton preterm delivery | 11 (7.28) | 28 (4.67) | .11 | 1.88 (0.87-4.07) | .11 | 2.04 (0.93-4.49) | .08 |
| Groups B (n = 146) vs A (n = 480 [reference])d | |||||||
| Live birth | 85 (58.22) | 253 (52.71) | .24 | 1.25 (0.86-1.82) | .24 | 1.20 (0.82-1.76) | .34 |
| Biochemical pregnancy | 114 (78.08) | 342 (71.25) | .10 | 1.44 (0.93-2.23) | .11 | 1.35 (0.86-2.12) | .19 |
| Clinical pregnancy | 97 (66.44) | 304 (63.33) | .49 | 1.15 (0.78-1.69) | .50 | 1.06 (0.71-1.58) | .78 |
| Ectopic pregnancy | 1 (0.68) | 5 (1.04) | .67 | 0.62 (0.07-5.40) | .67 | 0.46 (0.05-4.21) | .49 |
| Early miscarriage | 10 (6.85) | 40 (8.33) | .46 | 0.76 (0.36-1.58) | .46 | 0.74 (0.35-1.56) | .43 |
| Late miscarriage | 1 (0.68) | 6 (1.25) | .54 | 0.52 (0.06-4.35) | .54 | 0.48 (0.06-4.14) | .50 |
| Singleton preterm delivery | 11 (7.53) | 34 (7.08) | .83 | 1.09 (0.51-2.34) | .83 | 1.10 (0.51-2.37) | .81 |
Group A indicates hepatitis B surface antigen (HBsAg) positive and hepatitis Be antigen (HBeAg) negative; group B, HBsAg positive and HBeAg positive; and group C, HBsAg negative and HBeAg negative.
The multiple logistic regression model was adjusted for propensity scores (age of women, body mass index, duration of infertility, type of infertility, basal sex hormone level [estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing horomone (LH)], antimüllerian hormone [AMH] level, endometrial preparation protocols, endometrial thickness, the number of good-quality embryos transferred, and the type of embryos transferred) and luteinizing hormone level.
The multiple logistic regression model was adjusted for propensity scores (age of women, body mass index, duration of infertility, type of infertility, basal sex hormone level [estradiol, progesterone, FSH, and LH], AMH level, endometrial preparation protocols, endometrial thickness, the number of good-quality embryos transferred, and the type of embryos transferred).
The multiple logistic regression model was adjusted for propensity scores (age of women, body mass index, duration of infertility, type of infertility, basal sex hormone level [estradiol, progesterone, FSH, and LH], AMH level, endometrial preparation protocols, endometrial thickness, the number of good-quality embryos transferred, and the type of embryos transferred), age of women, and AMD level.
Discussion
Previous studies have found no link between maternal HBV infection and live birth, preterm birth, or pregnancy rates in women undergoing assisted reproductive technology.4,5 Our study confirms that maternal HBV serostatus is not associated with pregnancy outcomes in infertile women undergoing FET. However, HBV infection was significantly correlated with miscarriage and preterm birth during natural pregnancy.2 This correlation may be due to the accumulation of HBV DNA in the placenta and trophoblast cells that may lead to placental inflammation.2 Pregnant women with a high HBV viral load are at risk of transmitting the virus to the developing embryo, causing adverse pregnancy outcomes.6 Study limitations include the retrospective design, potentially introducing bias. Additionally, only the first FET cycle was analyzed, limiting the ability to assess the long-term effects of maternal HBV infection on pregnancy outcomes. In conclusion, maternal HBV serostatus was not associated with FET pregnancy outcomes. These findings suggest that women with HBV infection can safely undergo FET, which may reduce the psychological burden of infertile couples with HBV.
eMethods. Study Population and Design, Protocols, Outcome Measures, and Statistical Analysis
eReferences.
Data Sharing Statement
References
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Associated Data
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Supplementary Materials
eMethods. Study Population and Design, Protocols, Outcome Measures, and Statistical Analysis
eReferences.
Data Sharing Statement