Introduction
Since licensed by the U.S. Food and Drug Administration in 2006, human papillomavirus (HPV) vaccine, has been used among 72 million females worldwide [
1,
2]. Three HPV vaccines, including bivalent vaccine (2vHPV), quadrivalent vaccine (4vHPV) and nonavalent vaccine (9vHPV), are currently available [
3]. In many countries, HPV vaccines are recommended as part of the routine vaccination for female children aged 11–13 years [
1,
4]. Those females younger than 25 or 26 years, who have not received vaccination, are also recommended [
5,
6]. As a result, a large number of women at childbearing age may be exposed to HPV vaccination. These include those who may be inadvertently vaccinated during peri-conceptional period or pregnancy, particularly those who were unplanned or unrecognized pregnant [
7].
Although all the three HPV vaccines are inactivated, given the absence of well controlled studies in pregnant women, pregnancy is listed as a precaution condition for HPV vaccination [
4,
8]. Concerns have arisen as to whether the exposure of HPV vaccines before or during pregnancy would increase the risk of serious adverse pregnancy outcomes, such as spontaneous abortion, congenital defect, premature birth and stillbirth [
9‐
11]. Several studies have investigated the association between HPV vaccination and risk of adverse pregnancy outcomes [
2,
12‐
20]. In 2010, Wacholder et al. found higher risk of spontaneous abortion among women who conceived during less than 90 days from 2vHPV vaccination than among those in the control group (13.7% vs. 9.2%) [
17]. In another analysis, the authors showed that the incidence of spontaneous abortion among women who conceived within 30 days before or after 9vHPV vaccination was higher than that of conceived not within this specific period (17.5% vs. 8.6%) [
13].
Up to now, it remains largely uncertain whether the unintended exposure of HPV vaccination at the peri-conceptional period or during pregnancy will increase the risk of spontaneous abortion. This represents an important knowledge gap. Therefore, we conducted a systematic review and meta-analysis of all relevant clinical research evidence to address this unanswered important clinical question. In particular, we examined all of the available HPV vaccines to ensure a balanced assessment.
Discussion
To the best of our knowledge, this is the first meta-analysis to evaluate the risk of peri-conception and pregnancy exposure of HPV vaccination on spontaneous abortion. Our results suggested that administration of 2vHPV during Pre-90 days to pregnancy end, Pre-45 days to pregnancy end, and during pregnancy, did not increase the risk of spontaneous abortion with pooled RRs of 1.15 (95% CI, 0.95–1.39), 1.28 (95% CI, 0.96–1.70), and 0.85 (95% CI, 0.45–1.61), respectively. However, during the exposure window of Pre-45 days to LMP, 2vHPV vaccination seemed to increase the risk of spontaneous abortion with RR of 1.59 (95% CI, 1.04–2.45). In addition, our results showed 4vHPV vaccination during Pre-45 days to pregnancy end, Pre-45 days to LMP and during pregnancy, were not associated with higher risk of spontaneous abortion with pooled RR of 0.88 (95% CI, 0.73–1.06), 1.00 (95% CI, 0.80–1.24), and 0.79 (95% CI, 0.62–1.01), respectively. For 9vHPV, although only one study included, considering the high risk (RR = 2.04, 95% CI: 1.28–3.24), the possibility that administration of 9vHPV during peri-conception and pregnancy may increase spontaneous abortion cannot be ruled out.
Although a substantial number of clinical trials on the safety of HPV vaccines have been completed worldwide, the evidence of the association between peri-conceptional or pregnancy exposure of 2vHPV vaccination and spontaneous abortion was limited. In a long term follow-up study for pregnancy outcomes in women enrolled in the Costa Rica HPV Vaccine Trial [
14], the authors showed a higher risk of spontaneous abortion at 13 to 20 weeks for HPV vaccination (RR 1.35, 95% CI: 1.02 to 1.77). In another pooled analysis of clinical trials study, the incidence of spontaneous abortion among women who conceived during less than 90 days from 2vHPV vaccination was higher than that in control group (13.7% vs. 9.2%) [
17]. Similarly, in 2014, based on data from 42 completed/ongoing clinical trials, Angelo et al. reported that comparing with control group, 2vHPV vaccination during Pre-45 days of LMP increased the incidence of spontaneous abortion when compared with the control group (RR 1.59, 95% CI: 1.04–2.45) [
16]. Since routine pregnancy testing before HPV vaccination was not advised in currently clinical practice in the guidelines of WHO, America and many other countries [
8,
26,
27], and unintended pregnancies account for a large proportion (estimated rate up to 40%) of pregnancies [
28], the number of women in the world who inadvertent administration of HPV vaccine during peri-conceptional period or during pregnancy was enormous. If peri-conceptional or pregnancy exposure of HPV vaccine increases the risk of miscarriage, even if the risk is very weak, we should be vigilant.
For 4vHPV, no evidence suggested that administration during peri-conception and pregnancy might increase the risk of spontaneous abortion. Based on national database of Denmark, the risk of 4vHPV vaccination during pregnancy for spontaneous abortion in different gestational period was investigated in detail [
29]. In fully adjusted model, the authors indicated that 4vHPV vaccination during pregnancy did not increase the risk of spontaneous abortion during any of the gestational periods (< 7 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, and 13–22 weeks). In addition, different vaccine doses administered before and during pregnancy (1 dose or > 2 doses) were also not associated with higher risk of spontaneous abortion. Yet unexpectedly, the adjusted results showed that 4vHPV vaccination during pregnancy was even associated with lower spontaneous abortion rate during gestational week of 7, 9 and 11 [
29].
In 2018, Moreira et al. reported the safety profile of 9vHPV by combined analyzed 7 phase III clinical trials [
13]. The authors indicated that 9vHPV vaccine was well tolerated in subjects aged 9 to 26 years with any adverse events (AE) profile similar to that of the 4vHPV vaccine. However, the incidence of spontaneous abortion in conception date within 30 days of 9vHPV vaccination group (20.0%, 17/85) was higher than that of 4vHPV vaccination group (9.2%, 8/87) [
13]. In addition, when compared with the conception date not within 30 days of 9vHPV vaccination group, the incidence of spontaneous abortion in conception date within 30 days group was significantly higher (17.5%, 17/97 vs. 8.6%, 122/1418) with RR of 2.04 (95% CI, 1.28–3.24) [
13]. These results suggested that 9vHPV vaccination during peri-conception and early pregnancy may increase the risk of spontaneous abortion. At the same time, given the small number of pregnant women in the vaccination group, the results in this study require further research to confirm.
Based on the results of published studies, the risk of administration of HPV vaccine in different exposure windows for spontaneous abortion seemed different. Wacholder et al. reported the incidence of spontaneous abortion of conception during 0–30 days, 31–60 days, and 61–90 days between the nearest 2vHPV vaccination was 15.6% (24/153),14.5% (18/124), and 13.6% (16/117), respectively [
17]. Angelo et al. showed the incidence of spontaneous abortion of pregnant women who vaccinated 2vHPV within 45 days before pregnancy, and during the first trimester was 15.1% (48/317) and 11.7% (16/137), respectively [
16]. Whether the incidences of spontaneous abortion after exposure of HPV vaccine in different periods were similar or not, and whether exposure of HPV vaccine in a specific period around conception probably increased the risk of spontaneous abortion need additional research.
Although the association between HPV vaccination and spontaneous abortion has aroused great interest in recent years, the potential mechanism is rare known. One explanation is that spontaneous abortion may be caused by repeated antigen exposure [
15,
30]. Another explanation is that the ASO4 adjuvant in vaccine may alter the maternal immune system during early pregnancy, and then increase the risk of spontaneous abortion [
14,
31]. However, these two potential mechanisms are controversial, and need further exploration [
12,
14].
The main strength of this study was firstly conducting the meta-analysis, which targeting an unanswered important clinical question, the association between the unintended exposure of HPV vaccination at the peri-conceptional period or during pregnancy and spontaneous abortion. Meanwhile, the present meta-analysis involved two principal limitations which should be addressed. Firstly, exposure time windows of vaccination in included studies were not unified. Although the association between HPV vaccination and spontaneous abortion in long exposure time windows (e.g. Pre-90 days to pregnancy end) was showed in this study, for specific exposure time periods such as during 90 to 30 days before LMP, the risk of HPV vaccination was also unclear. Four exposure windows were generalized in this study, and this categorization may strengthen the effect of vaccination exposure farther from pregnancy, while in turn reduce the effect of exposure closer to pregnancy. Secondly, since only four included studies (two studies for 2vHPV and 4vHPV each) reported the adjusted RR of HPV vaccination for spontaneous abortion, we were unable to assess the contribution of confounding factors in our results. Women vaccinated during the peri-conceptional period were more likely unintended pregnancy, or women vaccinated during pregnancy were more likely unaware of pregnancy. When compared with awareness of pregnancy or planned pregnancy, all these women are more likely to be exposed to risk factors for spontaneous abortion, such as consumption of cigarettes or alcohol. Consequently, an individual patient data meta-analysis was needed to confirm the association between HPV vaccination in the peri-conceptional period or during pregnancy and spontaneous abortion.
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