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Pregnancy and the Myth of Influenza Vaccination-Is it safe, is it effective, is it necessary? What the CDC documents reveal.
On May 28th, 2004 the Advisory Committee on Immunization Practice (ACIP) of the Centers for Disease Control (CDC) published its annual report (1) on their recommendations for prevention and control of influenza. The fifty-one page document is intended to provide the most updated scientific basis for the safe and effective use of influenza vaccination. The purpose of this report is to critically assess the CDC’s current recommendations to include pregnant women amongst those who should receive the influenza vaccine.
Are pregnant women really at greater risk?
The influenza vaccine is not recommended for the general population but only those individuals and groups at higher risk than the general population for influenza-related complications. The ACIP states that pregnant women are at higher risk than non-pregnant counterparts:
"Because of the increased risk for influenza-related complications, women who will be pregnant during the influenza season should be vaccinated. Vaccination can occur in any trimester.”
The CDC’s most recent report cites two scientific papers that support this proclamation. First, a British study (2) compared maternal and neonatal outcomes of those women who were infected with the influenza virus during pregnancy with those without influenza. Although the authors reported a significantly greater frequency of overall complications in women with influenza infection than controls (p <. 0001), no single type of complication achieved statistical significance. The poorly designed study failed to describe how it defined any of the eighteen listed complications and some of the reported complications were actually only symptoms rather than a specific diagnosis. For example, influenza patients reported chest and abdominal pain more frequently, but no specific cause was identified (such as bowel obstruction, appendicitis, etc). Abdominal and chest pain could have been the natural consequence of a cough, for example, not unusual in patients with pneumonia, and would not constitute a “complication” of influenza, per se. When nonspecific complications were removed from the list, the two groups did not significantly differ. More importantly, the authors found no differences in pregnancy outcome measures between cases and controls, including mortality, preterm delivery and intrauterine growth retardation. Certainly, many of these complications could have been the result of other co-morbidities and unrelated to the flu.
A second study by Neuzil, et. al.,(3) appears to be the pivotal study that establishes the ACIP’s contention that pregnant women are high-risk for influenza complications.1 In this study of Medicaid women in a Tennessee registry, hospitalization rates of pregnant women during the flu season were compared to admission rates of non-pregnant and postpartum women. They discovered that women in their third trimester of pregnancy were 3-4 times more likely to be hospitalized for cardiopulmonary illness than their postpartum counterparts. There are numerous flaws with this paper. The study’s endpoint was only the event of a hospital admission and not any other specific morbidity. This significantly limits the scope of the study’s conclusions. Indeed, these researchers found no evidence of a difference in morbidity or mortality in the hospitalized women with influenza, a far more relevant conclusion. Furthermore, the authors of this study concede that the hospitalization rate was overestimated due to inclusion of delivery admissions. There was also no consistent manner in which the diagnosis of influenza infection was determined and distinguished from the cases of illness caused by non-influenza infections. In addition, the Medicaid population would be expected to have a greater amount of co-morbidity, also limiting any generalization of outcomes to a non-Medicaid population. Medicaid patients frequently do not receive adequate outpatient care, seek emergency room services at a more advance stage of illness and thus would be expected to have a greater admission rate than non-Medicaid patients.
Even the CDC researchers admit to the marginal impact of vaccination in pregnant women:
“Researchers estimate that an average of 1-2 hospitalizations can be prevented for ever 1,000 pregnant women vaccinated” (1, page 10)
It seems overly aggressive for the CDC to recommend that all pregnant women be vaccinated for influenza when, in fact, scientific data to date shows only marginal benefit to relatively few women. This is even more poignant when the only documented benefit seems to be fewer hospitalizations, not fewer morbidities or mortalities. The ACIP cites no scientific research that estimates the efficacy of the flu vaccine amongst non-Medicaid, pregnant women. One would assume that the non-Medicaid population would be far less likely to benefit from influenza vaccination.
Indeed, this is precisely what Black, et. al., discovered (5). Their study assessed the impact of influenza vaccination during pregnancy and subsequent risk of influenza-like illness amongst a northern California HMO population of 49,585 women and their offspring. The overall hospitalization rate from pneumonia during the flu season in this large population was very low at 1.8 cases per 10,000 pregnancies (about 1/6th that of Neuzil’s Medicaid population). All women recovered completely. The offspring hospital admission rate for pneumonia was only 0.35%. When they assessed the impact of immunization on the prevention of influenza-like illness, they found no statistically significant difference in illness rates amongst the vaccinated and unvaccinated women or their offspring. Vaccination even failed to have any impact amongst those women with asthma, a subgroup the CDC has claimed to be at high-risk for influenza complications.
Has safety testing been done on influenza immunization during pregnancy?
Because the benefit of influenza vaccination during pregnancy appears to be highly questionable, a safety-benefit analysis would not tolerate any risk to vaccine recipients or offspring, even at a theoretical level. According to the ACIP document, the safety of influenza vaccination during pregnancy is established by the following research:
One study of influenza vaccination of >2,000 pregnant women demonstrated no adverse fetal effects associated with influenza vaccine."2
This solitary reference cited to establish influenza vaccine safety was co-authored by researchers at Boston University in 1973 (6). Upon closer inspection of this key paper, the study appears to have very little to do with influenza vaccine safety, but rather that of polio vaccination safety during pregnancy. Furthermore, the outcomes measured were strictly limited to the occurrence of malignancy. The study highlighted the following:
• 58,807 pregnancies were studied
• malignancy rate in 1 y/o children of women given the killed polio vaccine during pregnancy was nearly twice that of the unvaccinated (7.6 vs. 3.9 per 10,000; p < .05)
• neural tumor rate in children of women given the killed polio vaccine during pregnancy was thirteen times more frequent than that of the unvaccinated (3.9 vs. 0.3 per 10,000; p < .01)
There is only one sentence that provides any data on influenza vaccination outcome:
“Among 2,291 mothers immunized with killed influenza vaccine during pregnancy, one child developed an astrocytoma of the spinal medulla.” (6), page 252.
The paper's alarming conclusion:
“The present data suggests that injection of killed polio vaccine in pregnant mothers were associated with malignancies, and tumors of neural origin in particular, in offspring born between 1959 and 1966.” (6)
The narrow scope of adverse reactions assessed and the very short period of follow-up severely limits the papers’ contribution to the issue of influenza vaccination safety. The presence of any non-malignant adverse events would have been completely unreported. The lifetime risk of malignancy was not calculated. Contrary to the ACIP’s contention, this paper simply did not attempt to genuinely assess immunization safety during pregnancy. More importantly, it raises serious concerns about polio vaccine safety and its link to cancers. Interestingly, the Institute of Medicine recently completed a study of the SV40 virus contamination of polio vaccines and its relationship to cancer and concluded:
“Because these epidemiologic studies are sufficiently flawed, the committee concluded in this report that the evidence was inadequate to conclude whether or not the contaminated polio vaccine caused cancer” (7)
It is inexplicable that the ACIP would cite a paper in support of its conclusion of influenza vaccine safety while the Institute of Medicine rejected the same paper on the basis of the flawed analysis of polio vaccine safety.
There is a clear paucity of peer-reviewed reports on the safety of influenza immunization during pregnancy. Review of the literature finds that two studies are often cited. Sumaya and Gibbs (8) analyzed the outcomes of influenza vaccination during pregnancy but in only fifty-six women. This is far too small of a population to identify those who are genetically or biologically susceptible to adverse reactions of the influenza vaccine. Similarly, Deinard and Ogburn (9) studied only one hundred eighty-nine pregnant women exposed to the influenza vaccine. Neither limited studies found any adverse perinatal outcomes.
Category of reactions
General adverse reactions
To illustrate how inadequately small the population sizes of these safety studies were, consider the historical analysis of other vaccine-related complications. The rotavirus vaccine was withdrawn on October 22, 1999 because the complication of intussusception was reported in an estimated one case per 5,000-11,000 vaccinated children. (10) Swine flu vaccination was halted on December 16, 1976 because the complication of Guillian-Barre Syndrome occurred with an estimated frequency of less than 1 case per 100,000 vaccinated. (11) Government health officials withdrew both of these vaccines after pre-marketing studies failed to detect those complications eventually shown in post-approval surveillance studies. It appears that government health officials have not learned from prior tragic vaccine safety failures. The CDC has already established a threshold for suspension of a vaccine with an adverse reaction incidence that would require the careful post-vaccination follow-up of at least several hundred thousand patients. Adequate safety testing of the influenza vaccine has simply not been performed.
Manufacturers of the current influenza vaccine, as clearly stated in the package inserts, claim that teratogenicity or reproductive studies have not been performed on this widely administered drug. As an example, the Fluzone package insert states:
“Animal reproduction studies have not been conducted with Influenza Virus Vaccine. It is not known whether Influenza Virus Vaccine can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.”
In a limited review of the literature (12), over one hundred publications were discovered that describe the occurrence of various complications attributed directly to influenza vaccines. (Table 1) Although the CDC has historically rejected case-reports and small series studies, it is hard to ignore this extensive list of reported adverse reactions. The CDC applies a double standard in its assessment of the scientific literature. It is of note that the ACIP report (1) ignored many of these peer-review citations when describing influenza vaccine complications yet embraced similar case-report studies that were in less conflict with CDC policy.
Table 1. List of papers reporting adverse reactions to influenza vaccination (12)
“Case reports and limited studies suggest that pregnancy may increase the risk for serious medical complications of influenza.” (1), page 10
The mercury concern. In July 1999, as a precautionary measure, the Public Health Service (including the CDC and FDA), the American Academy of Pediatrics, and vaccine manufacturers agreed that thimerosal levels in vaccines should be reduced or eliminated. Contradicting its own policy, the CDC then increased mercury exposure to the fetus and infant by allowing the inoculation of pregnant women and young infants with the mercury-containing influenza vaccine.
Although the complete discussion of the mercury-autism association is beyond the scope of this paper, some facts are pertinent (see reference 18 an overview). Few clinicians realize that most flu vaccines contain 25 micrograms of mercury per dose. Both the EPA and FDA’s allowable daily exposure limits are 0.1 microgram per kg, meaning that recipients of a flu vaccine must weigh at least 550 pounds to meet federal exposure guidelines. Mercury, which is used as a preservative in the form of thimerosal, is a known neurotoxin and crosses both the placental and blood-brain barriers. A growing number of experimental, epidemiological and biochemical research, has unequivocally shown that mercury is directly linked to the development of autism spectrum disorders and is significantly toxic to the gastrointestinal, immunological, metabolic and neurobiological systems in children. The developing fetus would receive a dose of mercury that exceeds the federal limits by several hundred-fold. Furthermore, all federal guidelines are based upon studies of exposure tolerances in adults, not the more vulnerable fetus. It is inexplicable that the CDC is so certain that ethylmercury can be safely injected into children or child-bearing women with no concern of harm while the FDA and EPA have warned that oral ingestion of methylmercury can have deleterious effects on the unborn:
“Yet, some fish and shellfish contain higher levels of mercury that may harm an unborn baby or young child's developing nervous system. . . . Therefore, the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) are advising women who may become pregnant, pregnant women, nursing mothers, and young children to avoid some types of fish and eat fish and shellfish that are lower in mercury. . . While it is true that the primary danger from methylmercury in fish is to the developing nervous system of the unborn child, it is prudent for nursing mothers and young children not to eat these fish as well.” (13)
The CDC and FDA assure clinicians that thimerosal underwent safety testing.
Since the wisdom of injecting mercury into humans, particularly children, has been challenged, the FDA and the CDC have provided several references of safety studies.
“Prior to its introduction in the 1930's, data were available in several animal species and humans providing evidence for its safety and effectiveness as a preservative. Since then, thimerosal has a long record of safe and effective use preventing bacterial and fungal contamination of vaccines, with no ill effects established other than minor local reactions like redness and swelling at the site of injection.” (14)
“Prior to its introduction in the 1930's, data were available in several animal species and humans providing evidence for its safety and effectiveness as a preservative (Powell and Jamieson 1931). Since then, thimerosal has been the subject of several studies (see Bibliography) and has a long record of safe and effective use preventing bacterial and fungal contamination of vaccines, with no ill effects established other than minor local reactions at the site of injection.” (15)
When the reference papers provided by the CDC and FDA are actually reviewed, however, a much different conclusion is reached. The Powell and Jamieson paper of 1931 reported that 88 of 170 rabbits died of mercury poisoning and fatal reactions were reported in rats. (16) Human trials referred to by Powell and Jamieson were more fully discussed in an earlier publication by the actual physician who treated meningitis patients with intravenous mercury. Dr. K.C. Smithburn (17) reported that 22 patients received thimerosal in a group of meningitis patients whose overall mortality rate was 65%. Unfortunately, the subset that received thimerosal fared worse- none survived (18).
Review of all eight additional citations offered by the FDA as evidence of thimerosal’s “long safety record”, in fact, fall far short of providing any proof of safety.3
Looking at the Big Picture
According to Dr. Nancy Cox of the CDC (19), only about 20% of the cases of “flu” are actually caused by the influenza virus. This means that, in theory, only 20% of all cases of influenza-like illness are preventable by influenza vaccination and only when there is a perfect antigenic match between the vaccine strain and the circulating virus. In practice, immunity to influenza may occur in as few as 50% of vaccinated individuals, even when the strains match perfectly (1). Indeed, regarding the 2003-04 flu season, the CDC reported “only 3 to 14 percent of those who got vaccinated were protected against the flu” (20).
The CDC and media often cite the statistic that there are nearly 36,000 influenza deaths annually. However, upon closer inspection of data from the National Center for Health Statistics of the CDC, this is a misleading figure. For example, the report of preliminary statistics of death in 2002 (21) shows that only 753 cases of influenza-related deaths were reported compared with 65,231 cases of pneumonia-related deaths. When the CDC compiled the final data, influenza and pneumonia cases are combined, yielding a misleading representation of reported influenza cases. Therefore, pneumonia deaths related to factors such as immunosuppression therapy, AIDS, malnutrition and a variety of other predisposing medical conditions are combined with seasonal influenza statistics. The constant broadcast of “36,000 annual influenza deaths” is misleading and unethical by its apparent intended use of fear to promote vaccination.
Furthermore, several published papers contradict the efficacy of influenza vaccination in other high-risk groups. A well-designed, double-blinded, placebo-controlled study showed no benefit amongst vaccinated asthmatic children in flu prevention (22). Unvaccinated children actually had 33% fewer asthmatic exacerbations than the influenza-vaccinated group. At least three other papers have confirmed these findings.
The ACIP also defended its recent addition of 6-24 month-old infants to the “high-risk” influenza category by citing another study of the Tennessee Medicaid population. This likewise prevents the generalization of the study findings to a larger, non-Medicare population. Indeed, a randomized study from Japan failed to demonstrate vaccination protection from influenza in healthy, 6-24 month-old children. (23)
Why is the CDC embracing marginal research and unsupported policy?
It may come as a surprise to most physicians that the CDC has a built-in conflict of interest with regards to its dual role in vaccine policy. One limb of the CDC that oversees vaccine safety has a budget of approximately $30 million while the limb that promotes vaccine usage (ACIP and NIP) has a $1 billion budget. (24)
Furthermore, CDC and FDA policy decisions are made through physician advisory panels whose members may have financial relationships, often undisclosed, with the very pharmaceutical industry they serve to regulate. In a congressional hearing discussing potential conflicts of interests at the FDA (25), investigators found that 60% of advisory members who voted to approve the ill-fated rotavirus vaccine had financial ties to the drug maker manufacturing the same vaccine. The CDC faired no better, with 50% of their members also tied to rotavirus manufacturers. It is little wonder Dr. Paul Offit, one such conflicted patent holder of the rotavirus vaccine, recently stated on a CBS broadcast (26) that vaccines were “safer than vitamins”. The veteran broadcast journalist failed to reveal that numerous injuries and deaths resulted in part from Dr. Offit’s approval of a vaccine that would have eventually paid him millions of dollars. Dr. Offit was correct, however, in stating to Dan Rather that “parents just need to trust experts and sometimes that’s a politically hard thing to do”. Dr Offit has contributed mightily to the mounting public distrust of government healthcare officials.
The CDC and the FDA do not have exclusive rights in coddling industry. As reported in JAMA (27), an investigation of doctors involved in co-authoring forty-four different Clinical Practice Guidelines (CPGs) concluded:
•85% of guideline authors have some sort of relationships with drug companies, and they are often not disclosed
•38% of respondents said they had served as employees or consultants for drug companies; 58% received research money
•59% had links with drug companies whose medications were considered in the particular guidelines they authored, almost all cases predating the guideline creation process
•These numbers may be even greater, as only 52% of authors responded
Most clinicians would be surprised by these revelations which challenge the blanket trust of a healthcare governance with uncomfortably close ties to the pharmaceutical industry.
The analyses of available papers cited by ACIP that are specifically designed to assess the safety and efficacy of influenza vaccination in pregnant women are of limited value. Not surprisingly, Medicaid patients seem to be hospitalized with greater frequency than the non-Medicaid counterparts, but even those of lower socioeconomic status do not have a higher morbidity and mortality when considering maternal, obstetrical and fetal outcomes. Available research on non-Medicaid patients failed to demonstrate any benefit from immunization. The studies cited by the ACIP in their recent annual report on influenza control and prevention fail to support the recently expanded vaccination policy to include pregnant women. Safety testing is notably absent or deficient in both scope of adverse reactions assessed and in duration of follow-up. Considering the rapid growth of autism and other related neurodevelopmental disorders and mounting number of papers demonstrating the causal relationship to mercury-containing vaccine preservatives, influenza vaccines should not be administered to pregnant women, and perhaps other high-risk groups, especially young children.
David M. Ayoub, MD
The Prairie Collaborative for Immunization Safety
1) Prevention and Control of Influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR: 53(RR06); 1-40, 2004.
2) Irving WL, et. al., Influenza virus infection in the second and third trimesters of pregnancy: a clinical and seroepidemiological study. British Journal of Obstetrics and Gynaecology; 107:1282-1289, 2000.
3) Neuzil KM, et. a;., Impact of influenza on acute cardiopulmonary hospitalizations in pregnant women. Am J Epidemiol; 148:1094-102, 1998.
4) Neuzil KM, Reed GW, Mitchel EF, Griffin MR. Influenza morbidity increases in late pregnancy. Abstracts of the IDSA, 34th Annual Meeting, 1996:48. (FALL 1996)
5) Black, SB et. al., Effectiveness of the influenza vaccine during pregnancy in preventing hospitalizations and outpatient visits for respiratory illness in pregnant women and their infants. Am J Perinatol; 21(6): 333-339, 2004.
6) Heinonen OP, et. al., Immunization during pregnancy against poliomyelitis and influenza in relation to childhood malignancy. Int J Epidemiol: 2; 229-35, 1973
7) press release, Institute of Medicine; Oct 22, 2002.
8) Sumaya and Gibbs. J Infect Dis. 1979 Aug; 140(2): 141-6.
9) Deinard and Ogburn. Am J Obstet Gynecol. 1981 Jun 1;140 (3):240-5.
10) Suspension of rotavirus vaccine after reports of intussusception -United States, 1999. MMWR; 53(34): 786-789, 2004.
11) Safranek, et. al., Reassessment of the association between Guillain-Barre syndrome and receipt of swine influenza vaccine in 1976-1977: results of a two-state study. Expert Neurology Group. Am J Epidem, 133; (9): 940-951, 1991.
14) http://www.hhs.gov/nvpo/vacc_safe/thim-qa.htm (accessed 11-1-04)
15) http://www.fda.gov/cber/vaccine/thimerosal.htm (accessed 11-1-04)
16) Powell, HM and Jamieson, WA. Merthiolate as a germicide. Am J Hygiene; 13:296-310, 1931
17) Smithburn, KC. Meningococcic meningitis. A clinical study of one hundred-forty-four epidemic cases. JAMA; Sept 13, 1930.
18) Mercury in Medicine – Taking Unnecessary risks. A report of the Subcommittee on Human Rights and Wellness, Committee on Government Reform, US House of Representatives. May 2003, page 15.
19) B. Fisher, Flu vaccine: Missing the mark. NVIC Special Report, Spring, 2004.
20) MMWR Jan 16, 2004
21) http://www.cdc.gov/nchs/pressroom/04news/infantmort.htm, page 16
22) HJ Bueving, et. al., Influenza vaccination in children with asthma. Randomized double-blind placebo-controlled trial. Am J Resp and Crit Care Med; 169: 488-493, 2004.
23) T Maeda, et. al., Failure of inactivated influenza A vaccine to protect children aged 6-24 months Ped Int; 46:122-125, 2004.
24) Congressman David Weldon, Chicago Illinois. May 28, 2004
25) Conflicts of Interest in Vaccine Policy Making. Majority Staff Report. Committee on Government Reform, U.S. House of Representatives, August 21, 2000.
26) CBS 60-Minutes, “Saying ‘No’ to Immunizations” Dan Rather. October 20, 2004. http://www.cbsnews.com/stories/2004/10/20/60II/main650368.shtml
27) Relationships between authors of clinical practice guidelines and the pharmaceutical industry. JAMA; 287: 612-617, 2002.
1The CDC must have felt the paper by Neuzil, et. al., was critical in establishing its policy to promote vaccinations amongst pregnant women. The research was first cited in the Spring 1997 MMWR report by ACIP, only a few months after it was presented at a national meeting (4) and nearly a year prior to its acceptance for publication in the American Journal of Epidemiology. It seems extraordinary that the CDC knew the paper would pass the peer-review process so far in advance of the publication date and risk citing it in this critical healthcare document. Perhaps the addition of one co-author, L Simonsen, an employee of the CDC, after the abstract was initially presented offered some level of assurance to the ACIP.
2 In the April 12, 2002 MMWR, this same statement was followed by the caveat “However, additional data are needed to confirm the safety of vaccination during pregnancy.” This comment was therefore dropped in the CDC’s 2004 version of the document, yet no new safety data was cited.
3 The topic of the eight papers cited by the FDA: eye drop preparations (4), nasal solutions (1), urine cytology preservatives (1). Two papers actually offer better alternatives for preserving biological reagents than thimerosal.