Hormonal Pregnancy Tests Research Articles

The Independent Medicines and Medical Devices Safety Review: Regulatory Reform and Remedies

For years, groups of patients and their families in the United Kingdom raised their concerns about three medical interventions. The first was a possible link between hormone pregnancy tests and fetal malformations and deaths; the second was the physical and neurodevelopmental impacts of in utero valproate exposure; and the third was life-changing adverse events caused by pelvic mesh implants for pelvic organ prolapse repair and stress urinary incontinence management. In response to their tireless campaigning, the Independent Medicines and Medical Devices Safety (IMMDS) Review was commissioned by the Secretary of State for Health and Social Care in 2018. The review, chaired by Baroness Cumberlege, found a catalogue of institutional, systems and structural failures within both the medical establishment and healthcare system more broadly. Drawing on the IMMDS Review findings on pelvic mesh, in this article, I consider the dire consequences when medical devices go wrong. Drawing on firsthand experience as lead researcher for the IMMDS Review, I examine some of the background, outline some key findings and reflect on the strategic changes recommended to medical device regulation and the redress prompted by the pelvic mesh scandal. In so doing, I contextualise and consider the relevant regulatory frameworks, the fundamental systems failures and the other issues identified. Three years on, this article also provides an opportunity to assess the extent to which the IMMDS Review recommendations have been successfully operationalised, as well as to take stock of the improvements that still need to be made.

Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs causing failed abortion in humans

Teratogenicity and Reactive Oxygen Species after transient embryonic hypoxia: Experimental and clinical evidence with focus on drugs with human abortive potential.Reactive Oxygen Species (ROS) can be harmful to embryonic tissues. The adverse embryonic effects are dependent on the severity and duration of the hypoxic event and when during organongenesis hypoxia occurs. The vascular endothelium of recently formed arteries in the embryo is highly susceptible to ROS damage. Endothelial damage results in vascular disruption, hemorrhage and maldevelopment of organs, which normally should have been supplied by the artery. ROS can also induce irregular heart rhythm in the embryo resulting in alterations in blood flow and pressure from when the tubular heart starts beating. Such alterations in blood flow and pressure during cardiogenesis can result in a variety of cardiovascular defects, for example transpositions and ventricular septal defects. One aim of this article is to review and compare the pattern of malformations produced by transient embryonic hypoxia of various origins in animal studies with malformations associated with transient embryonic hypoxia in human pregnancy due to a failed abortion process. The results show that transient hypoxia and compounds with potential to cause failed abortion in humans, such as misoprostol and hormone pregnancy tests (HPTs) like Primodos, have been associated with a similar spectrum of teratogenicity. The spectrum includes limb reduction-, cardiovascular- and central nervous system defects. The hypoxia-ROS related teratogenicity of misoprostol and HPTs, is likely to be secondary to uterine contractions and compression of uterinoplacental/embryonic vessels during organogenesis.

Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis.

Background: Oral hormone pregnancy tests (HPTs), such as Primodos, containing ethinylestradiol and high doses of norethisterone, were given to over a million women from 1958 to 1978, when Primodos was withdrawn from the market because of concerns about possible teratogenicity. We aimed to study the association between maternal exposure to oral HPTs and congenital malformations. Methods: We have performed a systematic review and meta-analysis of case-control and cohort studies that included data from pregnant women and were exposed to oral HPTs within the estimated first three months of pregnancy, if compared with a relevant control group. We used random-effects meta-analysis and assessed the quality of each study using the Newcastle-Ottawa Scale for non-randomized studies. Results: We found 16 case control studies and 10 prospective cohort studies, together including 71330 women, of whom 4,209 were exposed to HPTs. Exposure to oral HPTs was associated with a 40% increased risk of all congenital malformations: pooled odds ratio (OR) = 1.40 (95% CI 1.18 to 1.66; P<0.0001; I 2 = 0%). Exposure to HPTs was associated with an increased risk of congenital heart malformations: pooled OR = 1.89 (95% CI 1.32 to 2.72; P = 0.0006; I 2=0%); nervous system malformations OR = 2.98 (95% CI 1.32 to 6.76; P = 0.0109 I 2 = 78%); gastrointestinal malformations, OR = 4.50 (95% CI 0.63 to 32.20; P = 0.13; I 2 = 54%); musculoskeletal malformations, OR = 2.24 (95% CI 1.23 to 4.08; P= 0.009; I 2 = 0%); the VACTERL syndrome (Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb defects), OR = 7.47 (95% CI 2.92 to 19.07; P < 0.0001; I 2 = 0%). Conclusions: This systematic review and meta-analysis shows that use of oral HPTs in pregnancy is associated with increased risks of congenital malformations.

Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis.

Background: Oral hormone pregnancy tests (HPTs), such as Primodos, containing ethinylestradiol and high doses of norethisterone, were given to over a million women from 1958 to 1978, when Primodos was withdrawn from the market because of concerns about possible teratogenicity. We aimed to study the association between maternal exposure to oral HPTs and congenital malformations. Methods: We have performed a systematic review and meta-analysis of case-control and cohort studies that included data from pregnant women and were exposed to oral HPTs within the estimated first three months of pregnancy, if compared with a relevant control group. We used random-effects meta-analysis and assessed the quality of each study using the Newcastle-Ottawa Scale for non-randomized studies. Results: We found 16 case control studies and 10 prospective cohort studies, together including 71330 women, of whom 4209 were exposed to HPTs. Exposure to oral HPTs was associated with a 40% increased risk of all congenital malformations: pooled odds ratio (OR) = 1.40 (95% CI 1.18 to 1.66; P<0.0001; I 2 = 0%). Exposure to HPTs was associated with an increased risk of congenital heart malformations: pooled OR = 1.89 (95% CI 1.32 to 2.72; P = 0.0006; I 2=0%); nervous system malformations OR = 2.98 (95% CI 1.32 to 6.76; P = 0.0109 I 2 = 78%); gastrointestinal malformations, OR = 4.50 (95% CI 0.63 to 32.20; P = 0.13; I 2 = 54%); musculoskeletal malformations, OR = 2.24 (95% CI 1.23 to 4.08; P= 0.009; I 2 = 0%); the VACTERL syndrome (Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb defects), OR = 7.47 (95% CI 2.92 to 19.07; P < 0.0001; I 2 = 0%). Conclusions: This systematic review and meta-analysis shows that use of oral HPTs in pregnancy is associated with increased risks of congenital malformations.

A historical argument for regulatory failure in the case of Primodos and other hormone pregnancy tests.

The drug Primodos and other hormone pregnancy tests (HPTs) remained on the British market for about a decade after they were first implicated, in 1967, as a possible cause of birth defects. In November 2017, an expert working group (EWG) set up by the Medicines and Healthcare Products Regulatory Agency (MHRA) concluded against such an association. However, it was explicitly ‘not within the remit of the EWG to make formal conclusions or recommendations on the historical system or regulatory failures’, a situation that has left many stakeholders dissatisfied. Placing the question of a teratogenicity to one side, this article takes a more contextual and comparative approach than was possible under the auspices of MHRA. It asks why an unnecessary and possibly even harmful drug was allowed to remain on the British market when a reliable and perfectly safe alternative existed: urine tests for pregnancy. Based on archival research in several countries, this article builds a historical argument for regulatory failure in the case of HPTs. It concludes that the independent review which campaigners are calling for would have the potential to not only bring them a form of closure, but would also shed light on pressing issues of more general significance regarding risk, regulation and communication between policy makers, medical experts and patients.

Regulator seeks information on link between birth defects and hormonal pregnancy tests

Regulator seeks information on link between birth defects and hormonal pregnancy tests

Congenital bladder exstrophy associated with Duogynon hormonal pregnancy tests—Signal for teratogenicity or consumer report bias?

A combination of ethinylestradiol and 10mg norethisterone under the brand names of Duogynon (Germany) or Primodos (UK) was used as a pregnancy test until the 1970s. Until very recently there was continuing public concern about the safety of these drugs and legal proceedings were instituted against the medicinal authorization holder. Given the lack of epidemiological studies focusing on Duogynon/Primodos, the present study evaluates 296 consumer reports of the German Duogynon database and compares the reported birth defects with data from a population based birth registry. The most striking result is an increase of bladder exstrophy (OR=37.27; 95%-CI 14.56–95.28). Neural tube defects (OR=2.99; 95%-CI 1.85–4.84) and renal agenesis (OR=2.53; 95%-CI 1.17–5.45) were also significantly increased. Bladder exstrophy may be a yet undetected teratogenic effect of Duogynon, but may also represent a reporting bias. The present study highlights the difficulties of evaluating consumer reports which may be influenced by public media.

Hormonal pregnancy tests in sub-Saharan Africa.

Reproductive steroids were used until the mid-1970s to rule out or confirm pregnancy. However in the advent of fast accurate pregnancy tests this practice has nearly disappeared. Researchers surveyed family planning (FP) providers in Ghana Kenya and Zambia from May to July 2000 to follow-up on anecdotal reports of the use of combined oral contraceptives to induce menses. Data collected in sub-Saharan Africa suggest that the practice of inducing menses to rule out pregnancy is still widespread. 13% of the Kenyan providers and 22% of the Ghanaian providers reported that they had induced menses in their clients in the previous 6 months. Use of this practice appears to be most common with postpartum FP clients whose lactational amenorrhea makes it difficult for providers to rule out pregnancy with certainty.

Risk factors for Wilms tumor. Report from the National Wilms Tumor Study.

Previous epidemiologic studies have indicated that several factors may be associated with an increased risk of Wilms tumor including paternal occupational exposures, maternal exposure during pregnancy to cigarettes, coffee or tea, oral contraceptives, hormonal pregnancy tests, hair-coloring products, maternal hypertension, vaginal infection during pregnancy, and higher birth weight of the child. The current study examines the nonoccupational risk factors using questionnaire data from a large national collaborative clinical trial. Parents of 200 children registered with the National Wilms Tumor Study and 233 matched controls, identified using telephone random-digit dialing, completed a self-administered questionnaire about a variety of risk factors. As opposed to some previous studies, no association was found for mother's smoking during pregnancy (10+ cigarettes per day; odds ratio [OR] = 0.73; 95% confidence interval [CI] = 0.40-1.34), maternal consumption of coffee or tea during pregnancy (4+ cups per day; OR = 1.31; CI = 0.57-3.01), or hypertension during pregnancy (OR = 0.96; CI = 0.45-2.06). In addition, no association was found in this study for hormone exposure during pregnancy, hair dye use, vaginal infection during pregnancy, or high birth weight. A previously unreported association with a history of household insect extermination was found (OR = 2.16; CI = 1.24-3.75). In general, the study failed to confirm most of the previously reported maternal risk factors for Wilms tumor. Understanding the possible role of paternal exposures may be the best objective for further research on potential risk factors for Wilms tumor.

The abuse of high dose estrogen/progestin combination drugs in delay of menstruation: The assumptions and practices of doctors, midwives and pharmacists in a peruvian city

The results are presented of a field study of the use of high dose Estrogen/Progestin combination drugs in Cusco, Peru, 1987. In Western countries the sale of these products is restricted. In the 1970s the use of high dose Estrogen/Progestin combination drugs as a hormonal pregnancy test was assumed to cause birth defects. Still these drugs have high sales data in Third World countries, where they are marketed for the treatment of menstrual disorders and for pregnancy diagnosis. A widespread misuse as abortifacient is assumed, although the abortive effect has never been proved. In this study 112 gynaecological consultations by doctors and 53 by midwives were observed. Seventeen health professionals and 26 salesmen in pharmacies were interviewed. It turned out that doctors and midwives prescribe high dose Estrogen/Progestin combination drugs to women whose periods are delayed. Of the consults 33% concerned this complaint. Women prefer “hindsight” birth control methods. Abortion is illegal. Under the cover of menstruation regulation or pregnancy diagnosis health professionals meet the wishes of women who search for an abortifacient. The products can easily be obtained without prescription. It is suggested that high dose Estrogen/Progestin combination drugs should be withdrawn from the market.

Hormonal factors and risk of ovarian germ cell cancer in young women.

No previous controlled studies of ovarian germ cell tumours have been reported; however the tumour is similar to germ cell testicular cancer in terms of histology, age-specific incidence rates (i.e. highest rates in young adulthood), and secular trends of increasing incidence. The investigation was designed to determine if maternal hormonal factors which have been found to increase the risk of testis cancer in male offspring are also risk factors for the ovarian tumour. The analysis is based on 73 cases diagnosed before age 35 and 138 age-race matched controls. The cases were identified by tumour registries in Los Angeles (1972-84) and Seattle (1974-84) and controls were selected from friends and/or neighbourhood residents. Interviews were conducted on the telephone with mothers of cases and controls. The primary finding was that mother's use of exogenous hormones (including the hormonal pregnancy test, DES or other supportive hormones, and inadvertant use of oral contraceptives after conception) increased risk (Odds ratio, OR = 3.60, 95% CL = 1.2-13.1). Other maternal factors associated with elevated risk were high pre-pregnancy body mass (OR = 2.7, 95% CL = 1.0-7.6), more rapid achievement of regular menstruation after menarche (OR = 1.8, 95% CL = 0.9-3.8), and age at index pregnancy under 20 (OR = 2.8, 95% CL = 1.0-10.7). In conclusion, these results support findings from testis cancer studies regarding a hormonal aetiology for germ cell tumours, and a mechanism by which oestrogen may affect the germ cells is proposed.

Exogenous Sex Hormone Exposure and the Risk for Major Malformations

Several studies have suggested that maternal use of exogenous sex hormones during early pregnancy may be associated with various congenital malformations. We conducted a case-control study of first-trimester sex hormone exposure among mothers of 1,091 infants with Down syndrome or at least one of 11 major malformations. For each malformation category, the infants with other malformations served as the control group. Associations were found between esophageal atresia and (1) any sex hormone exposure (odds ratio, 2.84); (2) progestins (odds ratio, 2.87); (3) nonspecified sex hormones (odds ratio, 2.99); and (4) hormonal pregnancy tests (odds ratio, 2.81). We found no potentially confounding variables for these associations. We found no statistically significant association between any malformation category and oral contraceptive exposure. Even if the relationship between esophageal atresia and noncontraceptive sex hormone exposure is causal, the absolute risk would be low, on the order of six per 10,000 exposed live births. ( JAMA 1986;255:3128-3132)

Exogenous Sex Hormone Exposure and the Risk for Major Malformations

Several studies have suggested that maternal use of exogenous sex hormones during early pregnancy may be associated with various congenital malformations. We conducted a case-control study of first-trimester sex hormone exposure among mothers of 1,091 infants with Down syndrome or at least one of 11 major malformations. For each malformation category, the infants with other malformations served as the control group. Associations were found between esophageal atresia and any sex hormone exposure (odds ratio, 2.84); progestins (odds ratio, 2.87); nonspecified sex hormones (odds ratio, 2.99); and hormonal pregnancy tests (odds ratio, 2.81). We found no potentially confounding variables for these associations. We found no statistically significant association between any malformation category and oral contraceptive exposure. Even if the relationship between esophageal atresia and noncontraceptive sex hormone exposure is causal, the absolute risk would be low, on the order of six per 10,000 exposed live births.

CONGENITAL MALFORMATIONS AND EXPOSURE TO EXOGENOUS FEMALE SEX HORMONES

We conducted a case-control study of maternal sex hormone exposure and the risk for major malformations. Using population-based surveillance data from the Metropolitan Atlanta Congenital Defects Program, we analyzed interviews from 1970-1979 for first trimester exposures to sex hormones among mothers of children with the following defects: oro-facial clefts; Down syndrome; diaphragmatic hernia; limb reduction defects; and esophageal, intestinal, or anal atresia. During the study period, 1,396 children with at least one of these defects were born in the surveillance area and 79% of the mothers were interviewed. For each defect category, the other defect categories served as the comparison group. We found no associations between any defect and oral contraceptive exposures; however, we did find an association between esophageal atresia and sex hormone exposure (odds ratio (OR) = 2.8, p = 0.009). Sex hormone exposures were subdivided, and associations persisted between esophageal atresia and 1) progestins and non specified sex hormones combined, and 2) hormonal pregnancy tests. Our findings suggest a relationship between esophageal atresia and non contraceptive sex hormone exposures. If causal, however, exposure would have a low absolute risk, on the order of 6/10,000 exposed live births.

Prospective Study of Suspected Associations between Certain Drugs Administered during Early Pregnancy and Congenital Malformations

From 1964 to 1976, a cohort study was performed in West Germany to study the possible influence of various factors on pregnancy and child development. Results of the evaluation of 13,643 pregnancies are given with respect to possible teratogenetic effects of antiemetic drugs and sex hormones administered in early pregnancy. There was no evidence of an increased risk of major malformations following the intake of certain antiemetic drugs and progesterone. Also, the use of a hormonal pregnancy test was not significantly associated with an increase of major malformations.

Maternal characteristics and hypospadias: a case-control study.

Various characteristics were compared among mothers of 99 singleton male live births (in Upstate New York, 1970-1974) with hypospadias and mothers of 99 singleton male live births, matched for maternal age, race, and residence. Maternal (and paternal) education, maternal height and weight, and the frequency of maternal diseases did not differ between cases and controls. Mean age at menarche was significantly later, but delayed menarche (16 years) was not more frequent, in case vs. control mothers. In the latest year during which the mother was neither pregnant nor taking oral contraceptives, menstrual cycles were significantly more often asymptomatic in case vs. control mothers, implying a higher frequency of anovulatory cycles in case mothers. This suggests the need for further studies on menstrual symptoms. Among case-control pairs with a previous pregnancy, the first pregnancy was less likely to have resulted in a male fetus in case vs. control mothers. Maternal use of exogenous sex hormones (oral contraceptives, hormone therapy, and hormone pregnancy tests) during the index pregnancy did not differ significantly between cases and controls, but the relative risk of 3.50 for hormone pregnancy tests (seven cases vs. two controls) was noteworthy in view of the results of previous studies.

Maternal exposure to exogenous sex hormones in relation to birth weight of offspring.

Birth weight was analyzed among singleton live births (N = 665) in Upstate New York in 1974 to women who used oral contraceptives (OC) in comparison to live births to women who used no contraceptives (N = 716), within 11 months prior to last menstrual period (LMP). In addition, birth weight was examined among live births to women who received hormone support therapy (N = 97) and hormone pregnancy tests (N = 75) during pregnancy. There was no evidence for a reduction in mean birth weight, or an increase in frequency of lower weights, among births to OC users, including those who stopped using OC within 2 months of LMP. Generally similar findings held within three maternal age groups (less than 25, 25-29, and 30-39 years). There was no evidence for a reduction in birth weight among offspring of women who received hormone pregnancy tests. Mean birth weight was relatively low among male and female births to women who received hormone therapy for "threatened abortion," but this may reflect the selection of women for such treatment rather than an effect of exogenous hormones on fetal growth.

Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformations.

From 1964 to 1976, a cohort study was performed in West Germany to study the possible influence of various factors on pregnancy and child development. Results of the evaluation of 13,643 pregnancies are given with respect to possible teratogenetic effects of antiemetic drugs and sex hormones administered in early pregnancy. There was no evidence of an increased risk of major malformations following the intake of certain antiemetic drugs and progesterone. Also, the use of a hormonal pregnancy test was not significantly associated with an increase of major malformations.

ORAL CONTRACEPTIVES AND BIRTH DEFECTS

Although OCs (oral contraceptives) are not designed to be taken during pregnancy, in Europe and the U.S. they are taken by 2-5% of women in early pregnancy and by 1/4-1/3 of women 3-4 months prior to conception. The effects of OCs on folic acid and other vitamin metabolism are well known and provide a theoretical basis for possible teratogenicity, even when stopped prior to conception. Both hormone support therapy for threatened abortions and hormonal pregnancy tests have been abandoned in recent years, the first because it proved inefficacious, the second because there are better alternatives available. In neither of these cases were sex hormones shown to be teratogenic. Most cohort (prospective) and many case-control (retrospective) studies have shown no association between OC use and birth defects. Case-control methodology can be criticized because of recall bias and because of the difficulty of choosing entirely matched controls. Several studies have shown OC users to have characteristics slightly different from the general population, e.g., they are younger, more often unmarried, and are more likely to smoke during pregnancy. Any of these characteristics might influence the occurrence of teratogenicity. It is impossible to prove that OCs constitute a low-level teratogen. The author considers them nonteratogenic.

The relationship between hormonal pregnancy tests and congenital anomalies: a prospective study.

In a prospective study of some 20,000 pregnancies in the Child Health and Development Studies in the San Francisco East Bay area, 226 gravidas were tested for pregnancy with estrogen/progestogen preparations. The two control groups were women who were tested for pregnancy by either a serum or urine test. There were no statistically differences (p greater than 0.05) in the rates of severe congenital anomalies between the hormone test group and the two control groups. The relative risks and the 95% confidence intervals were 1.01 (0.47-2.19) for the hormone/serum test comparison and 1.60 (0.60-4.18) for the hormone/urine test comparison.