Kristina Gemzell-Danielsson
Kristina Gemzell Danielsson is professor, senior consultant and Chair of Obstetrics and Gynaecology and the Director of the WHO collaboration centre for Research in Human Reproduction at Karolinska Institutet, Sweden. She is a pioneer in research on medical abortion with mifepristone and a prostaglandin analoge which was first developed at the WHOcentre. She is a member of the International Committee for contraceptive research (ICCR), Population Council, and President of FIAPAC. In 2012 she was honoured by the FIGO award in recognition of her research. In 2013 she was invited as the Aw Bon Haw Honorary Professor, Hong Kong University.
Speeches:
-
More than 15 years of experience – new developments,
Kristina Gemzell Danielsson. MD. PhD, Associate Professor in Obstetrics and Gynecology at the Karolinska Institute, Stockholm, Sweden
Senior consultant in obstetrics and gynecology at the clinic of Sexual and Reproductive Health, Department of Woman and Child Health, Division for Obstetrics and Gynecology.at the Karolinska Hospital, senior research position at the Karolinska Institute sponsored by the Swedish Research Council
Head of the WHO collaborating centre for research in Human Reproduction, Karolinska Hospital, head of the research group at the WHO-centre. Supervisor of 3 PhDs and 9 PhD students. research nurses and laboratory technicians.
Secretary Swedish association of Obstetrics and Gynecology, task force on Family Planning
Board member of FIAPAC (International federation of abortion and contraceptive associates), and ICMA (International consortium of medical abortion)
------------
Medical abortion with a combined regimen of mifepristone and a prostaglandin analogue was first approved in France in 1988 followed by approvals in the UK and Sweden, and has been used in China since 1992. In China and France medical abortion is used to 49 days amenorrhea. In the UK and Sweden the method is approved to 63 days amenorrhea. Today medical abortion is available in around 30 countries. During the last 15 years since introduction of the method research has focused mainly on the following issues: To find the optimal dose of mifepristone, the optimal type, dose and route of administration of prostaglandin and to increase acceptability of the method
Pharmacokinetic studies have shown that single doses of mifepristone above 100 mg resulted in similar serum concentrations. Randomised controlled trials have shown that 600 mg of mifepristone is equally effective as 200 mg when followed by a sufficient dose and suitable type of prostaglandin. The prostaglandin most commonly used today is misoprostol (Cytotec, Pfizer), a prostaglandin E1 analogue widely available for the prevention of gastric ulcer in patients taking non-steroidal anti-inflammatory drugs. Although licensed for oral use vaginal administration of misoprostol is becoming a common practice in medical abortion. Several clinical studies have found that vaginal administration is more effective than oral administration. When the absorption kinetics was compared between oral and vaginal treatment it was shown that the systemic bio-availability after vaginal misoprostol was three times higher than after oral misoprostol. This was directly reflected in the effect on uterine contractility. A drawback with the vaginal route is the large individual variation in plasma levels suggesting inconsistent absorption through this route. Furthermore most women prefer to take the tablets by the oral route. Recently the new route of sublingual administration has been described. Preliminary studies suggest that sublingual administration is a promising method for medical abortion. This is supported by pharmacokinetic and uterine contractility data indicating that this is probably the most potent route to administer misoprostol in its present form.
Current research also focuses on the possibility to reduce the time interval between mifepristone and misoprostol. Furthermore home administration of prostaglandin has been shown to be safe and effective, to reduce the number of visits to the clinic and to be preferred by many women in both developed and developing countries
-
25 years of mifepristone
Kristina Gemzell Danielsson
Karolinska Institutet/ Karolinska University Hospital, Dept of Woman and Child Health, Division of Obstetrics and Gynecology, Stockholm, Sweden - Kristina.Gemzell@ki.se
Based on the combined regimen of a progesterone receptor modulator, RU 486, developed by Roussel Uclaf and the Nobel prize awarded discovery of prostaglandins, medical abortion with mifepristone and a prostaglandin analogue was developed into a safe and effective method for induced abortion in the 1980ies. A team of researchers led by Pr. Baulieu was critical in the development of mifepristone (RU486) as was the French Ministry of Health. Further researches from Pr. Bygdeman’s team in Sweden described the combined regimen with prostaglandin. Then the WHO and later the company Exelgyn further endorsed this method which provided women with an alternative to surgery. Since the 1980ies research has focused on improving the regimen and care of medical abortion. Today the prostaglandin analogue of choice is misoprostol and medical abortion is a safe option for termination of pregnancy at all gestational lengths. An increasing number of women worldwide benefit from this development. Besides even if there are still differences from country to country not only in access to medical abortions (legal situation, home use, gestational age) but also in the clinical routines of medical abortion care (protocol, reflection delay), Medical methods for termination of pregnancy tend to replace the surgical options in many countries. There is also an increasing recognition that medical abortion can improve access to safe abortion in countries with restrictive abortion laws or lack of abortion providers. However, several barriers remain that limit global access to safe abortion services. Simplifying medical abortion could potentially contribute to increased access and acceptability. Possible approaches include the option to self-administer misoprostol at home, also beyond 9 weeks of gestation. Another possibility is task sharing with midlevel providers to allow these health care professionals to be more involved with the care of healthy women undergoing medical abortion. These possibilities have major impact to increase access to safe induced abortion in countries were medical resources are scarce.
-
Increasing access to safe
abortion servicesMedical abortion with mifepristone and a
prostaglandin analogue was developed into a
safe and effective method for induced abortion
in the 1980’s. Today the prostaglandin analogue
of choice is misoprostol and medical abortion
is a safe option for termination of pregnancy
at all gestational lengths. However, several
barriers remain that limit global access to safe
abortion services. Simplifying medical abortion
could potentially contribute to increased access
and acceptability. Possible approaches include
the option to self-administer misoprostol at
home. Another possibility is task sharing with
midlevel providers to allow these health care
professionals to be more involved with the care
of healthy women undergoing medical abortion.
This possibility is likely to have major impact
to increase access to safe induced abortion in
countries were medical resources are scarce. A
simplified treatment regimen may also include
home self-evaluation of complete abortion, an
option which is currently being investigated. -
Mechanism of action of Emergency contraception
Kristina Gemzell MD, PhD, Professor, Kristina.gemzell@ki.se
Dept. of OB/Gyn, Karolinska University Hospital/Institutet, Stockholm, Sweden
Recently post-coital treatment with levonorgestrel (LNG) and the antiprogestin
mifepristone has emerged as the most effective hormonal methods available for
Emergency contraception and LNG in a single dose of 1.5mg has become the
recommended emergency contraceptive pill. However the mechanism(s) of action of these
methods when used for emergency contraception in humans remains largely unknown.
We therefore evaluated the effect of LNG in doses effective for emergency contraception,
on ovulation as well as tubal and endometrial development. Treatment with 1.5 mg LNG in
the late follicular phase inhibited the LH surge in all subjects. No effect on endometrial
development could be found either following preovulatory or postovulatory LNG treatment.
LNG was shown to have no effect on the tubal steroid receptor levels. Furthermore LNG
had no effect on endometrial progesterone receptor concentration and other suggested
markers of endometrial receptivity remained essentially unchanged. Taken together
available data suggest that emergency contraception with a single dose of 1.5 mg of LNG
inhibit or delay ovulation but does not prevent fertilization or implantation.
Increased knowledge on mechanism of action could hopefully increase the acceptability
and thus availability of these methods, to offer women a chance to prevent an unwanted
pregnancy and thus reduce the numbers of induced abortions. -
Medical abortion at 7 - 9 weeks gestation: Considerations and challenges
Kristina Gemzell (Sweden)
Dept. of Obstetrics &.Gynecology, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden
kristina.gemzell@ki.se
Medical abortion using the antiprogestin mifepristone (Exelgyn; Paris, France) combined with a prostaglandin has been available in Europe since 1988 for termination of pregnancy up to 49 days of amenorrhea. In the UK (1991), Sweden (1992) and later on Norway the method is approved up to 63 days of amenorrhea. Recently medical abortion up to 63 days has been approved also in the rest of Europe. With the recommended regimen the high efficacy and acceptability of the method can be maintained beyond 49days. Critical aspects to consider when medical abortion is used beyond 49days of pregnancy will be discussed in the workshop. These include the regimen of mifepristone and misoprostol, the interval between the drugs, pain medication and home-use of misoprostol. An increasing number of women in Europe opt for this choice instead of surgical abortion. A shift which is expected to continue in the next years world-wide. It is crucial that providers are familiar with the method and aware of the critical differences compared to medical abortion before 49 days of pregnancy.
-
Medical abortion general recommendations
Kristina Gemzell, MD, PhD, Professor
Dept. of OB/Gyn, Karolinska University Hospital/Institutet, Stockholm, SwedenMedical abortion using the antiprogestin mifepristone (Exelgyn; Paris, France) combined
with a prostaglandin has been available in Europe since 1988 for termination of pregnancy
up to 49 days of amenorrhea. In the UK (1991), Sweden (1992) and later on Norway the
method is approved up to 63 days of amenorrhea. Today medical abortion is available in
around 30 countries. Since the introduction of the method research has focused mainly on
the following issues: To find the optimal dose of mifepristone, the optimal type, dose and
route of administration of a prostaglandin analogue, to increase acceptability of the method
and to define the duration of pregnancy for which it can be used.
During this time it has been shown that the dose of mifepristone can be reduced without
affecting its priming effect on the myometrium and cervix. Misoprostol has emerged as the
most optimal prostaglandin analogue with its effect being dependent on the duration of
pregnancy, and on the dose and route of administration. Based on pharmacokinetics and
effect on uterine contractility, it could be hypothesised that a newly developed slow-release
form of misoprostol may offer an alternative to conventional misoprostol. Our studies
further confirm the safety, efficacy and high acceptability of home-use of misoprostol.
Home-use of misoprostol allows women more flexibility, privacy and control in their
abortions.
With the introduction of mifepristone the non-surgical, non-invasive methods for 2nd
trimester abortion could be dramatically improved and has become the recommended
method in many centres. More recently medical abortion has also become increasingly
used in the interval 9 to 13 weeks.
In conclusion the combined treatment with mifepristone and misoprostol is a highly
effective and safe method to terminate pregnancy provided that the dose and route of
misoprostol is adjusted to the pregnancy length. Detailed counseling, adequate pain
management and information and the possibility of getting advice on the telephone are
likely to increase acceptability. -
Beyond the first trimester: Medical methods
Kristina Gemzell Danielsson MD, PhD, Dept of Obstetrics and Gynecology,
Karolinska University Hospital/ Institute, Stockholm, Sweden
Second trimester abortion constitute 10-15% of all induced abortions but are responsible for two thirds of all major complications. The non-surgical methods to terminate 2nd trimester abortion have shown a considerable development during the last 30 years. In the beginning of the 70ies prostaglandins become available on this indication. The non-invasive mode of administration has certainly facilitated the treatment and reduced the risk for complications. With the introduction of mifepristone the method could be further improved.
Mifepristone has been registered in Sweden since 1992 for termination of early pregnancy until 63 days and from 1994 for termination of second trimester pregnancy in combination with gemeprost. With the approved regimen 600 mg mifepristone followed by 1 mg gemeprost vaginally every 6 hours the median prostaglandin to abortion interval was shown to be 9.0 (1.4-40.5) hours for primigravidae and 7.2 (0-152.5) hours for multigravidae. The medium number of gemeprost pessaries to induce abortion was 2. Our data confirms the efficacy and safety of mifepristone combined with gemeprost for termination of second trimester pregnancy when used on a routine basis in the clinic. Today, another prostaglandin analogue, misoprostol, has been shown to be an attractive alternative to gemeprost with higher efficacy and a lower rate of side effects. Various regimens of misoprostol with or without mifepristone have been investigated. Recently it has been shown that sublingual administration of misoprostol is also an effective alternative for second trimester abortion.
-
Medical methods: Advantages and disadvantages
Kristina Gemzell (Sweden)
Dept. of Obstetrics &.Gynecology, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden
kristina.gemzell@ki.se
Delayed diagnosis of fetal anomalies, logistic and financial difficulties in obtaining abortion services, and failure to recognize an undesired pregnancy in the first trimester all contribute to the continuing need for late abortions. Second trimester abortion constitutes 10–15% of all induced abortions worldwide but is responsible for two-thirds of all major abortion-related complications. During the last decade, medical methods for second trimester induced abortion have shown a considerable development and have become safe and more accessible.
Today, in most cases, safe and efficient medical abortion services can be offered or improved by minor changes in existing health care facilities. The combination of mifepristone and misoprostol is now an established and highly effective method for termination of second trimester pregnancy. In some places medical abortion has become the recommended method for second trimester abortion leading to increased access. In countries where mifepristone is not available or affordable, misoprostol alone has also been shown to be effective, although a higher total dose is needed and efficacy is lower than for the combined regimen. Therefore, whenever possible the combined regimen should be used. Efforts should be done to reduce unnecessary surgical evacuation of the uterus after expulsion of the fetus and future studies should focus on improving pain management. More studies are also needed to explore the safety of medical abortion regimens in women with a previous caesarean section or uterine scar. Advantages and possible disadvantages with medically induced abortion in the second trimester will be discussed.
-
Midlevel versus physician provision of medical
termination of pregnancy– a randomised controlled
study
Gemzell-Danielsson, K1; Johansson, M1;
Salomonsson, E2; Gomperts, R1; Kopp Kallner, H1
1 Department of Obstetrics and Gynaecology, Karolinska Institute,
Stockholm, Sweden; 2 Karolinska University Hospital, Stockholm,
Sweden
Objective: To evaluate feasibility, efficacy and acceptability of
midlevel provision of medical termination of pregnancy (TOP) in
clinical practice through a randomised study of midwife or
physician examination and counselling prior to medical TOP.
Background: Midlevel provision of medical TOP is common in
less developed countries and has been shown to be acceptable.
However, access to a gynaecologist is a limiting factor in medical
TOP also in developed countries and causes unnecessary waiting
periods. In developed countries vaginal or abdominal ultrasound
is routinely performed before TOP and has been an obstacle to
midlevel provision of medical TOP.
Methods: Two midwives highly experienced in TOP care with no
previous training in ultrasound were trained in vaginal ultrasound
of early pregnancy. Inclusion criteria for this study were being
healthy with no ongoing medication and willing to participate.
Women signed informed consent and were randomised
accordingly. All patients with pregnancy longer than 63 days
gestational age or without having visible intrauterine pregnancy
were referred to a gynecologist.
Results: So far 1200 patients have been included. A total of 1260
women will be randomised. No serious adverse events have been
recorded. Preliminary results show that acceptability of midlevel
provision of medical TOP is higher than physician provision.
Conclusion: Midlevel provision of medical TOP in a clinical
setting in a developed country is highly feasible. Midwives can be
trained in vaginal ultrasound and thereby provide the complete
spectrum of early TOP services. -
Misoprostol and management of missed and incomplete abortion
Kristina Gemzell-Danielsson, Professor, MD, PhD, Dept. of Woman and Child Health, Div. of Obstetrics
and Gynecology, Karolinska Institutet/ Karolinska University Hospital, Stockholm, Sweden
Misoprostol, a synthetic prostaglandin E1 analogue, is commonly used for medical abortion, cervical priming, the management of miscarriage, induction of labor and the management of postpartum hemorrhage. Thus, misoprostol is a very versatile drug in obstetrics and gynecology. Knowledge of the pharmacokinetic profiles is important for designing regimens for various applications. Misoprostol can be given orally, vaginally, sublingually, buccally or rectally. Studies of misoprostol’s pharmacokinetics and effects on uterine activity have demonstrated the properties of the drug after various routes of administration. These studies can help to design the optimal dose and route of administration of misoprostol for the management of missed and incomplete abortion.
-
Mode of action: No evidence for effect post-fertilization
Kristina Gemzell (Sweden)
Dept. of Obstetrics &.Gynecology, Karolinska University Hospital/Karolinska Institutet, Stockholm, Sweden
kristina.gemzell@ki.se
Recently post-coital treatment with levonorgestrel (LNG) and the antiprogestin mifepristone has emerged as the most effective hormonal methods available for emergency contraception. LNG in a single dose of 1.5mg has become the recommended emergency contraceptive pill. However the mechanism(s) of action of these methods when used for emergency contraception in humans remains a matter of concern.
We therefore evaluated the effect of LNG in doses effective for emergency contraception, on ovulation as well as tubal and endometrial development. Treatment with 1.5 mg LNG in the late follicular phase inhibited the LH surge in all subjects. No effect on endometrial development could be found either following preovulatory or postovulatory LNG treatment.
LNG was shown to have no effect on endometrial progesterone receptor concentration and other suggested markers of endometrial receptivity remained essentially unchanged. The effect of mifepristone and levonorgestrel was further studies in an in vitro implantation model. Taken together our data suggest that emergency contraception with a single dose of 1.5 mg of levonorgestrel acts mainly to inhibit or delay ovulation but does not prevent fertilization or implantation. Increased knowledge on mechanism of action could hopefully increase the acceptability and thus availability of these methods, to offer women a chance to prevent an unwanted pregnancy and thus reduce the numbers of induced abortions.
-
News in emergency contraception
Kristina Gemzell Danielsson, MD, PhD, Professor Dept. of Obstetrics &.Gyneacology,
Karolinska University Hospital / Karolinska Institutet, Stockholm, Sweden
Unintended pregnancy is a global reproductive health problem. Emergency Contraception (EC) provides women with a safe means of preventing unwanted pregnancies after having unprotected intercourse. While 1.5 mg of levonorgestrel (LNG) as a single dose has been the gold standard EC regimen, a single dose of 30 mg ulipristal acetate (UPA) has recently been approved for EC use up to 120 hours of unprotected intercourse with similar side effect profiles as LNG. The main mechanism of action of both LNG and UPA for EC is delaying or inhibiting ovulation. However, the ‘window of effect’ for LNG EC seems to be rather narrow, beginning after selection of the dominant follicular and ending when luteinizing hormone peak begins to rise, whereas UPA appears to have a direct inhibitory effect on follicular rupture which allows it to be also effective even when administered shortly before ovulation, a time period when use of LNG is no longer effective. These experimental findings are in line with results from a series of clinical trials conducted recently which demonstrate that UPA have higher EC efficacy compared to LNG and thus represents a new evolutionary step in EC treatment.
-
Recent developments
Kristina Gemzell MD, PhD, Professor
Dept. of OB/Gyn, Karolinska University Hospital/Institutet, Stockholm, Sweden
Medical abortion using the antiprogestin mifepristone (Exelgyn; Paris, France) combined
with a prostaglandin has been available in Europe since 1988 for termination of pregnancy
up to 49 days of amenorrhea. In the UK (1991), Sweden (1992) and later on Norway the
method is approved up to 63 days of amenorrhea. Further development of the method will
be discussed in the workshop and include reduced doses of mifepristone, research on the
optimal type, dose and route of administration of the prostaglandin analogue and reduced
treatment intervals. Furthermore home-use of misoprostol allows women more flexibility,
privacy and control in their abortions. More recently medical abortion has also become
increasingly used in the interval 9 to 13 weeks as well as for midtrimester terminations with
an increased need to optimise pain management.
Anti-D immune globulin is given in most places after early abortion, although evidence is
lacking for the need of this intervention. As a result of the lack of evidence-based data, a
high number of women are receiving foreign immune globulins based on a questionable
indication. Furthermore this practice increases the costs of induced abortion. The need for
studies to clarify the indication of RH-prophylaxis is obvious especially when it comes to
medical abortion.
The generally accepted obligation in medicine to offer every patient the best evidence
based care should also apply to women with an unwanted pregnancy. An increasing
number of women in Europe now opt for medical instead of surgical abortion. A shift which
is expected to continue during the next year’s world-wide.
The need for more research to further improve the procedure, reduce side effects and
facilitate access is obvious. -
LS01.3
A tailored pregnancy test offers new possibilities to women for follow-up after medical abortion
Kristina Gemzell Danielsson
Karolinska Institutet, Stockholm, SwedenOne reason for limited access to medical abortion is that women are required to make multiple visits to the clinic. The purpose of a follow-up visit after medical abortion has been to ensure that pregnancy has successfully terminated, to detect complications and to start contraceptives. However, in case of complications women should not wait until a routine follow-up visit and, importantly, to help women start contraception after the abortion contraceptive counselling and provision should be done at the first visit to the abortion clinic and should not be postponed to the follow-up. Hence the main purpose of a routine follow-up visit after medical abortion is to detect an on-going pregnancy. Most service delivery guidelines recommend that women return at 2-3 weeks for a follow-up visit. However, an increasing number of women choose not to return for follow-up after their medical abortion.
Recently, studies have assessed alternative methods of follow-up after medical abortion, such as using a low-sensitivity urine pregnancy test, semi-quantitative urine pregnancy test or a high sensitivity pregnancy test followed by a telephone follow-up or through text message or online. A few studies have also investigated women’s experiences and perceptions of self-assessment and safety and effectiveness of self-assessment in low resource settings, including women who reside in rural areas, have low literacy levels and limited access to telephone and transport facilities.
Overall there is no increased risk of complications in women who self-assessed their treatment outcome compared with women who attend clinical follow-up. Self-assessment of treatment success after early medical abortion has a resource-saving potential. Women need to be counselled about the risk of continuing pregnancy and any strategy for self-assessment will need to be carefully assessed for test and user performance before introduction.
A simple, reliable test for self assessment allows a one-stop clinic for medical abortion. -
Today many women are reluctant to use any of the existing contraceptive methods due to side effects or fear of experiencing such effects. Unsafe abortion is a major contributor to maternal mortality. Therefore effective methods for contraception and safe and acceptable methods for termination of unwanted pregnancies are prerequisites for reproductive health, for gender equality and for the empowerment of women. New methods for contraception are also needed including improved methods for emergency contraception and new mechanisms of action as well as mode of delivery. Additional health benefits of contraceptive methods such as protection against various cancers, and a wide range of other benefits need to be better recognized. Based on their mechanisms of action Progesterone receptor modulators (PRMs) can be used for emergency contraception as well as regular contraception by various modes of delivery. Progesterone receptor modulators have been shown to be effective when used on demand post coital, as daily pills, once-weekly or once-a-month and is a well establish method for medical first and second trimester abortion. The use of progesterone receptor modulators for contraception and positive health benefits such as the possible protection against breast cancer as well as prevention of uterine leiomyomas and endometriosis deserves to be further explored. Progesterone receptor modulators have also been studied for “late emergency contraception” and for menstrual induction. Very early medical abortion (VEMA) before an intrauterine pregnancy can be visualized by ultrasound has been shown to be acceptable, safe and effective. Medical abortion is also highly effective later in the first trimester and can be self administered by women. Thus PRMs such as mifepristone if offered in a suitable dosage provides a model for a woman centred contraceptive continuum with added health benefits and increased autonomy for women.