Current 26.1

Obstetrics,
Gynaecology
and Reproductive
Medicine
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Editor-in-Chief
Philip N Baker FRCOG, FMedSci
Pro-Vice-Chancellor and Head of the College of Medicine, Biological Sciences and Psychology,
Dean of the School of Medicine, University of Leicester, UK
Deputy Editor-in-Chief
Alec McEwan BA BM BCh MD MRCOG
Consultant in Fetal and Maternal Medicine, Department of Obstetrics and Gynaecology,
Queens Medical Centre, Nottingham, UK
Associate Editors
Sabaratnam Arulkumaran MBBS MD PhD FRCS (Ed) FRCOG
Professor of Obstetrics and Gynaecology,
Department of Obstetrics and Gynaecology,
St. Georges Hospital Medical School, London, UK
Fiona Reid MD MRCOG

Consultant Urogynaecologist,
St Marys Hospital, Manchester, UK
Shreelata Datta BSc(Hons) MBBS MRCOG LLM

Consultant Obstetrician and Gynaecologist,
Kings College Hospital, London, UK
Mahmood I Shafi MB BCh MD DA FRCOG

Consultant Gynaecological Surgeon and Oncologist,
Addenbrookes Hospital, Cambridge, UK
Tahir A Mahmood MD FRCOG FRCPI MBA FACOG(Hon)

Consultant Obstetrician and Gynaecologist,
Victoria Hospital, Kirkcaldy, Fife, UK
Trainee Editor
Catherine Aiken MB/BChir MA PhD MRCP MRCOG
Specialist Registrar (ST5) and Academic Clinical Lecturer in Obstetrics and Gynaecology,
Addenbrookes Hospital, Cambridge, UK
Obstetrics, Gynaecology and Reproductive Medicine has an eminent editorial board, all of whom are recognized experts in their field.
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REVIEW
The principles of
screening tests as applied
to obstetrics and
gynaecology
restriction and certain genetic as well as structural anomalies in

the fetus. In this review, we will discuss the principles of
screening in obstetrics and gynaecology in light of new advances
in the field. We have selected three key areas for review:
screening for pre-eclampsia (PE), Downs syndrome, and ovarian
cancer.
The concept of screening

Historical
The concept of screening in medicine tool accelerated in the late
1800s with the development of health checks on well people with
the aim of identifying early disease. The periodic examination
was introduced in the USA from 1900, with the intention of
improving the health and thereby productivity of the workforce.
This was performed by physicians but driven by employers, insurance companies and the desire for healthy armed forces
personnel. By the 1950s in the USA, blood tests and questionnaires became incorporated into this idea of annual screening.
The 1951 Commission on Chronic Illness Conference defined
screening as the presumptive identification of unrecognised
disease or defect by application of tests, examination, or other
procedures which can be applied rapidly.
In 1968, Wilson and Jungner were commissioned to report on
screening for the World Health Organisation (WHO). In their
landmark paper, Wilson and Jungner classified screening into
mass population screening, selective screening of high-risk
groups, and multiphasic screening (ie including radiology,
blood tests etc). They laid out the key principles that ensure the
validity of screening tests, namely efficiency, reliability, good
disease yield and economic viability (Box 1). Their report highlighted the importance of having an acceptable treatment for the
disease of interest, to avoid doing harm to the patient. Screening
for cancer of the cervix, anaemia, venereal disease, urinary tract
infections and streptococcus are all mentioned in their
recommendations.
Lara Morley
Nigel Simpson
Abstract
Screening in reproductive healthcare in the UK has expanded rapidly
since the introduction of cervical screening by the NHS in 1981.
Women are offered comprehensive antenatal care screening for a
range of pregnancy complications, now including pre-eclampsia and
gestational diabetes, with the aim of early disease detection and management. With the advances in molecular medicine in recent years,
novel biomarkers are being developed that have the potential to accurately predict these diseases long before their clinical onset. Likewise,
non-invasive testing in fetal medicine for a variety of genetic conditions may supersede traditional rst trimester screening. In oncology,
new tools for population screening for ovarian cancer are being sought
via prospective samples stored in biobanks. Tracking serial measurements from each patient may optimize the current use of CA125 rather
than using predetermined thresholds. These developments highlight
the move towards more personalized medicine. However challenges
in implementing new screening will include cost efcacy and ethical
considerations such as informed consent.
Keywords non-invasive fetal testing; ovarian cancer; pre-eclampsia;

screening
Introduction
Modern screening programmes
The use of cervical cytology for the early detection of cervical

cancer is one of the most widely cited, and successful, examples
of a medical screening programme. Most other screening strategies within gynaecology are related to early detection of gynaecological cancers. Within obstetrics, the aim of screening is to
detect women at risk of adverse pregnancy outcomes. This involves screening the expectant mother for pre-existing conditions
which may worsen during pregnancy, the development of
pregnancy-specific conditions, and disorders with postnatal and
even long-term health consequences (Table 1). Screening with a
combination of serum markers and ultrasound scanning aims to
detect those pregnancies at high risk of intrauterine growth
In the UK, screening programmes such as cervical cytology were

adopted within the NHS, but their oversight and implementation
within a national framework were formalized by the introduction
of the National Screening Committee (NSC) in 1996. For
example, the NSC has regulated cervical cancer detection by
introducing Quality Assessment and Reporting Guidelines,
Liquid Based Cytology, Human Papilloma Virus triage and
standards for the reporting of results.
A central tenet of the NSC is to look at new screening technologies carefully prior to their introduction. This role of the
NSC, and other bodies with an interest in screening, is likely to
be of particular importance in the coming years, with scientific
advances broadening the capabilities of screening programmes.
Further developments are expected as the result of breakthroughs in other areas. In 2001, Nature published the initial
sequencing and analysis of the human genome. This has enabled
the rapid identification of candidate disease genes. At the time of
that publication, at least 30 disease genes had been cloned secondary to the availability of the genome. Sequencing also
revealed mechanisms leading to chromosomal deletion disorders, such as Di George syndrome on chromosome 22. Although
Lara Morley MBChB BSc PgC is an Academic Clinical Fellow and

Specialty Registrar (ST4) in the Department of Obstetrics and
Gynaecology, Leeds General Inrmary, Leeds, UK. Conicts of
interest: none declared.
Nigel Simpson MBBS MRCOG is a Consultant Obstetrician and
Gynaecologist at Leeds General Inrmary, Leeds, UK. Conicts of
interest: none declared.
OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1
2016 Elsevier Ltd. All rights reserved.
REVIEW
Current standard NHS antenatal care package

Area
Screening
Downs syndrome
Haematology
Pre-eclampsia
Infectious diseases
Social circumstances
Others
Selective screening for at-risk women
Dating USS, nuchal translucency, triple or quadruple test (depending on gestation)

Anaemia, blood group and red-cell alloantibodies, haemoglobinopathies
Hypertension, proteinuria
Asymptomatic bacteriuria, HIV, syphilis, hepatitis B, rubella
Drug use, domestic violence, housing and working conditions
BMI, extremes of maternal age, mental health conditions, pre-existing medical conditions
Gestational diabetes, thrombophilia, Group B streptococcus carriage
Table 1
the rapid advances in genomics may lead to large public health

gains through genetic screening, the ability of doctors and policymakers to review the benefits versus disadvantages of introducing new tests into clinical practice may be lagging behind.
This moves Wilson & Jungners concept of early disease detection towards pre-clinical disease detection, using a combination
of molecular and non-molecular diagnostics. The validity of their
gold standard principles of screening has therefore been called
into question. There have been multiple attempts to re-invent
their criteria, such as the 2009 ACCE evaluation tool for the
newborn screening programmes; an acronym for analytical validity, clinical validity, and clinical utility, ethical, legal and social
implications. As genetic screening tests become more widely
available and economical, adequate resources will be required to
ensure appropriate regulation, education, counselling and

follow-up services are provided.
The principle of screening in resource-poor settings also needs
consideration. Wilson & Jungner recognized the difficulties with
screening in the developing world, referring to the admirable
method of combating disease but snags in practice. Cervical
cancer remains the leading cause of cancer-associated death in
women in most resource-poor countries. Hindrances to effective
screening include the technical expenses and follow-up of patients. Alternative approaches to cervical screening have been
trialled, such as direct visualization of the cervix, followed by
HPV detection or smear test only if the first inspection appeared
abnormal.
Screening for adverse pregnancy outcomes

Pre-eclampsia (PE)
Although PE is not part of the current NHS screening programme,
the justification for its prediction is based on the premise that
detection in the early clinical stages of the disease will reduce the
risk of pregnancy complications for both mother and baby. Preeclampsia is certainly an important health problem, being one
of the commonest causes of premature delivery. Severe PE can
also lead to life-threatening complications for the mother, such as
eclampsia, intracerebral haemorrhage and pulmonary oedema.
Current screening is based upon mass screening to identify
maternal risk factors (Box 2), and checking blood pressure and
urine at appointments. These tests fulfil the screening criteria of
being cost-effective and acceptable to the public and may be
successful at detecting the disease in its early stages. However,
the prospect of developing tools to accurately predict PE before
its onset, enabling patient-specific care, is an exciting one.
Potential screening tests have now been targeted through
improved understanding of the various aetiologies of PE. The
disease has long been regarded as having familial inheritance;
twin studies suggest that the heritable component of PE is greater
than 50%. A 10-year analysis of the Swedish national birth registry estimated the contribution of maternal genetics to the
development of PE to be 35%, the fetal genome in 20%, couple
effects in 13%, shared sibling environment in 1%, and 30% due
to the environment. A Norwegian study of 400,000 women
looking at the paternal contribution found that patients whose
male partners were the offspring of a PE pregnancy were more
likely to develop PE themselves.
Attempts to unravel the genetic aspects of PE have included
genome-wide association studies (GWAS), microarray studies of
The 10 Wilson-Jungner principles of early disease

detection
1 The condition should be an important health problem
2 There should be an accepted treatment for patients with
recognised disease
3 Facilities for diagnosis and treatment should be available
4 There should be a recognisable latent or early symptomatic
stage
5 There should be a suitable test or examination
6 The test should be acceptable to the population
7 The natural history of the condition, including development
from latent to declared disease, should be adequately
understood
8 There should be an agreed policy on whom to treat as
patients
9 The cost of case-finding should be economically balanced in
relation to possible expenditure on medical care as a whole
10 Case-finding should be a continuing process and not a once

and for all project
Box 1
REVIEW
up to 90%. In this paper, prediction rate of up to 100% could be

obtained by combining all of these biomarkers with ultrasound.
However, all of the included studies were retrospective, underpowered due to low numbers of pre-eclampsia cases, and presented data with wide confidence intervals. A subsequent good
quality, well-powered observational study of 2434 low risk
nulliparous women found similar results. There was a significant
correlation between low PlGF and PE (p < 0.001), although the
first trimester sensitivity was 32% with a specificity of 80% (95%
CI 25e39). Combining 6 biomarkers only generated a sensitivity
of 38% (95% CI 31e46) for a fixed 80% specificity. However, for
severe PE, the sensitivity of these biomarkers rose to 48%.
The low sensitivity may either represent late involvement of
these proteins in the disease process and/or the wide heterogeneity in disease phenotype. Alteration in the ratio of PlGF to sFlt
is known to precede the onset of clinical PE, therefore these
biomarkers may have a better role in early diagnosis, prediction
of disease severity and of timing delivery, rather than first
trimester screening.
The large, multi-national SCOPE (Screening for Pregnancy
Endpoints) study aimed to accurately validate a novel set of
biomarkers in independent sample sets. Mass spectrometry was
used in the validation of large sets of potential biomarkers in
maternal serum. The authors highlighted that in the high-risk
hospital antenatal setting, the rate of PE is approximately 20%,
and therefore new screening tests should have a positive predictive value of 20% to be clinically useful.
The challenges in developing a first trimester screening tool
for low risk women are likely secondary to the multifactorial
nature of PE. This difficulty relates to the point made by Wilson &
Jungner: screening tests should be used for diseases where the
pathogenic mechanisms from latent phase to clinical decompensation are well understood. In the future, screening for PE
may involve risk scoring based upon key clinical risk factors and
a select panel of biomarkers. Research would therefore be well
placed to better define the clinical phenotypes of PE.
Risk factors for pre-eclampsia

Family history (maternal and paternal)
Nulliparity
Previous PE
Multiple pregnancy
<6 months post partum or long
inter-pregnancy interval
New partner/donor sperm
Chronic hypertension
Renal disease
Metabolic syndrome
Diabetes (gestational
and pre-existing)
Advancing maternal
age
Obesity
Box 2
placental gene expression and single nucleotide polymorphisms

(SNPs) in selected genes of women with PE. Several candidate
genes have been proposed, for example Factor V Leiden mutation, leptin gene, VEGF TT-460 SNP, mannose-blinding lectin
gene polymorphism and Toll-like receptor 4 variants. Therefore,
the polygenic nature of PE may hamper efforts to develop a
screening method based on genetics. These complex geneegene
interactions are likely to be affected by epigenetic factors, some
of which are listed in Box 2, resulting in clinical disease.
The current understanding of the pathophysiological mechanism of PE is underpinned by reduced placental perfusion.
Abnormal invasion of the extravillous trophoblast into the
maternal spiral arteries is thought to result in impaired vascular
remodelling and defective implantation of the developing
placenta. This triggers a cascade of immune cell recruitment and
inflammation, vascular shear stress, maternal endothelial
dysfunction and placental ischaemic damage and hypoxia. One
measure of vascular resistance used to help predict PE is uterine
artery Doppler velocimetry in the 2nd trimester.
Multiple biomarkers have also been considered, largely those
which reflect the placental development such as ADAM-12 (a
disintegrin and metalloproteinase 12) and PAPP-A (Pregnancyassociated plasma protein-A). The latter is known to cleave
IGFBP-4 and may be involved in trophoblastic invasion with
placental protein 13 (PP13). Placental growth factor (PlGF) is a
member of the vascular endothelial growth factor (VEGF) family
and is thought to have a pro-angiogenic role. A VEGF receptor
biomarker is soluble fms-like tyrosine kinase-1 (sFlt-1), thought
to be anti-angiogenic. Others include soluble endoglin, the free bsubunit of human chorionic gonadotropin, inhibin A and activin
A.
Given that the detection rates based upon known risk factors
alone ranged from 23% for early onset disease and 83% for later
onset PE, the appropriate population to be targeting with biomarkers would be healthy nulliparous women. A 2011 systematic review of trials measuring these biomarkers in the first
trimester of low risk women found that PIGF had the highest
prediction rate (41%e59% for early-onset PE and 33% for late
onset). For comparison, the detection of an abnormal uterine
artery Doppler ultrasound correlated very variably with prediction of PE in this review; 29e83% for early onset disease versus 5
e62% for late onset disease. When combining these markers, the
positive predictive value of PP13 and uterine artery Doppler was
Screening for Downs syndrome

Downs syndrome is one of the most chromosomal abnormalities, with an overall incidence of one per 700 live births. An
additional 60% of cases miscarry spontaneously and 20% are
stillbirths. Non-dysjunction in meiosis accounts for approximately 96% of trisomy 21, inherited from the mother in 85% of
cases and from the paternal lineage in 15%. The remaining cases
are due to a balanced translocation of chromosome 21, a de novo
translocation or mosaicism.
As part of the NHS fetal anomaly screening programme
(FASP), current practice is to offer all pregnant women screening
for Downs syndrome. This service developed from the initial
findings that low maternal serum a-FP was associated with
Downs syndrome. In 1998, Carick et al found that measuring
bhCG in the 2nd trimester could offer antenatal screening for
Down syndrome with a detection rate of approximately 30%.
They found that using the combination of maternal age with
bhCG, a-FP and uE3 the detection rate was >60% for affected
pregnancies. A 2012 Cochrane review included 59 studies of
adequate quality (n 341,261) comparing 54 combinations of
biochemical screening tests for Down syndrome. Meta-analysis
REVIEW
revealed that combinations involving a-FP, uE3 and bhCG provided the best detection rates (6e7/10 affected pregnancies, with
a 5% false positive rate). Adding inhibin A did not significantly
affect the detection rate. The authors highlighted the lower sensitivities of the screening tests when used in women over 35
years of age.
The measurement of nuchal translucency (NT) alone by ultrasound has a detection rate for Down syndrome of 75% with a
5% false positive rate. When this is combined with first trimester
PAPP-A and hCG, this detection rate can increase to 90% for a
5% false positive rate. However, care must be taken with the NT
measurement as it is only accurate within a crown-rump length
of 45e80 mm (11e14 weeks gestation). Nuchal translucency
thickness can also be raised in a range of medical conditions,
such as fetal cardiac anomalies. Additional ultrasonographic
features of Down syndrome include absence of the nasal bone
and abnormal ductus venosus Doppler. If these features are
looked for, the false positive rate of the screening scan is
reduced, although the technical difficulties of performing these
scans may limit their clinical utility.
The current NICE guideline therefore recommends mass
screening with the combined test for patients who are 11 0 to
14 1 weeks of gestation. This includes a nuchal translucency
measurement and maternal serum assays for hCG and PAPP-A.
Women between 14 0 and 20 weeks of pregnancy should be
offered the quadruple test, involving hCG, a-feto protein, unconjugated estriol (uE3) and inhibin A. Other combinations
include the integrated test (nuchal translucency, PAPP-A in the
first trimester with hCG, a-FP, uE3 and inhibin A in the second
trimester), or the serum integrated test (PAPP-A in first trimester
with hCG, a-FP, uE3 and inhibin A in the second trimester). It
should be noted that only the combined test is recommended by
the NSC at present. When women have a high risk result, they
will be offered a diagnostic test with either amniocentesis or
chorionic villus sampling (CVS), both of which carry a risk of
miscarriage.
testing with amniocentesis or chorionic villus sampling (CVS) as

NIPT is not considered a diagnostic test. The false positive rate
with NIPT varies between tests and conditions, but is 0.03% for
the detection of Downs syndrome. This may be due to fetal DNA
from a demised twin pregnancy and therefore women should be
scanned prior to the test to identify a multiple pregnancy.
Additional causes include placental mosaicism or the detection of
a maternal chromosomal abnormality. A negative result suggests
that the pregnancy is highly unlikely to be affected by Down
syndrome, as the detection rate is greater than 98%. A false
negative result may be due placental mosaicism, too low a level
of DNA i.e. early gestation or high maternal BMI, or a technical
fault. An inconclusive result may be due to insufficient DNA is
the sample, so a re-test is offered.
NIPT is currently only available privately in the UK, although
it is currently being evaluated for a role within the NHS screening
service. The NIPT for Down syndrome evaluation study is
currently being led by a team at Great Ormond street hospital and
the NSC, involving eight different centres. Given the greater accuracy of NIPT compared with combined screening, using this
approach will mean less women undergo invasive testing with
CVS or amniocentesis. However, NIPT is not regarded as a
diagnostic test, so invasive testing for confirmation would still be
required. It is therefore vital that women are counselled appropriately and consented for either NHS screening or NIPT. Patients
should also be informed that NIPT will not routinely detect other
chromosomal abnormalities, such as microdeletions, or structural anomalies.
Specific tests may also become available enabling the early
detection of single-gene disorders, sex-linked disorders such as
Klinefelters and Turners syndromes, haemoglobinopathies such
as sickle cell anaemia and thalassaemia, and X-linked diseases
like haemophilia. Assessing the fetal genotype is also useful for
screening for the risk of haemolytic disease of the newborn in
women who are Rhesus negative. Testing fetal DNA using this
methodology can also determine the sex of the fetus. This is
relevant for the early detection of X-linked disorders, for example
Duchenne muscular dystrophy affecting male fetuses.
The rapid uptake of NIPT raises several ethical and policymaking difficulties. Concerns have been raised with regards to
sex selection using NIPT, resulting in the termination of a healthy
fetus of an unwanted gender. With the rapid innovation and
reduced cost of DNA sequencing, screening tests could be
expanded to include congenital abnormalities, childhood and
potentially adult-onset diseases, raising concerns about genetic
determination and eugenics. Disability rights groups argue that
the relative ease of undergoing NIPT may result in more positive
results and consequently increasing the termination of pregnancy
rate. Their narrative is one of non-directed counselling prior to
NIPT, with equal information about the positive aspects of living
with disability in the family. The cost effectiveness of NIPT also
needs to be determined before it could be implemented within
NHS screening service. Although currently, there is costinequality whereby a private and fee-paying service is offered
and consented for within the NHS to patients able to afford to
undergo testing.
In resource-poor settings screening for disorders such as
haemoglobinopathies may be clinically relevant and useful,
requiring fewer trained staff to perform invasive testing.
Non-invasive prenatal testing

Non-invasive prenatal testing (NIPT) offers a new method of
screening for Down syndrome alongside Edwards, Pataus and
Turners chromosomal abnormalities. This test is run on
maternal serum during the pregnancy and detects DNA fragments (cell-free DNA). The majority of cell-free DNA is maternal
in origin, but 10e20% is fetal DNA. Cell-free fetal DNA is shed
from the placenta and reaches sufficient levels for testing from 10
weeks of gestation. The quantity of DNA sequences mapping to
each individual chromosome is analysed, for example, excessive
chromosome 21 in maternal plasma is indicative of fetal Downs
syndrome. The fetal DNA is cleared from the maternal circulation
rapidly post-delivery and this is therefore specific to the current
pregnancy.
Since its introduction in 2011 in Hong Kong, there has been
rapid expansion in the commerciality and demand for NIPT.
Examples of companies offering NIPT and their tests include,
Ariosa (USA: Harmony), BGI Health (China: NIFTY), Natera
(USA: Panorama), Sequenom (USA: MATERNIT21 PLUS),
and Illumina (USA: Verifi). A NIPT result may be positive,
suggesting that the fetus is affected by Down syndrome. The
current protocol is that these patients should be offered invasive
REVIEW
However, cost and implementation burdens are limitations

currently.
It is therefore essential that staff offering NIPT are adequately
trained in delivering balanced and informed counselling to patients. A recent Nature article (Dondorp et al 2015) argues for a
cautious expansion of NIPT, requiring scrutiny from healthcare
professionals, health authorities and governments.
addition of serum markers was likely to reduce the false positive

rate associated with the detection of USS lesions that proved to
be benign.
The protocol for this study described women with a normal
ROC, who remained in the annual screening pool; intermediate
ROC, requiring repeat CA125 in 12 weeks; and elevated ROC
requiring repeat CA125 and TVS within 6 weeks. This process of
screening, triage and clinical assessment continued for the
participating women. Those with a higher risk based on their
ROC score were recommended for surgery regardless of the TVS.
The sensitivity and specificity for this model were tested at fixed
CA125 limits of more than 35, more than 30 and more than 22
kU/L. However, the focus of this study was to track serial CA125
measurements in individuals.
After 296,911 women-years of annual screening, 640 women
underwent surgery. Of those, 133 had primary ovarian cancer, 22
of which were within 1 year of screening. The sensitivity of this
multimodal screening was 85.8% (95% CI 79.3e90.9) with a
specificity of 99.8% (95% CI 99.8e99.8) in these low-risk postmenopausal women. An adverse effect of cancer screening may
be the surgical morbidity encountered by patients with false
positive results. In this study, four additional women underwent
surgery for each ovarian cancer diagnosed. The surgical
complication rate for these patients who had normal or benign
histology was 4.5%. The mortality data from this study are
awaited later in 2015.
Screening in ovarian cancer

Ovarian cancer is associated with the highest mortality of all
gynaecological cancers and is the second most common. Most
ovarian tumours are of epithelial origin, with the remainder
arising from other ovarian lines, such as germ cells and sex-cord
stromal cells. Unfortunately, at the time of diagnosis approximately 60% of epithelial ovarian cancers have reached an
advanced stage. The stage of disease at the time of presentation
often governs long-term survival, where stage 4 has an approximate 5-year survival rate of 10%, compared to 85% for stage 1.
Despite advances in surgery and chemotherapeutics, the mortality rate for ovarian cancer remains high. The argument for
screening for ovarian cancer is therefore strong, given the advantages of earlier disease detection.
Risk factors for ovarian cancer include advancing age, nulliparity and infertility. Up to 10% of cases may be inherited, with
high penetrance susceptibility genes including BRCA1/BRCA2
and HNPCC. Current advice from the Society of Gynecologic
Oncology recommends bilateral salpingooophorectomy after
women have completed their families. In this high-risk population, the Gynecologic Oncology Group is currently conducting a
prospective trial comparing bilateral salpingooophorectomy
against screening with cancer antigen 125 (CA125) measurement
and ultrasound.
The efficacy of whole population screening for ovarian cancer
has previously been studied in the USA as part of the Prostate,
Lung, Colorectal and Ovarian (PLCO) trial. This involved 30,630
participants who were screened with transvaginal Doppler ultrasound scanning (TVS) and CA125 (cut off 35 kU/L) for 4
years. The sensitivity of the tests for primary ovarian cancer
detection was 69.5%, although there was no improvement in
mortality with 118 cancer deaths in the screened arm versus 100
in the non-screened (mortality ratio 1.18 (95% CI 0.9e1.54))
after 12 years of follow up. This lack of improvement in mortality
led the USA Preventative Services Task Force to recommend
against screening for ovarian cancer in 2012. The Kentucky
screening study of 25,327 women showed higher sensitivity rates
sensitivity (81%) and improved 5-year survival outcomes in the
screened patients, although this study was not randomised and
groups are not directly comparable.
In May 2015 the BBC broadcast the headline Blood test
boost in ovarian cancer fight. This referenced the recent publication by the UK Collaborative Trial of Ovarian Cancer
Screening (UKCTOCS), which studied 46,237 women aged 50
years or older over a 14-year period. This study recruited women
from 2001 to 2005, who were randomised to no intervention or
annual surveillance with CA125 profiles based on their individualized risk of ovarian cancer (ROC) algorithm and TVS. This
algorithm was calculated on the basis of age-specific incidence of
ovarian cancer and the patients own serial CA125 profile. The
New advances in ovarian cancer research

Attempts to increase the earlier detection of ovarian cancer have
explored the early pathogenesis of the disease. There is now
strong evidence supporting the theory that epithelial ovarian
cancer may arise from the fimbrial end of the fallopian tube.
Histological examination of specimens from salpingoophorectomies has found tubal carcinoma in situ within the fimbrial
epithelium. As such, the antecedent events for ovarian cancer
may be present well before the detection by ultrasound monitoring. Novel biomarkers would therefore be extremely helpful,
although CA125 remains the most clinically useful.
Human Epididymis Protein 4 (HE4) has the highest sensitivity
after CA125, and may be used in pre-operative triaging but not
currently for screening purposes. Biobanks of prospective samples collected during large and multicentre studies may prove
useful for the identification and validation for new predictive
markers. Recently-highlighted potential biomarkers include
mesothelin, platelet factor 4 and connective tissue-activating
peptide.
When new strategies become available, it will need to be
determined whether the at risk population will be targeted, or
whether whole population screening could be rolled out. Until
then, ovarian cancer screening is best performed with a combination of TV USS and CA125. However, recent data support the
use of velocity-based algorithms for CA125, rather than fixed cutoffs.
Future direction of screening

Since Wilson & Jungner published their landmark paper, the
scope of screening has widened dramatically. This is largely due
to the advances in molecular medicine, making tests faster, more
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affordable and more accurate. The result is the availability of

screening tests and the potential for prenatal diagnosis of conditions, such as Downs syndrome, at earlier and earlier gestations. Genotyping may also be incorporated into determining
individual risk of developing cancer of the ovary, uterus and
cervix. Any new screening programmes will need to adapt to
emerging knowledge of gene contributions alongside environmental and lifestyle exposures.
New screening technologies have the potential to benefit patients and the NHS through the prevention of advanced disease.
There is the potential to develop highly individualized medicine
through a combination of clinical history, genotyping and
velocity-tracked biomarkers. Research is therefore required to
explore the validity of any new screening test, for example in
women at the extremes of maternal age and in different ethnic
populations.
Thorough consideration of ethical questions is also required
before widespread implementation. The cost efficacy must be
determined, alongside governance to ensure equity in distribution across society. Patients must also be fully informed of
the potential screening test results and consequences. Regulation must also be in place to ensure tests are not used inappropriately, for example, in fetal sex determination. It is
therefore vital that as new screening tools become available,
Wilson & Jungers principles of having an agreed policy on
whom to treat, an accepted treatment and cost-efficacy should
not be forgotten.
A
Kuc S, Wortelboer EJ, van Rijn BB, Franx A, Visser GH, Schielen PC.
Evaluation of 7 serum biomarkers and uterine artery Doppler ultrasound for rst-trimester prediction of preeclampsia: a systematic
review. Obstet Gynecol Surv 2011; 66: 225e39.
Lander ES, Linton LM, Birren B, et al. Initial sequencing and analysis of
the human genome. Nature 2001; 409: 860e921.
Menon U, Grifn M, Gentry-Maharaj A. Ovarian cancer screening
ecurrent status, future directions. Gynecol Oncol 2014; 132:
490e5.
Myatt L, Clifton RG, Roberts JM, et al. First-trimester prediction of
preeclampsia in nulliparous women at low risk. Obstet Gynecol
2012; 119: 1234e42.
Nezhat FR, Apostol R, Nezhat C, Pejovic T. New insights in the
pathophysiology of ovarian cancer and implications for screening
and prevention. Am J Obstet Gynecol 2015 (doi: 10.1016 Epub
ahead of print).
NICE. Antenatal care. NICE clinical guideline 62. 2008 (updated 2014),
http://guidance.nice.org.uk/cg62.
Nicolaides KH, Heath V, Cicero S. Increased fetal nuchal translucency
at 11e14 weeks. Prenat Diagn 2002; 22: 308e15.
UK National Screening Committee. History of the UK NSC. http://
www.screening.nhs.uk/history.
Vanstone M, King C, de Vrijer B, Nisker J. Non-invasive prenatal
testing: ethics and policy considerations. J Obstet Gynaecol Can
2014 Jun; 36: 515e26.
Wilson JMG, Jungner G. Principles and practice of screening for disease. Public health papers 34. Geneva: World Health Organisation,
1968.
FURTHER READING
Alldred SK, Deeks JJ, Guo B, Neilson JP, Alrevic Z. Second trimester
serum tests for Downs syndrome screening. Cochrane Libr 2012.
Art. No.: CD009925. http://dx.doi.org/10.1002/14651858.
CD009925.
Denny LM, Kuhn L, Pollack A, Wainwright H, Wright TC. Evaluation of
alternative methods of cervical cancer screening for resource-poor
settings. Cancer 2000; 89: 826e33.
Dondorp W, de Wert G, Bombard Y. Non-invasive prenatal testing for
aneuploidy and beyond: challenges of responsible innovation in
prenatal screening. Eur J Hum Genet 2015 (doi: 10.1038 Epub
ahead of print).
Hall AE, Chowdhury S, Hallowell N, et al. Implementing risk-stratied
screening for common cancers: a review of potential ethical, legal
and social issues. J Public Health 2013; 36: 285e91.
ndez-Daz S, Toh S, Cnattingius S. Risk of pre-eclampsia in rst
Herna
and subsequent pregnancies: prospective cohort study. BMJ 2009;
http://dx.doi.org/10.1136/bmj.b2255.
Practice points
C
Newer screening tests may be combined with the known risk

factors for pre-eclampsia to more accurately predict the subset of
patients likely to be affected by the disease
Within fetal medicine, the use of non-invasive prenatal testing is
likely to become more commonplace, with the ability to test for
an increasing number of conditions
Patients with high susceptibility genes for ovarian cancer, such as
BRCA1/BRCA2 and HNPCC are currently offered a bilateral salpingoophorectomy after they have completed their families
Biobanks of samples collected during large studies may prove
useful for the identification and validation of new predictive
biomarkers in ovarian cancer research
REVIEW
Outpatient hysteroscopy
in the OP setting or if a procedure has previously failed in the

outpatient setting they may require a GA. Women should not be
excluded if they are nulliparous or have had previous treatment
to their cervix.
Anna Graham
Shreelata Datta
The service
The Royal College of Obstetricians and Gynaecologists(RCOG)
now recommend that all services should have a dedicated
outpatient hysteroscopy service away from the operating theatre
with an appropriately sized and staffed treatment room with
adjoining private changing facilities and toilet. Written patient
information should be provided before the appointment and
consent for the procedure should be taken. A chaperone should
be present regardless of the sex of the clinician, they should act
as an advocate for the woman undergoing the procedure with so
called verbal anaesthesia reassuring and relaying any anxieties
the patient may have.
Abstract
The face of gynaecology is changing, and as it develops into a mainly
ambulatory speciality. Surgical procedures previously carried out as
day case surgery or as in patient are now increasingly performed in
the outpatient setting. This is true of hysteroscopic procedures that
were traditionally theatre based in hospital, but are now are performed
in the outpatient setting as rst line in many centres. Crucially this has
been shown to be both cost effective and acceptable to patients. This
review will provide an overview of the indications, current guidelines
and best practice techniques for clinicians performing both diagnostic
and therapeutic outpatient hysteroscopies.
Keywords
ambulatory;
diagnostic;
hysteroscopy;
outpatient;
Procedure for diagnostic hysteroscopy
therapeutic
Patient selection
Patient selection is crucial for successful OP hysteroscopy (and
all ambulatory procedures). The patient has to fully understand
the procedure and be positively motivated to undertake it.
Additionally if the patient has found a speculum or pipelle biopsy
in clinic too uncomfortable, it may not be appropriate to manage
them in the OP setting. Other exclusions are patients who have
not been able to tolerate a procedure previously or where pregnancy cannot be excluded. Previous treatment on the cervix such
as a large loop excision of the transformation zone (LLETZ),
being nulliparous, or previous myomectomies are not contraindications for OP hysteroscopy.
Hysteroscopy is a common procedure used in gynaecology to

assess the uterine cavity for suspected endometrial pathology. A
specialised endoscope is passed transcervically into the uterine
cavity to visualise and assess the endometrium. The hysteroscopic approach is suitable for a range of surgical techniques
including endometrial biopsies, polypectomies, fibroid resection,
endometrial ablation and sterilisation. Hysteroscopy was traditionally performed under a general anaesthetic (GA) in a theatre
setting (inpatient or day surgery). However with the advent of
smaller, flexible hysteroscopes and technological advances in
surgical equipment, it is being performed more frequently in the
outpatient (OP) setting with little or no analgesia. This avoids the
need for a general anaesthetic, shortens appointment times, is
acceptable to patients and additionally saves money.
A diagnostic hysteroscopy is usually performed for investigation of abnormal uterine bleeding (AUB), where endometrial
pathology cannot be excluded or is suspected via transvaginal
ultrasound scan (TVUSS), speculum, smear, swabs and pipelle
(Table 1). AUB includes intermenstrual bleeding (IMB), post
coital bleeding (PCB), menorrhagia, irregular bleeding or postmenopausal bleeding (PMB). Much pathology will be excluded at
the gynaecology outpatient appointment with hysteroscopy only
being necessary in a small proportion of cases.
Patient preparation
Prior to the procedure verbal and written information should be
provided to the patient, explaining what to expect and advising
them to eat, drink and take simple analgesia (preferably nonsteroidal anti-inflammatory drugs(NSAIDs) if no contraindications) 1 hour before the appointment. Written consent should be
obtained, and if indicated a pregnancy test performed, as it is
crucial to exclude pregnancy before entering the uterus. Last
menstrual period, or the date of the menopause should be
documented, together with the use of any hormonal contraception or HRT. There is no evidence that the prior use of cervical
preparation make the procedure easier and less painful.
The patient should be introduced to the team members,
usually a doctor and assisting nurse prior to undressing. She
should also be reassured that she is in control of the procedure
and if at any time she would like the procedure to stop then this
will occur and she will be supported in her decision. The patient
should remove their lower garments, empty their bladder and
wear a gown tied at the back. They should be positioned in lithotomy on a surgical couch and covered appropriately to respect
their dignity.
Contraindications
There are relatively few contraindications to OP hysteroscopy;
these include pregnancy or inability to exclude pregnancy and
patient preference. If a patient finds the technique unacceptable
Anna Graham BA(Hons) MBBS is an ST2 in Community Sexual and

Reproductive Health at Kings College Hospital, London, UK. Conicts of interest: none declared.
The equipment
Shreelata Datta BSc(Hons) MRCOG LLM is a Consultant in Obstetrics

and Gynaecology at Kings College Hospital, London, UK. Conicts
of interest: none declared.
There are many different types of hysteroscope available and the

RCOG recommend using the smallest available for diagnostic
REVIEW
Once inside the uterus the ostia should be identified for

confirmation of the correct positioning within the uterus and
images (preferably digital) taken and stored. The anterior and
posterior walls of the uterus should be examined and biopsies
taken under direct vision from any abnormal looking area or
from two separate sites if the endometrium looks normal. The
biopsy sites should be checked to ensure that the bleeding has
seized.
The hysteroscope should then be slowly removed, being
careful to consider all aspects of the endometrium on the way
out.
Indications for a diagnostic hysteroscopy

Presenting problem
Indications for hysteroscopy
Pre-menopausal:
Intermenstrual bleeding
Post coital bleeding
Menorrhagia
Irregular menstrual bleeding
Oligo-amenorrhoea
Tamoxifen and irregular
bleeding
Post-menopausal
bleeding
Endometrial polyp/submucosal
fibroid suspected at TVUSS
Inappropriately thickened
endometrium
Subfertility and recurrent

miscarriage
Post procedure
Following the procedure the patient should be given a few
minutes to recover, helped to sit up and there should be a
waiting area for her to recover in if necessary. Most women will
dress and feel well enough to leave immediately, following a
discussion on the procedure and its findings. The patient
should be given written information about what to expect post
procedure and contact details in case of late occurring
complications.
TVUSS endometrial thickness >5 mm

Or Endometrium cannot be
clearly seen
Pipelle endometrial sampling
inadequate
Only if uterine abnormality
suspected on TVUSS
Table 1
Operative hysteroscopy
hysteroscopy. These have a diameter of 2.7 mm with a 3e3.5
mm sheath which reduce the need for cervical dilation resulting
in less discomfort for the woman. The hysteroscopes come with a
variety of angle options ranging from 0 to 70 degrees. The 0 degree scope provides a panoramic view of the uterus whereas the
angled scopes allow for improved views of the ostia or abnormal
shaped cavity. Scopes also come as flexible or rigid. Flexible are
associated with less discomfort but an increased procedure time
and failure rate. The type and angle of the scope should therefore
be left at the discretion of the operator. The equipment should
remain sterile and be assembled with the help of the nurse
assisting at the patients side.
All of the techniques outlined below for operative hysteroscopy

have been shown to be acceptable to patients in the OP setting
but often require local anaesthesia, dilatation of the cervix and
sometimes opiate analgesia (particularly for endometrial ablation) (Table 2).
Endometrial biopsies and polypectomies
Many diagnostic hysteroscopes have an operative channel or
sheath through which specially designed forceps, scissors or
graspers can be inserted in order to take biopsies or remove
polyps under direct visualization. This reduces the risk of injury
or incomplete removal compared to when performed blindly.
These are suitable for small polyps which can be removed
through the narrow sheath (Figure 1). This technique would not
be suitable for larger polyps or fibroids due to their size or more
fibrous tissue.
Distension media
Carbon dioxide and normal saline can both be used as distention
medium and should be left up to the discretion of the operator,
however normal saline has been shown to facilitate faster procedure times, less vasovagal reactions, better image quality and
can be used for operative procedures.
Indications for operative hysteroscopy
The procedure
Device
Indications
The patient should be cleaned and draped in lithotomy to

maintain a sterile field as in a theatre setting, reducing the risk of
infection. Vaginoscopy has been shown to cause the least
discomfort for the patient and the lack of a speculum allows for
greater manoeuvrability; however, it may be useful to inspect the
vagina and cervix and therefore in some cases, a speculum may
be used prior to hysteroscopy. The hysteroscope should be
placed into the vagina, guided along the operators finger and the
fluid turned on to distend the vagina and identify the cervix. The
external os should be slowly entered and the cervix dilated by the
fluid. The images will appear on the screen and the black area
should be followed to find the internal os and uterus. Careful
attention should be paid to the patient to ensure that they are not
in too much discomfort.
Diagnostic hysteroscope with

operative sheath e forceps,
polyps, scissors
Resectoscopes and Morcellators
Endometrial biopsies
Small polypectomies
Intrauterine adhesions
Large polypectomies
Submucosal fibroid resection
Intrauterine adhesions
Intrauterine septum resection
Permanent sterilization
Heavy menstrual bleeding
ESSURE sterilisation
Endometrial ablation:
Bipolar frequency
Thermal balloon
Microwave energy
Table 2
REVIEW
Figure 1 Hysteroscopic polyp forceps.
Hysteroscopic resection and morcellation

Operative hysteroscopes for polyp, fibroid or septum resection
include bipolar resectoscope or morcellator devices. Traditional
bipolar devices have been modified to immediately remove the
resected tissue, improving views and reducing the need for
repeated removal and insertion of devices.
Hysteroscopic morcellators (Figure 2) have also now been
introduced which have been shown to be safe and reduce procedure times compared to the bipolar resection. These work with
a vacuum system that draws the tissue into a window and then
resects it, immediately removing it from the cavity. These have
an out sheath diameter of 6.25 m.
Figure 3 Hologic NovaSure endometrial ablation device. (Reproduced

with permission from Hologic).
and can be used in the OP setting with local anaesthesia. These

include bipolar radiofrequency energy, high temperature fluid
within a balloon and microwave energy. Not all women will be
suitable for endometrial ablation; they must have completed
their families, willing to continue using contraception until the
menopause, and they must not have large submucosal fibroids.
Additionally it is relatively contraindicated in very large cavities
where the endometrium may not be completely ablated or small
cavities where the equipment cannot be accommodated. It is also
essential to have an endometrial biopsy prior to ablation to
exclude endometrial pathology especially among women who
are >45.
Hysteroscopic sterilization
In the UK the device licensed for hysteroscopic sterilization is the
Essure Permanent Birth Control System. Hysteroscopic sterilization involves placement of a flexible micro insert into each fallopian tube. This induces scar tissue to develop and each
fallopian tube to occlude, therefore preventing pregnancy from
occurring. Following the insertion of the micro inserts, the patient is required to attend for a follow up appointment with
TVUSS or hysterosalpingogram (HSG) at 3 months post procedure to check occlusion. Extra contraception should be used
during this time.
Difculties and complications that may arise

Cervical stenosis
There may be cervical stenosis, in which case the cervix can be
dilated. The patient may tolerate this without anaesthesia,
however usually a local cervical block will be necessary. This
will allow the cervix to be dilated with ease but will not help
alleviate any crampy pelvic pain from the uterus. In certain
Endometrial ablation
Women with heavy menstrual bleeding who would like a permanent method of reducing their bleeding while avoiding a
hysterectomy can undergo endometrial ablation (Figure 3).
There are three techniques that are currently licensed in the UK
Figure 2 Hologic MyoSure morcellator device. (Reproduced with permission from Hologic).
REVIEW
Pathway to hysteroscopy
Patient attends GP with AUB
History
Examination
Investigations
Managed by GP
Patient Treated/
Reassured and
Discharged
Patient referred to Gynaecology

History
Examination
Investigations: swabs,
smear, bloods, pipelle
endometrial biopsy
TVUSS
Managed in GOPD/
referred on/
back to GP
Patient Treated/
Reassured and
Discharged
Endometrial pathology cannot be excluded or is

suspected at GOPD appointment:
Endometrium cannot be clearly seen on TVUSS
Endometrium looks abnormal on TVUSS
Pipelle biopsy is inadequate
Polyps / fibroids / septum seen on TVUSS
Patient requests sterilisation or endometrial
ablation or for fertility assessment
Patient referred for Diagnostic/

Operative Hysteroscopy
Endometrial cavity visualised
Endometrial biopsy taken
Operative techniques
sterilisation, polypectomy,
fibroid resection, adhesiolysis
Figure 4
cases, misoprostol may be considered pre-operatively to soften

the cervix.
Pain
Pain may occur and the patient has the prerogative to stop
the procedure whenever she wishes. Women usually find the
pain tolerable especially when they are fully informed about
how long it will take and the discomfort that they may
experience.
Uterine perforation
Uterine perforation is a rare complication, occurring in less than
1% cases. Riskfactors include cervical stenosis, severe uterine
anteflexion or retroflexion, infection, fibroids, and adhesions.
Most cervical traumas and uterine perforations occur during
dilation of the cervix. There is also an increased risk of perforation in therapeutic hysteroscopy.
Bleeding
Bleeding may occur during the procedure, particularly secondary
to fibroid resection. In most cases the fluid will distend the uterus
and tamponade the bleeding, however if this is insufficient,
bimanual uterine massage and misoprostol can be given. An
alternative is the insertion of a Foley catheter balloon for removal
after 24 hours. Definitive management would be embolization of
the uterine artery or a hysterectomy (rare).
Cervical damage
Cervical damage is a rare complication associated with tenaculum or vulsellum use.
Vasovagal attacks
A vagal response of bradycardia, hypotension and syncope secondary to manipulation of the cervix is rare. If this occurs the
patient should be managed symptomatically with the procedure
being halted, the head being lowered and intravenous (IV) fluids
administered.
Infection
Infection is a rare complication of hysteroscopy and prophylactic
antibiotics are not indicated. The patient should be advised to
contact the clinician for further assessment if malodorous
discharge or ongoing bleeding occurs.
10
REVIEW
Costs and tariffs
Mercier R, Zerden M. Intrauterine anaesthesia for gynecologic procedures: a systematic review. Obstet Gynaecol 2012; 120: 669e77.
Monitor and NHS England. NHS National Payment System for
2014/2015. London, October 2013. www.gov.uk/governmentt/
consultations/nhs-national-tarriff-payment-system-for-2014-2015.
National Institute for Health and Care Excellence Clinical Guidance 44.
Heavy menstrual bleeding. NICE, 2007.
RCOG Green-top Guideline No. 59 Best practice in outpatient hysteroscopy March 2011.
Wortman M, Daggett A, Ball C. Operative hysteroscopy in an ofcebased surgical setting: review of patient safety and satisfaction in
414 cases. JMIG 2013; 20: 56e63.
Financially, outpatient hysteroscopy compares favourably with

the equivalent procedure in day surgery due to reduced staffing
numbers; one nurse assistant compared to an anaesthetist, scrub
team and recovery staff. It also frees theatre space for essential
procedures in patients with additional medical morbidities. In
addition to this NHS England and Monitor have currently set best
practice tariffs (BPT) that pay more for outpatient hysteroscopy
and sterilization than the equivalent DSU procedure. In addition
to this the patient has shorter appointment times. In addition,
due to the absence of a GA, patients are able to return to work on
the same day (Figure 4).
Conclusion
Outpatient hysteroscopy, both diagnostic and therapeutic, has
many benefits over the traditional general anaesthetic approach.
It is acceptable to patients and cost effective. There will always
be a need for hysteroscopy in the theatre setting but increasingly
this will be a procedure reserved for complicated cases.
A
Practice points
C
FURTHER READING
Kremer C, Duffy S, Moroney M. Patient satisfaction with outpatient
hysteroscopy versus day case hysteroscopy: randomised
controlled trial. BMJ 2000; 320: 279e82.
C
C
11
Outpatient hysteroscopy is a safe procedure which is acceptable

to patients
All gynaecology services should be offering a dedicated outpatient hysteroscopy service
Careful patient selection is essential for successful OP procedures
Patients tolerate the procedure well with little or on analgesia
There are massive financial savings that can be made by performing hysteroscopy in the OP setting rather than in DSU
REVIEW
Management of preterm
labour
Definition of preterm deliveries gestation

Gestation
(weeks)
% Of
premature
deliveries
Sarah A Hamilton
Extreme
Prematurity
Severe
Prematurity
Premature
Near Term
Clare Mullan
Abstract
Preterm birth is dened as birth before 37 weeks of gestation and is
the single biggest cause of neonatal morbidity and mortality. The UK
preterm birth rate is 7.9%, therefore approximately 1 in 13 babies
are born prematurely. This is despite advances in prediction of those
at risk, prevention strategies and treatment. Transvaginal ultrasound
and fetal bronectin have been the major advances in the prediction
of preterm labour, and with the use of both of these tests it may be
possible to predict up to 75% of those who will deliver prematurely.
At best, tocolytics are able to delay preterm labour long enough for
the administration of corticosteroids. Labour involves complex and
co-ordinated events, greater knowledge of which is necessary to understand processes involved in premature labour and advance healthcare in this eld.
28 to 31 6
15
32 to 33 6
34 to 36 6
20
60
Table 1
Incidence of preterm birth

The incidence of preterm birth is increasing in both the UK and
USA. The UK preterm birth is around 7.9%, compared to
approximately 12% in the USA. This rate has not altered despite
advancing knowledge of risk factors related to preterm labour
and the introduction of many public health and medical interventions, such as tocolysis, e.g. Atosiban and Nifedipine,
designed to delay preterm birth.
Keywords high risk; obstetric labour; pregnancy; premature;

progesterone/therapeutic use; tocolysis
Causes of preterm birth

The principal pathways leading to preterm birth are spontaneous
preterm labour (PTL), preterm prelabour rupture of the membranes (PPROM) and iatrogenic causes. Approximately 45% of
births occur following spontaneous PTL, 30% are iatrogenic and
15% follow PPROM. PPROM is defined as preterm spontaneous
rupture of membranes, at least 1 hour before the onset of contractions. In addition to prematurity, PPROM is particularly
associated with maternal sepsis and chorioamnionitis. Iatrogenic
causes are deliveries (labour induction or Caesarean section) for
maternal or fetal indications, such as pre-eclampsia and fetal
growth restriction.
There are several maternal characteristics associated with
preterm labour (Table 2). Maternal ethnicity has a significant
impact on risk of preterm delivery. In the USA in 2003, the
preterm birth rate for African-American women was 17.8%,
compared to 10.5% in Asian and Pacific Islanders and 11.5% for
Caucasian women. Previous preterm delivery increases the risk
of a subsequent preterm delivery 2.5 fold, with those women
with a previous preterm delivery at the lowest gestations at
highest risk.
PTL is a complex process and is likely the endpoint of multiple
influencing factors (Figure 1). It is useful to consider the management of PTL in three sections: the detection of those women
at high risk, prevention of PTL in high risk women and finally
diagnosis and treatment of those women in PTL.
Introduction
Preterm birth, defined as birth before the 37th week, can be
further subdivided according to gestational age as shown in
Table 1. Preterm birth contributes to substantial neurocognitive, pulmonary and ophthalmologic morbidity and globally accounts for 28% of neonatal deaths. Over the past decade,
survival rates have dramatically improved. However this is due
to improvements in neonatal care rather than improvements in
obstetric care, and while babies born at extremely low gestations
are surviving in greater numbers, they still having similar rates
of intraventricular haemorrhage, necrotizing enterocolitis,
chronic lung disease and retinopathy of prematurity as they
were 10 years ago. For example, babies born at 26 weeks of
gestation and above now have a survival rate of approximately
75%, however approximately 40% will suffer from some form of
disability. It has been shown that prolonging a pregnancy from
30 weeks to 34 weeks gestation decreases the neonatal mortality
from 9.6% to 0.9%. A key factor in improving outcomes for
these babies is to therefore aim to predict and prevent preterm
birth.
Sarah A Hamilton MBChB MD MRCOG is Subspecialist Trainee in Fetal

and Maternal Medicine at St Marys Hospital, Central Manchester
University Hospitals NHS Foundation Trust, Manchester, UK.
Conicts of interest: none declared.
Prediction e in the general population and those at

increased risk
There are several studies that have been carried out to investigate
methods of predicting PTL in women at high risk. In addition to
the identification of risk factors (Table 3); the main methods used
are transvaginal ultrasound and fetal fibronectin (FFN).
Clare Mullan MBChB MRCOG is Consultant Obstetrician at St Marys

Hospital, Central Manchester University Hospitals NHS Foundation
Trust, Manchester, UK. Conicts of interest: none declared.
<28
12
REVIEW
relative risk of preterm delivery can be assigned to a particular

cervical length. For example, a woman with a cervical length of
22 mm has a relative risk of PTL of nine-fold while a women with
a cervical length of <13 mm has a relative risk of fourteen-fold,
when compared with longer cervical length. In the general population, only 1.7% of women have a cervical length less that 15
mm and these women account for 100% of births prior to 26
weeks, 80% of births prior to 30 weeks of gestation and 60% of
births prior to 32 weeks of gestation. Therefore, a cervical length
less than 15 mm is a sensitive predictor of severe prematurity, as
it is associated with a 50% risk of delivery prior to 32 weeks of
gestation.
Funnelling, which is opening of the internal os with closed
cervix below, has also been shown in some studies to be associated with an independent risk factor for PTL, while other
studies have contradicted this. It is likely that the length of the
closed cervix below the funnel is more important. The RCOG
have advised that funnelling of the cervix should not be used as
an independent factor for the insertion of a cervical suture
without shortening of the cervix below.
In order for a screening test to be effective, there needs to be
an effective available treatment. At present there is no
conclusive evidence that any one intervention helps to prevent
preterm labour following the identification of cervical shortening or funnelling. Therefore the main benefit of transvaginal
ultrasound screening may be its high negative predictive value
of 90% for cervical length over 30 mm at 24 weeks. Women
may be reassured, avoiding further clinic visits and
intervention.
The guidance from the RCOG is to offer serial sonographic
surveillance of cervical length for women with a history of
spontaneous second trimester loss or preterm delivery, as there is
evidence to suggest that those who experience cervical shortening are at an increased risk of subsequent early delivery and
may benefit from ultrasound-indicated cerclage. However, as this
area is still lacking in evidence, women should be informed that
expectant management is a suitable alternative to serial cervical
Survival rates at extreme premature gestations following

admission for neonatal care
Gestation
Total %
survival
rate
(without disability)
Morbidity at 6 years
of age in all infants
born <27 weeks
23
29 (15)
24
46 (28)
25
69 (47)
26
78 (61)
22% severe disability

(cerebral palsy and not
walking, low cognitive
scores, blindness, profound
hearing loss)
24% moderate disability
(cerebral palsy but walking,
cognitive scores in special
educational needs range,
lesser degree of visual of
hearing impairment)
34% mild disability
(low cognitive scores,
visual disturbance requiring
glasses)
20% no problems
Table 2
Transvaginal ultrasound
Transvaginal ultrasound to measure cervical length and funnelling has been studied as a screening test for preterm labour. It has
been shown to be safe, acceptable, and reproducible. Cervical
length at 24 weeks has been shown to be normally distributed
with a mean length of 35.2 mm 8.3 mm. In normal pregnancies
delivered at term, the cervical length stays relatively constant
until the third trimester.
There is an inverse relationship between cervical length and
incidence of preterm delivery and it has been shown that a
Factors associated with preterm labour

Uterine distension
Previous preterm
labour
Multiple pregnancy
Fertility treatment
Maternal stress
PRETERM LABOUR
Smoking
Decidual haemorrhage
Ascending infection
PPROM
Previous mid-trimester
miscarriage
Figure 1
13
REVIEW
correlation between the FFN value and the risk of preterm birth
where the higher the level of fetal fibronectin, the higher the
relative risk of delivery prior to 28 weeks. A recent study has
demonstrated that combining cervical length and quantitative
FFN levels can help predict spontaneous preterm birth in high
risk asymptomatic women. It has shown similar levels of accuracy in both singleton and twin pregnancies.
Risk factors for spontaneous preterm labour

Maternal
characteristics
Pregnancy
complications
Obstetric
history
Non-white ethnicity
BMI <19.8
Multiple pregnancy
Infection
Shortened cervix
Cervical surgery
e.g. Cone biopsy/
multiple LLETZ
procedures
1 previous preterm
labour 13e21% risk
2 previous preterm
labours 42% risk
Previous 2nd trimester
miscarriage
prev history of repeat
TOP
Age less than 18

and over 40
Poor nutrition
Bleeding
<24 weeks
Smoking
Low socioeconomic
status
Therapeutic interventions to prevent PTL in those at high

risk
Cervical suture
Cervical suture or cerclage has been widely used in the management of pregnancies at high risk of preterm delivery. It was
initially introduced as a treatment for cervical incompetence
where the cervix was believed to have some form of inherent
weakness. However, true cervical incompetence is very difficult
to diagnose, therefore it is not recommended as an indication for
a cervical suture. The current uses of cervical cerclage are as an
elective or preventative procedure, conducted on the basis of
previous history or ultrasound findings, or as an emergency,
when the cervix is found to be effacing and dilating at a previable gestation (a rescue cerclage as discussed below). Current recommendations are that a history-indicated cervical cerclage should only be offered to women with a history of three
spontaneous preterm births or mid-trimester losses. Such sutures
should be placed at around 14 weeks gestation. Women with a
history of fewer preterm births or second trimester losses should
be offered ultrasound surveillance.
There are three main forms of cervical suture, the Shirodkar
suture described in 1954, the Macdonald suture described in
1957 and abdominal cervical cerclage. The most common
method of cerclage used is the Macdonald suture, which is a
purse string suture around the cervix. A Shirodkar suture is
placed at the level of the internal os and requires dissection of the
vaginal mucosa and bladder, with the vaginal mucosa then
closed over the suture. A meta-analysis of Shirodkar vs Macdonald cervical cerclage was performed in women at high risk of
preterm birth and no differences were seen in the rates of preterm birth. Further analysis was carried out for those women
with short cervices diagnosed on ultrasound scan and again no
difference was seen in outcome between the two types of suture.
Abdominal sutures are used less often as they require more
specialist expertise, and tend to be used in women with an
extremely short, lacerated or scarred cervix or when transvaginal
cerclage has previously failed. A UK-based multicentre randomised controlled trial (MAVRIC) which compared outcomes
following repeat cervical suture via the vaginal route versus
abdominal suture in women who had previously had a failed
cervical suture is awaiting publication and until then, there is
little evidence to recommend one type of suture over another.
Abdominal sutures are usually inserted around 11e12 weeks
gestation, but can also be inserted pre-conceptually. There is no
current evidence to recommend laparoscopy over laparotomy for
the insertion of abdominal sutures. Approximately 80e90% of
those women who have an abdominal suture will deliver at term.
All types of cervical cerclage have associated complications, such
Table 3
Rates of diagnosis of PTL with FFN and transvaginal

scanning
Test
Delivery in 48
hours %
Delivery in
7 days %
Transvaginal Ultrasound
Cervix <15 mm
Fetal fibronectin
FFN ve
Both test used in conjunction
36.7
56.7
19.2
34.6
48.3
75
Table 4
length measurements, as most women who have suffered a

previous spontaneous preterm birth will deliver after 33 weeks.
Fetal bronectin
Fetal fibronectin (FFN) is an extracellular matrix glycoprotein
localized at the maternalefetal interface of the amniotic membranes, between chorion and decidua. Thus, it is found in the
cervico-vaginal secretions prior to labour in both preterm and
term labours. In a normal pregnancy, FFN should not be present
in cervico-vaginal secretions between 20 and 36 weeks gestation.
Only 3e4% of cervico-vaginal secretions between 21 and 37
weeks are positive for fetal fibronectin, suggesting disruption
between the membranes and the decidua has occurred.
In order to be accurate, the swab for FFN must be taken
correctly. The swab should be taken from the posterior fornix or
ectocervix. False positive results can occur with the use of
lubricant gel, recent sexual intercourse, vaginal bleeding, and
rupture of membranes.
Qualitative FFN kits are now available and a value of greater
than or equal to 50 ng/ml is considered to be associated with a
40% increased risk of spontaneous preterm birth. There is a
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REVIEW
agent, which acts by inhibiting myometrial contractions and

cervical ripening, down regulating gap junctions and inhibiting
chemokine production. Progesterone has been studied extensively to assess whether it is effective at preventing preterm labour. A recent meta-analysis has shown that progesterone
reduces the risk of PTL in women with a singleton pregnancy and
a previous history of a preterm delivery when compared with
placebo, with the number needed to treat to prevent one PTL
being 16. Progesterone has also been shown to reduce preterm
birth when administered to women with a short cervix. A metaanalysis of 775 women found that administration of vaginal
progesterone to asymptomatic women with a cervical length less
than 25 mm in the midtrimester was associated with a reduction
in preterm delivery and composite neonatal morbidity and
mortality. For this latter reason, progesterone is probably used
over cervical suture in the USA.
In the UK, concerns over neonatal outcomes have limited its
widespread use prior to the completion of an ongoing clinical
trial, OPTIMMUM (see below). A Cochrane review carried out in
2009 concluded that the use of progesterone in women with a
past history of spontaneous preterm labour was associated with a
reduction in delivery prior to 34 weeks gestation and 37 weeks
gestation. However, it also concluded that further information
was needed on the optimal route of administration and dose of
progesterone, as well as long term follow up data on the infants
health outcomes.
Although it may be beneficial in reducing the risks of preterm
labour in women at high risk, there is currently little evidence to
indicate an improvement in neonatal outcomes. One randomized
control trial, which included neonatal factors as secondary outcomes, suggested that treatment with progesterone significantly
reduced the rates of necrotizing enterocolitis and intraventricular
haemorrhage, and the need for supplemental oxygen. Only one
study has attempted longer term follow up of children whose
mothers were administered progesterone. This study showed no
effect of progesterone on either physical examination or development. However, there was significant loss to follow up and the
study was underpowered.
In contrast to singleton pregnancy, there is no evidence of
benefit from the use of progesterone in multiple pregnancies. The
largest double blinded randomised control trial of progesterone
in twin pregnancy was the STOPPIT trial. The primary outcome
was delivery or intrauterine death prior to 34 weeks gestation.
The results demonstrated that 24.7% of women in the progesterone group had either a delivery or fetal death in-utero prior to
34 weeks compared to 19.4% in the placebo group, showing that
progesterone does not reduce the combined risk. Other studies in
twin pregnancies using different progesterone regimes have had
similar results. Therefore, progesterone is of no benefit in multiple pregnancy, and may confer some harm.
Given the lack of evidence for long term benefit of progesterone treatment, and the hypothesis that maintaining a fetus in
adverse environment may be harmful, the RCOG Preterm Birth
study group issued a statement that progesterone use should be
restricted to randomised controlled trials. A UK multicentre
randomised controlled trial investigating progesterone use, the
effect on PTL and long term neonatal outcome (OPTIMMUM) is
as rupture of membranes, bleeding, pregnancy loss, bladder

injury and anaesthetic risks. Abdominal sutures remain in situ
and are not removed, and the baby is delivered by Caesarean
section. This poses particular problems in the event of a fetal
death in-utero and there are no studies to inform opinion on the
best way of managing this. It has been reported that successful
dilatation and curettage has been performed up to 18 weeks
gestation and there have been cases where the suture has been
cut via a posterior colpotomy. It may be that a hysterotomy or
Caesarean section is required, depending on the gestation.
Macdonald and Shirodkar sutures should be removed as soon as
possible if labour occurs (to prevent cervical laceration), or
electively before spontaneous labour, usually around 36 1e37
0 weeks gestation. A Macdonald suture can often be removed
without the need for anaesthetic, whereas a Shirodkar suture will
need an anaesthetic for removal.
Studies have suggested that ultrasound-indicated cerclage
may reduce the risk of preterm labour. A meta-analysis of 607
pregnancies from 4 randomised controlled trials suggested cerclage was associated with relative risk of 0.61 (95% confidence
interval 0.40e0.92) for delivery less than 35 weeks compared
with expectant management. This was similar to the largest
randomised control trial which suggested that cerclage in women
less than 22 weeks gestation when the cervix measured less than
25 mm reduced the rate of pre-viable delivery from 14% to 6.1%.
A recent (2012) Cochrane review has also suggested that cervical
sutures reduce the risk of PTL in women at risk, although there
was no reduction in perinatal death or neonatal morbidity.
Therefore, women with singleton pregnancies and a history of
PTL or second trimester loss should be offered a cervical suture if
the cervical length on ultrasound scan is less than 25 mm at less
than 24 weeks gestation. Studies have not shown any benefit for
cervical cerclage in women without any history of PTL or second
trimester loss, who have incidentally been found to have a
shortened cervix on ultrasound scan. Similarly, cervical suture
based on ultrasound or history should not currently be recommended to women with multiple pregnancy as there is evidence
that they may be harmful. All available studies of multiple
pregnancies are small and suggest either no benefit to cervical
sutures, or report increased premature delivery rates or losses in
association with suture use.
Cervical pessary
Given the controversies surrounding insertion of cervical sutures
in some situations, it has been suggested that insertion of a
pessary, which is a silicone ring that fits around the cervix, may
be beneficial instead. This would eliminate the operative risks
associated with insertion of cervical sutures. A recent Cochrane
review (2013) reported a favourable effect of cervical pessaries in
reducing preterm labour in those women found to have a
shortened cervix on transvaginal scanning. This review contained only one randomised controlled trial and further studies
are ongoing, including in multiple pregnancies, which may influence future practice.
Progesterone
Progesterone has been of interest for the prevention of preterm
labour for many years. Progesterone is an anti-inflammatory
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REVIEW
awaiting publication. However a recent NICE consultation

document on PTL has suggested that prophylactic progesterone
should be considered in women with a cervical length less than
25 mm even without a prior history of PTL. There is currently
limited evidence to guide the best dosing regimes and routes of
administration. The dosage being used by OPTIMMUM is a 200
mg vaginal pessary daily.
greater than or equal to 50 ng/ml has been shown to be a better

predictor of PTL than clinical assessments alone. However, the
main benefit of FFN is the high negative predictive value of
99%, which can allow clinicians the ability to avoid unnecessary interventions such as tocolysis and to reassure women.
An additional benefit of obtaining a FFN result less than 50 ng/
ml is that unnecessary admission and administration of steroids
can be avoided. Many units will have a policy of discharging
women with a negative FFN result. It is more difficult to make
clinical decisions on those women in whom symptoms of PTL
persist or in those who have a positive FFN result. A period of
inpatient monitoring may be suitable. Transvaginal ultrasound
in combination with FFN may be helpful in the diagnosis of PTL
in these cases, although this requires expensive equipment and
expertise. A study performed by Gomez et al looked at the use
of FFN and transvaginal ultrasound in the diagnosis of preterm
labour. The results of the study are shown below (Table 4).
They showed that the combining the use of these two diagnostic tests can identify 75% of those women who will deliver
within 7 days.
Genital swabs and use of antibiotics

Several organisms have been linked with PTL such as Ureaplasma urealyticum, Mycoplasma Hominis (those typically
associated with bacterial vaginosis), Trichomonas vaginalis,
Chlamydia trachomatis, and Neisseria gonorrhoeae. Antenatal
screening and treatment of asymptomatic vaginal infection has
shown conflicting results. One randomised controlled trial
showed that treatment of bacterial vaginosis found on routine
screening prior to 22 weeks gestation can reduce the rate of PTL
by 10%. Furthermore a large study with 2058 women in the
intervention group has shown that infection screening and
treatment in early second trimester, between 15 weeks and 19
weeks and 6 days, for bacterial vaginosis, T. vaginalis and
candidiasis can significantly reduce the preterm birth rate when
compared with control group (3% versus 5.3%). Furthermore,
screening and treatment of those women with infection was
found to be cost effective due to its reduction in neonatal care.
Other studies disagree although most of these have looked at
treating bacterial vaginosis up to 26 weeks of gestation. The
RCOG therefore suggest that treatment of BV prior to 20 weeks
gestation maybe beneficial in reducing PTL.
A more recent study has been carried out using prophylactic
azithromycin at 16 weeks and again at 24 weeks in a population
at high risk of preterm labour. This study has shown no significant reduction in PTL in these women when compared with no
treatment.
Treatment of PTL
Tocolysis
Several drugs have been investigated for their tocolytic properties, but, to date, no study has shown that tocolysis reduces
rates of preterm delivery or improves neonatal outcome.
However, pregnancy can be prolonged for up to 48 hours in
approximately 80% of cases, which beneficial in allowing time
for administration of corticosteroids and in-utero transfer. The
main tocolytics used in the United Kingdom are COX inhibitors
(e.g. Indomethacin), calcium channel blockers (e.g. nifedipine)
and oxytocin antagonists (e.g. Atosiban). It should be noted,
however, that the only licensed drugs in the UK for this indication are Ritodrine and Atosiban. Ritodrine, a b-2 adrenergic
receptor agonists, which induced uterine relaxation, was previously used but is no longer recommended due to significant
adverse maternal side-effects.
Diagnosis of PTL
The presentation of women to the labour ward with symptoms
suggestive of threatened PTL is common, but diagnosis is
hampered with inaccuracy. Only a small proportion, 8%e24%,
of those who present with symptoms will go on to deliver prematurely. The diagnosis is usually made on the clinical basis of
regular uterine contractions associated with cervical change, as
assessed on vaginal examination. The poor association between
clinical symptoms and the likelihood of delivery means that a
large number of women receive treatment unnecessarily, and
this also causes significant problems for trials of potential treatments. Therefore, a better means of diagnosis is needed to prevent women receiving steroids, tocolysis and possible transfer to
a tertiary centre unnecessarily, all of which represent a significant financial cost to NHS resources.
FFN has been shown in some studies to be of predictive
value in women presenting with symptoms of preterm labour
with intact fetal membranes. A recent meta-analysis of 32
studies suggested that FFN is a good short term predictor of
preterm birth with a sensitivity of 76% and specificity of 81%
for delivery within the next 7 days. A fetal fibronectin value of
Nifedipine
Nifedipine is not licensed for use in threatened preterm labour
and there have been no randomised control trials of nifedipine
versus placebo in the treatment of threatened preterm labour.
However, in comparison to other tocolytic drugs (usually betaagonists), nifedipine appears to reduce the risk of delivery with
one week of administration and before 34 weeks gestation.
Nifedipine is the only tocolytic drug for which there are any reports of neonatal benefit, in that it was associated with less
respiratory distress, less necrotising enterocolitis and less risk of
intraventricular haemorrhage. Nifedipine is also associated with
maternal side effects including flushing, headache, palpitations
and hypotension. In particular, nifedipine should be avoided in
women with cardiac disease and care should be taken in women
with diabetes or multiple pregnancy, as there are reports of
pulmonary oedema in the literature.
Advantages of nifedipine over other tocolytics are that it is
cheap and can be given orally. There is no standard protocol
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REVIEW
for the administration of nifedipine but the suggested dose

is currently an initial oral dose of 20 mg, followed by 10e20
mg 3e4 times per day for up to 48 hours. This can be adjusted
in response to observed uterine activity. Total doses higher
than 60 mg are associated with an increased risk of side
effects.
Emergency cervical sutures (Rescue sutures)

Emergency cervical sutures are performed when the cervix is
objectively open and the membranes are at or below the
external os prior to 26 weeks gestation. In a retrospective
study over an 8 year period, 46 emergency cervical cerclages
were inserted with a 44% success rate for delivery after 36
weeks; this is similar to other studies quoting a 50% success
rate. There is limited availability of prospective data, with only
one randomised control trial that included 23 women.
Compared to expectant management, a rescue suture may increase the length of the pregnancy by 4e5 weeks. Indicators of
poor outcome are membranes below the external os, dilatation
over 4 cm, signs of infection (raised C-reactive protein or white
blood cell count) and continued vaginal bleeding. Failure of
the suture was also closely associated with post delivery
chorioamnionitis.
Atosiban
Atosiban is the only drug licensed for treatment of threatened
preterm labour in common use in the UK. It is a competitive
oxytocin antagonist that acts at the uterine oxytocin receptors. It
is given as an initial bolus of 6.75 mg over 1 minute, followed by
an infusion of 18 mg/hour for 3 hours then reduced to 6 mg/hour
for up to 45 hours. Similar to nifedipine, it should only be
continued for 48 hours.
Atosiban has not been shown to reduce the preterm labour
rate when compared with beta-agonists or to improve neonatal
outcomes. There is a report of a higher number of neonatal
deaths in the atosiban compared with placebo group, but this
could have been due to a higher number of women at less than
26 weeks gestation randomised to the atosiban group. Atosiban
has also been compared with betamimetics, such as salbutamol,
terbutaline and ritodrine. In these studies, atosiban efficacy was
similar to betamimetics, in that it did not significantly alter delivery before 48 hours. However, atosiban was better tolerated
than betamimetics. Reported side effects for atosiban include
nausea, vomiting, chest pain and dyspnoea. Importantly, atosiban is not contraindicated in cardiac disease or diabetes. There
has been no direct comparison of atosiban and nifedipine in
clinical trials.
Antibiotics
Extreme preterm birth is usually associated with infection, most
commonly ascending infection from the vagina and several
studies have assessed antibiotic use in the prevention of preterm labour. The largest study performed to date was the
ORACLE II study which investigated women presenting with
symptoms of spontaneous preterm labour with intact membranes. The primary outcome was a reduction in neonatal
death with the use of antibiotics. The routine prescribing of
antibiotics to women in spontaneous preterm labour did not
reduce neonatal death, but did reduce the risk of maternal
infection. Further follow up of the participants of the ORACLE II
study at 7 years found an increased risk of cerebral palsy in the
children who received antibiotics (odds ratio 1.93 (95% confidence interval 1.21 to 3.09) for erythromycin and 1.69 (1.07
e2.67) for co-amoxiclav). When antibiotics were combined,
risks were higher still than with erythromycin alone (4.55% v
2.29%). It has been suggested that the use of antibiotics could
be masking a subclinical infection and keeping a baby within a
hostile environment longer, thus increasing the risk of cerebral
palsy. Therefore, routine prescription of antibiotics is not recommended in the presence of intact membranes and should be
restricted to specific clinical indications such as chorioamnionitis, group B streptococcus and prelabour premature rupture
of membranes.
COX inhibitors
There are several cyclo-oxygenase inhibitors used for tocolysis,
such as Ketorolac, Celecoxib, Indomethacin and Sulindac. The
one most commonly used in the UK is Indomethacin. When COX
inhibitors have been compared with other tocolytics such as
ritodrine they have equal efficacy at prolonging gestation for 48
hours. COX inhibitors inhibit uterine contractions, are easily
administered and have few maternal side-effects. However,
adverse effects have been reported in the newborn following
exposure to COX inhibitors, including premature closure of the
ductus arteriosus, renal and cerebral vasoconstriction, and
necrotising enterocolitis. For these reasons, indomethacin is
usually used in the UK at only very early gestations.
In summary, there is no good evidence that tocolysis is of
clinical benefit. It therefore is reasonable not to administer any
tocolytic drug. At best, tocolysis delays delivery by between 48
hours and 7 days, giving enough time for corticosteroids to be
administered, or for in-utero transfer to occur. Choice of drug
varies with unit policy but first line agents are usually atosiban
or nifedipine, with indomethacin only being administered at
less than 32 weeks gestation. Nifedipine and atosiban are
probably of similar effectiveness and both have an acceptable
side effect profile. There are no studies of cost effectiveness, but
atosiban costs substantially more than nifedipine. There is
insufficient evidence for the use of tocolysis in multiple pregnancies, but case reports associating nifedipine with pulmonary
oedema suggests that atosiban should be first line in these
women.
Corticosteroids
Corticosteroids are used in PTL to increase fetal surfactant and
accelerate fetal lung maturity. They have been shown to be
beneficial in reducing neonatal death, respiratory distress syndrome (RDS), necrotising enterocolitis, cerebrovascular haemorrhage and neonatal intensive care admissions. For maximum
benefit, the optimum time between administration of steroids
and delivery is from 24 hours to 7 days, though there has been a
trend towards benefit following 7 days. In addition, studies have
shown a reduction in risk of neonatal death where there has been
less than 24 hours between steroid administration and birth;
therefore steroids should still be used if delivery is likely within
this time period. A single course of corticosteroids, two intramuscular injections of 12 mg betamethasone 24 hours apart or
four doses of 6 mg dexamethasone 12 hours apart, has been
shown to confer no harm to the fetus in long term follow up
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REVIEW
of neonatal deaths. In the US, preterm birth is the most frequent

cause of infant death, accounting for one third of infant mortality in
2002. Prolonging a pregnancy from 30 weeks to 34 weeks gestation
decreases the in-hospital mortality from 8.1% to 0.4%. Respiratory
distress syndrome also reduces from 43.8% at 30 weeks gestation
to 2.6% at 34 weeks, even with steroid use in both groups. Therefore, the ability to prolong a pregnancy has the potential to have a
huge impact on the health of the child. Understanding more about
the mechanisms of term and preterm labour is essential to identify
targets for novel therapies to prevent PTL.
Despite significant advances in neonatal care, preterm delivery is still the largest cause of neonatal morbidity and
mortality. The UK multicentre study EPICure collected data on
2327 births in 2006 between 22 weeks and 25 weeks 6 days. Of
these births, 72% of babies survived to be admitted to neonatal
units and of these 61% survived to be discharged. The survival
rates at discharge from hospital show a great improvement
from the previous EPICure study in 1995, in which only 39%
of those admitted to neonatal units were discharged home.
There is also improvement of those children being disability
free at the age of 3 years of age. With approximately 49%
being disability free at 2.5 years, while in 2006, 69% of the
surviving children were disability free. Despite these advances
in neonatal care, the morbidity and mortality of premature
delivery remains high.
The Nuffield Council on Bioethics has developed guidelines
on the critical care in fetal and neonatal decisions. In this report it
is stated that normal practice of full intensive care and support
should be offered to all neonates from 24 weeks gestation, unless
the patient or clinicians decide it is not in the babys best interests due to her/his condition. They also state that between 23
weeks, 0 days and 23 weeks, 6 days, precedence should be given
to the wishes of the parents as to whether they wish for full
intensive care for the child. However, this should not be
completely against clinical judgement, if treatment would be
futile. Prior to 23 weeks, it suggested that resuscitation should
not be offered.
In conclusion, PTL remains poorly understood. Treatment and
diagnostic strategies continue to be limited in their success.
Further research is needed within this area to improve preventative strategies and treatment of PTL.
A
studies and every effort should be given to administer steroids to

all women at risk of preterm labour between 24 and 346 weeks
gestation. It has also been shown that there is benefit in treating
women up to 36 weeks gestation, though the number needed to
treat to prevent one case of RDS is considerably increased. Steroids can be considered between 23 0 and 23 6 weeks
gestation as they may confer benefit. However, the RCOG suggest
that it should be a senior decision to administer at this extreme
gestation, with careful consideration of the whole clinical
picture.
There has been considerable debate about the use of repeat
doses of corticosteroids in women who have not delivered within
7 days but remain at risk of delivery. Studies have shown
(including a recent Cochrane review) that repeated doses probably reduce the risks of neonatal lung disease and other short
term outcomes. However, there is also evidence from human and
animal studies showing that repeated courses of steroids may be
associated with reduced growth and smaller head size. Animal
studies have suggested adverse effects on brain function.
Therefore, current RCOG recommendations is that repeat doses
are not advised but cautious use of a single rescue course can be
considered where the initial dose was given at less than 26 weeks
gestation.
Magnesium sulphate
Risks of cerebral palsy are significant in preterm infants, with
rates of 14.6% being reported at less than 28 weeks gestation and
6.2% between 28 and 31 weeks. Although magnesium sulphate
is not recommended as a tocolytic agent, there is evidence from
several studies suggesting that maternal administration of magnesium sulphate may reduce the risks of cerebral palsy in the
preterm neonate. A Cochrane review reported that magnesium
sulphate was associated with a lower relative risk of cerebral
palsy of 0.68 (95% confidence interval 0.54e0.87) and lower
relative risk of gross motor dysfunction of 0.61 (95% confidence
interval 0.44e0.85). Whilst the dose regimen remains unclear,
consideration of magnesium sulphate for neuroprotection at the
same doses given for the prevention of eclampsia should be a
consideration for women at risk of severe preterm delivery (less
than 32 weeks).
Delayed cord clamping
It has been suggested that delayed cord clamping after preterm
delivery may be associated with improved neonatal outcomes.
Delaying clamping for between 30 and 120 seconds improves
placental perfusion and increases the infants blood volume at
birth by around 30%. A 2012 Cochrane review suggested that it
reduced the need for blood transfusion and reduced the risks of
necrotising enterocolitis and intraventricular haemorrhage.
However, it was also associated with higher serum bilirubin level
(and therefore increased need for phototherapy). There was
insufficient data to conclude on the effects on severe brain injury
and neonatal mortality.
FURTHER READING
1 Abdel-Aleem H, Shaaban OM, Abdel-Aleem MA. Cervical pessary
for preventing preterm birth. Cochrane Database Syst Rev 2013;
http://dx.doi.org/10.1002/14651858.CD007873.pub3.
2 Costeloe KL, Hennessy E, Haider S, Stacey F, Marlow N,
Draper ES. Short term outcomes after extreme preterm birth in
England: comparison of two birth cohorts in 1995 and 2006 (the
EPICure studies). BMJ 2012; 345: e7976.
3 Kenyon S, Pike K, Jones DR, et al. Childhood outcomes after
prescription of antibiotics to pregnant women with spontaneous
preterm labour: 7-year follow-up of the ORACLE II trial. Lancet
2008 Oct 11; 372: 1319e27.
4 Moore T, Hennessy EM, Myles J, et al. Neurological and
developmental outcome in extremely preterm children born in
Consequences of preterm birth

Preterm birth contributes to substantial neuro-cognitive, pulmonary, and ophthalmologic morbidity and globally accounts for 28%
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REVIEW
7
8
9
10
England in 1995 and 2006: the EPICure studies. BMJ 2012; 345:
e7961.
Norman JE, Mackenzie F, Owen P, et al. Progesterone for the
prevention of preterm birth in twin pregnancy (STOPPIT): a randomised, double-blind, placebo-controlled study and meta-analysis. Lancet 2009; 373.
Rabe H, Diaz-Rosello JL, Duley L, Dowswell T. Effect of timing of
umbilical cord clamping and other strategies to inuence placental
transfusion atpreterm birth on maternal and infant outcomes.
Cochrane Database Syst Rev 2012; http://dx.doi.org/10.1002/
14651858.CD003248.pub3.
RCOG Green-top Guideline No. 7. Antenatal corticosteroids to
reduce neonatal morbidity and mortality October 2010.
RCOG Green-top Guideline No. 1b. Tocolysis for women in preterm labour. February 2011.
RCOG Green-top Guideline No. 60. Cervical cerclage. May 2011.
RCOG Scientic Impact Paper No. 29. Magnesium sulphate to
prevent cerebral palsy following preterm birth. August 2011.
Practice points
C
C
19
The aetiology of PTL is multifactorial

Antenatal corticosteroids for are the only drug proven to improve
neonatal outcome in PTL
Tocolysis can at best delay PTL for long enough for the maximum
benefit of steroids
Diagnosis of PTL is difficult but can be improved with use of FFN
and Cervical scanning
Cervical cerclage in selected patients may prolong pregnancy but
there is limited evidence of neonatal benefit
Further research is needed to investigate the use of progesterone
for the prevention of PTL in women at risk prior to its widespread
use
Magnesium sulphate and delayed cord clamping have potential to
improve some neonatal outcomes
REVIEW
Surgical management of
stress urinary
incontinence
available conservative and surgical options for treating SUI and

up to date guidelines to be able to counsel women appropriately
and obtain informed consent for surgery.
Initial assessment
The NICE guideline CG171 Urinary Incontinence: The Management of Urinary Incontinence in Women, published in 2013 recommends that a history is taken to categorise urinary
incontinence into stress, mixed incontinence or urge incontinence and that treatment is started accordingly. Initial assessment should aim to identify relevant predisposing and
precipitating factors and other diagnoses that may require
referral for additional investigation and treatment (Box 1). Desire
for future childbearing should be elicited as this may influence
the choice of treatment. A bladder diary should form an integral
part of preoperative assessment as it can give valuable information on fluid intake (type and amount) and frequency and
volume of voids.
Rashda Imran
Rohna Kearney
Abstract
Women are seeking treatment for stress urinary incontinence more
readily due to increasing awareness of minimally invasive surgical solutions and greater expectations of pelvic oor health with advancing
age. Concerns have been raised regarding the safety of tape procedures and clinicians need to be aware of the recent guidance published on this by the MHRA. Surgery for stress urinary incontinence
should only be undertaken in women following a comprehensive
assessment and when conservative treatments have failed after a
multidisciplinary team discussion. The current evidence favours a
retro-pubic mid-urethral tape procedure using the bottom-up
approach, or colposuspension. Pubo-vaginal slings using autologous
rectus sheath fascia have a good success rate, but also have signicantly higher incidence of operative morbidity and voiding problems.
Urethral bulking agents are a safe alternative, especially in those
women where more invasive surgery is not desired. It is important to
counsel that they have a lower success rate and repeat injections
are often needed.
Management of stress urinary incontinence

Conservative management in terms of supervised pelvic floor
muscle training by a trained pelvic floor physiotherapist should
be offered prior to surgery. Other conservative measures in terms
Assessment of women with urinary incontinence
Keywords incontinence procedure; stress urinary incontinence
History
C
Age
C
Parity
C
Severity of incontinence, pad usage
C
Overactive bladder symptoms
C
Voiding
C
Fluid intake e type and amount
C
Prolapse
C
Bowel symptoms, constipation and faecal incontinence
C
Sexual function, coital incontinence
C
Previous surgery
C
Medical health including current medications
C
Neurological symptoms
C
Future childbearing wishes
C
Social history and lifestyle
C
Concerns, expectations and wishes for treatment
Introduction
The International Continence Society defines stress urinary incontinence (SUI) as any involuntary leakage of urine on exertion
or effort, or on sneezing or coughing. A recent postal survey of all
women over the age of 21 years from a single UK GP practice
reported that 40% of women suffered from urinary incontinence
with 8.5% reporting that it caused significant problems. Stress
urinary incontinence was the most common type. Obesity and
parity are significant risk factors for SUI.
Many women suffer in silence in the belief that it is a condition of old age for which nothing can be done. As women are
becoming more aware of the improvements in the treatment
choices for urinary incontinence there is a rise in the number of
women seeking treatment for SUI. However media reports and
patient advocacy groups have raised concerns regarding the use
of synthetic material to treat stress urinary incontinence leading
to the suspension of synthetic mid-urethral tapes in Scotland in
2014. Hence gynaecologists need to be aware of all currently
Examination
C
BMI
C
Blood pressure
C
Urinalysis
C
Cardiovascular, respiratory status
C
Abdominal masses, scars
C
Vulval skin e excoriation, oedema, atrophy, lichen sclerosis
C
Prolapse
C
Pelvic floor muscle function
C
Pelvic masses
C
Neurological e tone, power, anal reflex
Rashda Imran MRCOG is a Clinical Fellow in Obstetrics and

Gynaecology at St Marys Hospital, Manchester, UK. Conicts of
interest: none.
Rohna Kearney MD FRCOG is a Consultant Urogynaecologist at St
Marys Hospital, Manchester, UK. Conicts of interest: none.
Box 1
20
REVIEW
of lifestyle modifications such as fluid management, weight loss

and smoking cessation should also be emphasised. Treatments
such as duloxetine and continence devices may be considered
but are not recommended routinely as first line treatment
(Figure 1).
Kelly plication anterior repair, MarshalleMarchettieKrantz

(MMK) and needle suspensions procedures are no longer
recommended.
Mid-urethral tapes
Mid-urethral tapes are the most commonly performed procedure
for stress urinary incontinence. Women have reported serious
and debilitating problems following these procedures and the
MHRA, at the request of the Chief Medical Officer of England,
have published a summary on the benefits and risks of vaginal
mesh implants. The MHRA reports that at 10 years following
surgery significant long-term benefits are achieved in the majority of women and that the overall benefit outweighs the relatively low rate of complications. The three most common type of
tapes performed are retropubic, transobturator and mini-slings.
A tape manufactured from type 1 polypropylene is
recommended.
Surgery for stress urinary incontinence

When conservative management has failed a discussion
regarding surgery should take place. NICE guidelines recommend
that urodynamics are not performed in the small group of women
in whom a history of pure stress incontinence is elicited with
normal assessment. However two professional bodies, British
Society of Urogynaecology (BSUG) and British Association of
Urological Surgeons (BAUS) recommend urodynamics for all
women prior to surgery for SUI. A systematic review of women
undergoing surgery for stress urinary incontinence or stress
predominant incontinence reported that urodynamics did not
improve outcome.
NICE recommends that women considering surgery are
informed about the risks and benefits of surgery and non-surgical
options and that surgery is only offered after a multi-disciplinary
team review. The procedures that NICE recommends are retropubic mid-urethral sling, open colposuspension or an autologous
rectus fascial sling. These procedures are discussed below.
Women should be offered written information on all the options
for surgery and given time to fully consider their choices.
Retropubic tapes
Bottom-up approach: the original tension free vaginal tape
(Gynecare, TVT) procedure was described by Ulmsten in 1996.
The tape measures 40 cm long by 11 mm wide. There are many
other similar tapes on the market. The TVT has now virtually
replaced the Burch colposuspension as the operation of choice
for a primary procedure for SUI in view of being minimally
invasive procedure with low intra and post-operative morbidity,
quicker recovery and equivalent long term success rates.
Management of stress urinary incontinence

Lifestyle changes
Pelvic floor muscle training
Consider urodynamics
Offer invasive therapy
Multidisciplinary team review
Retropubic mid-urethra
synthetic sling
Colposuspension
Urethral bulking agents
Rectus fascia sling
Transobturator synthetic sling
Adapted from NICE guidelines.

Recommended procedures highlighted in red. Other procedures that may be considered are in green.
Figure 1 The management of stress incontinence.
21
REVIEW
Technique e the TVT sling procedure is performed through a

small suburethral incision in the vagina and two small lower
abdominal incisions (2 cm each side of the midline) above the
pubic bone. It may be done with either local or general anaesthesia. Prilocaine and adrenaline diluted with saline is injected in
the retropubic space for hydrodissection followed by incisions as
above. Vaginal wall tissue is dissected off the urethra to expose
the midurethra along with paraurethral dissection toward the
endopelvic fascia. A catheter guard is then placed to deflect the
bladder away.
The TVT trocar attached to the tape is then advanced from the
vaginal incision through the space of Retzius and to the anterior
abdominal wall. The trocar must hug the posterior wall of pubic
symphysis during this manoeuvre (Figure 2) to reduce the risk of
bowel perforation. After a cystoscopy, to rule out bladder
perforation, the plastic sheath covering the tape is removed and
the tape is adjusted without excessive tension. The tape is then
trimmed and the vaginal and skin incisions are closed with
absorbable sutures.
Outcome evidence e TVT is the most extensively evaluated
procedure. The longest reported follow-up to date by Nilsson
et al. showed a subjective and objective cure rate of 77% and
90% at 11.5 years after TVT.
Reich et al. found an objective cure rate of 89.8% at a mean
follow-up of more than 7 years. In a multicentre randomised trial
comparing TVT with colposuspension, results at 5 years followup show equal efficacy of TVT to colposuspension for cure of
stress urinary incontinence (81% for TVT and 90% for colposuspension, P 0.21).
Voiding dysfunction, development of de novo urgency,
bladder injury, vascular injury and haemorrhage and mesh
erosion and vaginal extrusion are the commonly reported complications. One of the main surgical complications is bladder
injury, however in most cases it has no long term effects if recognised at the time and the trocar repositioned. The reported
incidence of bladder injury in literature is 1e10%. A combined
experience of 92 surgeons indicated a 7% bladder perforation
rate in a study population of over 12,000 patients. Bowel injury is
a rare but potentially fatal complication of retropubic tapes.
Top-down approach (Suprapubic Arc e SPARC Sling System):

the top down approach was developed with a view to more
control over the passage of the needles in the retropubic space.
The SPARC Sling system (American Medical Systems) consists of
two disposable needles with dilator-connector tips to create the
sling tract and also help to attach the ends of the plastic sheath
enclosing the mesh. The mesh is a 4e0 loosely knitted polypropylene with an absorbable tensioning suture within.
Outcome evidence e a randomised controlled trial (RCT) of
TVT and SPARC in 301 operations showed similar objective cure
rates at 6 weeks (97.3% vs 97.4%) but a higher subjective cure
rate with TVT (87.1% vs 76.5%). A retrospective study
comparing TVT and SPARC in 122 women showed higher
objective (95% vs 70%) and subjective (86% vs 60%) cure rates
as compared with the TVT procedure. A retrospective study of 46
patients who had the SPARC procedure reported a subjective
cure rate of 52% and an objective cure rate of 76% at 5 years.
The complications and success rate are similar to the TVT
procedure. Acute urinary retention requiring loosening of the
tape is more common after the SPARC procedures. This procedure is not commonly performed in the UK.
Transobturator tapes
In the Netherlands in 1998, Nickel et al. reported a successful
sling procedure using a polyester ribbon passed through the
obturator foramen and around the urethra for treatment of refractory urethral sphincter incompetence in female dogs. In
France in 2001, Delorme introduced the transobturator sling
procedure in humans. This was an outside-in procedure (TOT).
Dargent et al. then performed the operation in 71 patients using
the technique introduced by Delorme and found the short-term
results of the transobturator sling procedure similar to those of
the TVT. The aim of this technique as compared to TVT was to
decrease the risk associated with the passage of trocars in the
retropubic space, especially the risk of bladder or bowel injury.
Subsequently an inside-out procedure (Gynecare TVT-O) was
introduced by J de Leval.
Outside-in approach (TOT):
Technique e the patient is placed in lithotomy position with
hyper flexion of the hip to 120 which is different from the 70
used in the retropubic procedures. A vaginal incision is made at
the level of midurethra and dissection is done laterally towards
the ischiopubic ramus. A small skin incision is made on either
side 1.5 cm lateral to the ischiopubic ramus. Using specially
designed needles the obturator membrane is perforated and then
the needle is turned medially. It is then guided with a finger in
the vaginal incision to exit in the vagina. The tape is then loaded
on to the needle and pulled through the skin incision. Tension is
adjusted so that a dissecting scissors can lie flat easily between
the tape and urethra. The incisions are closed with absorbable
sutures. Cystoscopy was originally not described as necessary
after this procedure, however with case reports of bladder &
urethral injury following this procedure it is good practice to
perform a cytoscopy.
Inside-out approach (TVT-O):
Technique e the TVT-O procedure uses plastic tubes containing the tape, helical passers and an introducer (Figure 3). The
Figure 2 Anatomical diagram demonstrating the placement of a retropubic midurethral tape.
22
REVIEW
Mini slings (single incision slings)

The 3rd generation mini-slings inserted via a single incision were
introduced in 2006 to theoretically reduce iatrogenic morbidity and
complications associated with the retropubic and transobturator
tapes. The TVT-Secur (TVT-S; Gynecare) was described first and
subsequently a number of other single-incision slings such as
MiniArc (American Medical Systems) were reported. These tapes
do not have exit points on the skin and have different types of self
anchoring tips. They can be performed under a local anaesthetic as
a day case procedure with low morbidity.
Outcome evidence: the Cochrane group identified 31 trials of
mini-slings and reported that women were more likely to remain
incontinent after mini-sling surgery compared with retropubic
tapes and inside-out transobturator slings. The adverse event
profile was worse with mini-slings although long-term pain
appeared to be lower. Most of this data was from the TVT-Secur
which has now been withdrawn from use. NICE guidance states
that the outcome evidence of single-incision slings for safety and
efficacy is inadequate and that they should only be used as part
of research or submission to BSUG database.
Figure 3 Anatomical diagram demonstrating the placement of a

transobturator midurethral tape using inside-out technique.
vaginal incision and dissection are the same as in the outside-in

approach. The obturator membrane is punctured with scissors
and the introducer (wing guide) is passed at a 45 angle through
the vaginal incisions. Groin incisions are made at a point 2 cm
above the urethra and 2 cm lateral to the inner thigh folds. The
tubing attached to the helical passer is placed within the introducer (wing guide) and rotated to exit through the groin incisions. The tubing is then pulled from the passer as the passer is
brought back out through the vaginal incision and the tape is
pulled through.
Outcome evidence for comparison between retropubic and
transobturator tapes
A multicentre, randomised equivalence trial by Richter et al.
comparing outcomes with RP and TO slings at 12 months
showed that objectively assessed success rates with both approaches met the criteria for equivalence. A systematic review
and meta-analysis comparing transobturator and retropubic
tapes in women with intrinsic sphincter deficiency by Ford et al.
reported that the need to undergo repeat surgery in the long term
was higher with the transobturator route (RR14.4, CI 1.95e106).
There is a lower incidence of bladder and bowel injury with the
transobturator approach, however the incidence of vaginal perforations or erosions and groin pain are reported to be higher
than the retropubic approach.
A prospective RCT comparing TVT and TOT in 87 patients
with a median follow-up of 100 months reported a mid to longterm trend of decreasing continence rates in patients undergoing TOT compared with a stable rate for TVT.
Outcome evidence for comparison between outside-in and
inside-out tapes
One of the first reported direct meta-analysis by Madhuvrata
et al. comparing both routes of transobturator tapes showed no
significant difference in efficacy and impact on womens QOL at
1-year follow-up. However the inside-out route was associated
with significantly fewer vaginal angle injuries but with trends
towards higher risk of postoperative groin pain. Similarly a single
blind RCT of 341 women comparing TVT-O to TOT (Aris) reported no difference in subjective and objective cure rate at 1 and
3 years but a fall in success in both groups at 3 years.
Colposuspension
The Burch procedure was originally described in 1961. The most
commonly performed colposuspension is the Tanagho modification of a Burch colposuspension published in 1976. He recommended tying the suspension sutures from the endopelvic
fascia on either side of the urethra and bladder neck to the iliopectineal ligaments, without excessive elevation and compression of the urethra against the posterior surface of the symphysis
pubis. The aim was to reduce the voiding dysfunction and irritative voiding symptoms associated with the Burch colposuspension. This method has now been considered the gold
standard for a long time. Vancaille and Schuessler described a
laparoscopic method of colposuspension in 1991.
Technique: in open colposuspension, the retropubic space is
entered through a low transverse abdominal incision and blunt
dissection. Two non absorbable sutures are placed on each side
in the endopelvic fascia on either side of the urethra and bladder
neck and these sutures are attached to the ipsilateral iliopectineal
ligament. The sutures are tied without causing hyper elevation of
the urethra.
In the laparoscopic approach, three or four ports are used
(umbilical, suprapubic and two lateral). Either a transperitoneal
or extraperitoneal approach can be used to enter the space of
Retzius. Two non absorbable sutures are placed in either side as
in open procedure.
Complications of colposuspension include haemorrhage and
bladder trauma. Cystoscopy is recommended at the end of the
procedure to rule out bladder trauma and confirm ureteric
patency. The other potential complications include voiding difficulties, de novo urgency, chronic pain, dyspareunia, osteitis
pubis and prolapse especially of the posterior compartment. The
decision to perform an open or laparoscopic procedure depends
upon the skills of the surgeon. The laparoscopic procedure requires the surgeon to have advanced laparoscopic suturing skills.
NICE guidelines state that laparoscopic colposuspension should
be undertaken only by an experienced laparoscopic surgeon
23
REVIEW
working in a multidisciplinary team with expertise in the

assessment and treatment of urinary incontinence.
procedure for primary stress incontinence but can be considered

in women who do not want a synthetic tape procedure.
Outcome evidence: colposuspension has the longest follow-up

data of all operations for stress urinary incontinence. The
overall long term success rates are reported as 68.9%e88.0%.
Carey et al. and Kitchener et al. published RCTs in 2006
comparing open and laparoscopic colposuspension. Both
showed no significant difference in the objective and subjective
cure rate between open and laparoscopic procedures at 24
months. Urinary retention rate of up to 21% has been reported
and the risk of de novo urinary urgency has been reported as
5%e30 %. Richter et al., very recently, studied patient-related
factors associated with long-term urinary continence after
Burch colposuspension or pubovaginal fascial sling surgery for
stress urinary incontinence and found that preoperative and
postoperative urgency incontinence symptoms, prior stress urinary incontinence surgery, Burch urethropexy, and menopausal
status were significantly and negatively associated with longterm continence rates. A systematic review of 39 trials
comparing retropubic tapes, colposuspension and pubovaginal
slings reported that women experienced slightly better cure rate
with RT tapes than with colposuspension but a higher intraoperative complication rate.
Urethral bulking agents

Injectable therapy using bulking agents composed of synthetic
materials, bovine collagen, or an autologous substance augments the urethral wall by creating artificial cushions in the
urethral submucosa, improving urethral coaptation, increasing
urethral resistance to urinary flow and hence preventing urinary
leakage. They can be performed as an outpatient procedure,
injected transurethrally or paraurethrally with or without
cystoscopic guidance. The ideal agent for injection should be
long lasting, hypoallergenic, and non-migratory and should
cause the least inflammatory response. There are various agents
available at present such as GAX-collagen (Contigen), ethylene
vinyl alcohol copolymer (Uryx), carbon-coated zirconium beads
(Durasphere), calcium hydroxyapatite (Coaptite), vulcanised
silicone (Macroplastique) and polyacrylamide (Bulkamid).
NICE guidance states that the current evidence on safety and
short term efficacy of intramural urethral bulking procedures is
adequate to support the use of these procedures provided normal
arrangements are in place for clinical governance and audit. It
also states that patients should be counselled that the benefits of
these procedures diminish in the long term but there is a scope of
repeating the procedure.
Autologous fascial slings (AFS)

Historically, surgeons have used fascial slings for recurrent SUI.
Furthermore, this operation has been used extensively for the
treatment of primary ISD. There has been resurgence in interest
in autologous fascial slings with greater understanding of the
mechanism of urinary continence following DeLanceys
hammock theory and Petros and Ulmstens integral theory.
Technique: the procedure is performed usually with autologous material such as rectus sheath or fascia lata. A lower
abdominal transverse incision is made and a strip of rectus
sheath of adequate length and width, usually 10 cm by 2 cm is
harvested. Sutures are attached to each end of the strip of rectus
sheath. The vagina is incised at the level of the bladder neck and
the retropubic space is dissected bilaterally. A retropubic needle
is inserted suprapubically and directed towards the vaginal
incision, sutures attached to the sling are pulled up and the end
of the sling is brought up to the rectus sheath. The sutures are
then tied to the lower edge of the rectus sheath after adjusting the
tension on the sling. The Aldridge method leaves the end of the
sling attached to the rectus sheath medially cystoscopy is performed at the end to confirm that suspension sutures have not
traversed the bladder.
Outcome evidence: a Cochrane review of periurethral injection

therapy for urinary incontinence in women in 2012 included 14
trials and reported there is insufficient data for meta-analysis. It
also suggested that transurethral route resulted in fewer complications than paraurethral administration.
Recurrent stress urinary incontinence

There is no consensus on the correct procedure for the management of recurrent stress urinary incontinence. However it is
recommended that these patients are evaluated in the context of
a subspecialty level service incorporating multidisciplinary
assessment. A thorough assessment of these patients is critical
to detect any detrusor overactivity. The most commonly performed procedures for primary stress incontinence is a suburethral sling and many tertiary centres reserve colposuspension
and autologous fascia pubovaginal slings for recurrent incontinence. A recent systematic review and meta-analysis by Pradhan
et al. showed good cure rates of SUI after mid-urethral sling
surgery following previous incontinence surgery (62e100%).
There seemed to be a lower cure rate with transobturator
compared to the retropubic tape for recurrent SUI after previous
surgery.
Outcome evidence: a multicentre RCT comparing the pubovaginal sling using autologous rectus fascia and the Burch colposuspension by Albo et al. showed that at 24 months the success
rate was higher with the autologous fascial sling (66% vs 49%, P
< 0.001). However the incidence of urinary tract infections,
voiding difficulty and postoperative urge incontinence was
higher with the autologous fascial slings. Autologous fascial
slings are an appropriate procedure for recurrent stress incontinence. The greater operative morbidity, longer recovery and
higher incidence of voiding difficulty makes it a less suitable
Articial urinary sphincter (AUS)

Foley described an artificial sphincter in 1947 that was an
externally worn urethral cuff attached to a pump kept in the
patients pocket. The first artificial urinary sphincter to resemble
the current model was developed by Dr. Brantley Scott in 1972.
This is an implantable device which comprises of an inflatable
cuff, a balloon to regulate pressure and a control pump. Essential
characteristics of an ideal patient for AUS include motivation,
manual dexterity, relatively normal detrusor, absence of urinary
24
REVIEW
tract infection (UTI), failure of alternative means of incontinence

control, and realistic expectations.
6 Ward KL, Hilton P, UK and Ireland TVT Trial Group. Tension-free

vaginal tape versus colposuspension for primary urodynamic
stress incontinence: 5-year follow up. BJOG 2008; 115: 226e33.
7 Abdel-Fattah M, Ramsay I, Pringle S, et al. Randomised prospective single blinded study comparing inside-out versus
outside-in transobturator tapes in the management of urodynamic stress incontinence: 1-year outcomes from the E-TOT
study. BJOG 2010; 117: 870e8.
8 Kitchener HC, Dunn G, Lawton V, Reid F, Nelson L, Smith AR.
Colpo study group. Laparoscopic versus open colposuspension
e results of a prospective randomised controlled trial. BJOG
2006; 113: 1007e13.
9 Nambiar A, Cody JD, Jeffery ST. Single incision sling operations
for urinary incontinence in women. Cochrane Database Syst Rev
2014 Jun 1; 6: CD008709, http://dx.doi.org/10.1002/14651858.
CD008709.pub2.
10 Hussain M, Greenwell TJ, Venn SN, Mundy AR. The current role of
the articial urinary sphincter for the treatment of urinary incontinence. J Urol 2005; 174: 418e24.
Technique: it can be placed vaginally or abdominally where the

cuff surrounds the bladder neck, the balloon is placed in the
pelvis and the pump is placed in the labium majus. There seems
to be a higher infection rate with vaginal placement; hence most
surgeons choose the abdominal route.
Outcome evidence: the largest study of artificial urinary
sphincter in the literature reports that 90% of patients have a
functional artificial urinary sphincter in place at a mean followup of 5 years, with a 28% revision rate.
Conclusion
Surgery for stress incontinence is only indicated after failed
conservative therapy. The current evidence is in favour of midurethral tape procedure using the retropubic route with a type 1
mesh, a colposuspension or an autologous fascial sling as first
line operations.
A
Practice points
FURTHER READING
1 Cooper J, Annappa M, Quigley A, Dracocardos D, Bondili A,
Mallen C. Prevalence of female urinary incontinence and its
impact on quality of life in a cluster population in the United
Kingdom (UK): a community survey. Prim Health Care Res Dev
2015; 16: 377e82.
2 National Institute for Health and Clinical Excellence. Urinary incontinence. The management of urinary incontinence in women.
NICE clinical guideline 171. London: NICE, 2013.
3 Does pre-operative urodynamics improve outcome for women
undergoing surgery for stress urinary incontinence? A systematic
review and meta-analysis. Rachane S Latthi BJOG 2015; 122:
8e16.
4 Ulmsten U, Henriksson L, Johnson P, Varhos G. An ambulatory
surgical procedure under local anesthesia for treatment of female
urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 1996; 7:
81e6.
5 DeLorme E. Transobturator tape urethral suspension: miniinvasive procedure in the treatment of stress urinary incontinence
in women. Prog Urol 2001; 11: 1306e13.
25
Surgical management of stress urinary incontinence should be

offered only after conservative management has failed and a
multidisciplinary team discussion has taken place
The current evidence supports the retropubic synthetic sling with
a bottom-up approach, a colposuspension or an autologous
fascial sling as primary procedures for stress urinary incontinence
Women considering a synthetic tape procedure should be provided with written guidance on mesh such as that provided by the
MHRA
Surgery should only be performed by surgeons with training in the
management of incontinence, who work as part of a multidisciplinary team and who regularly carry out incontinence
surgery
Urethral bulking agents are safe procedures in women with
contra-indications for surgery, but have lower success rate and
need to be repeated
ETHICS/EDUCATION
Maternal mortality in the

UK: an update
deaths in 2009e12. The maternal mortality rate of 10.1 per

100,000 maternities in 2010e12 represents a statistically significant reduction of 27% since 2003e5 (relative risk [RR] 0.73, 95%
confidence interval [CI] 0.61e0.89). Almost all of this observed
reduction is due to a decline in direct (obstetric) deaths, which
fell by 48% over this period (RR 0.52, 95% CI 0.39e0.69). The
mortality rate from indirect deaths has, however, remained unchanged for more than 10 years (RR 0.90, 95% CI 0.72e1.11).
This observed reduction in the maternal mortality rate has
occurred on the background of an increase in the number of
maternities, and alongside rising levels of obesity, advancing
maternal age, and an increasing proportion of births amongst
women born outside the UK; all of which serve to increase the
risk of maternal death.
Bryn Kemp
Marian Knight
Abstract
The latest report of the United Kingdom Condential Enquiry into
Maternal Mortality, conducted by the MBRRACE-UK collaboration,
was published in December 2014. The report has moved from triennial
to annual publication with a chapter on each specic cause of
maternal death included once every 3 years. In 2010e12, overall
maternal mortality fell to 10.1 per 100,000 maternities; a 27% decrease
compared to 2003e5. Whilst the maternal mortality rate from genital
tract sepsis more than halved from its 20-year high in 2006e2008,
sepsis per-se accounted for almost 25% of deaths. One in 11 of all
deaths were associated with sepsis related to inuenza, the majority
2009/A H1N1 inuenza, which, in the presence of an effective vaccine,
were largely preventable. The benets of inuenza vaccination should
be promoted and women offered vaccination at any stage of pregnancy. Thrombosis was the leading cause of direct death, highlighting
the ongoing importance of thromboprophylaxis.
The women who died

Amongst the 321 women who died, 30% were still pregnant at
the time of death. Of these, one third were under 20 weeks
gestation. Amongst all women: 74% had pre-existing medical
complications; 27% were obese, an independent risk factor for
maternal death; almost 1 in 10 received no antenatal care, and
25% received care below the minimum standard defined by the
National Institute of Health and Clinical Excellence (NICE).
Direct and indirect deaths: key facts
Whilst the maternal mortality rate from genital tract sepsis more
than halved from its 20-year high in 2006e2008 (RR 0.44, 95% CI
0.22e0.87), sepsis from all causes accounted for almost 25% of
deaths. In particular, 1 in 11 of all deaths were associated with
sepsis related to influenza, the majority 2009/A H1N1 influenza,
which, in the presence of an effective vaccine, were largely
preventable. The benefits of influenza vaccination should be
promoted and women offered vaccination at any stage of pregnancy. Thrombosis was the leading cause of direct death, highlighting the ongoing importance of thromboprophylaxis.
Keywords epilepsy; haemorrhage; inuenza; maternal mortality;

sepsis
Introduction
The UK Confidential Enquiry into Maternal Deaths recognizes
that every maternal death is a tragedy; to families, to the staff
involved, and to the wider communities left behind. Since the
first report in 1952, the maternal mortality rate in the UK has
fallen from approximately 90 per 100,000 to 10 per 100,000
maternities. The Enquiry is now conducted by the MBRRACE-UK
collaboration and the latest report includes for the first time review of the care of women from Ireland. In addition, there is a
move to publication of annual rather than triennial reports, with
a chapter on each specific cause of maternal death included once
every 3 years, alongside topic specific reviews of episodes of
maternal morbidity. In the 2014 report, chapters reviewed
morbidity and mortality relating to maternal sepsis along with
deaths related to haemorrhage, amniotic fluid embolism,
anaesthesia-related deaths and deaths from neurological and
other indirect causes.
Between 2009 and 2012, 357 women died during, or within 6
weeks of the end of their pregnancy in the UK. Thirty-six deaths
were classified as coincidental, thus there were 321 maternal
General messages for care

Clinical observations: all women showing any signs or symptoms of ill health require a full set of basic observations,
including heart rate, temperature, respiratory rate and blood
pressure; the results should be documented and acted upon. The
reviewers frequently found that the respiratory rate was not
measured. This is as important a physiological measure as the
pulse rate, blood pressure and temperature. Sepsis causes an
increased respiratory rate to meet an increased oxygen demand
of the tissues, as well as in possible compensation for metabolic
acidosis or due to the presence of acute respiratory distress
syndrome (ARDS). The threshold for the upper limit of normal in
pregnancy is 20 breaths per minute.
Avoid referral delays: delays in escalating the care of complex
cases contributed to poor outcomes in a number of cases, and it
is important to be aware of red flags for escalating care such as
those highlighted in relation to sepsis below. Junior medical and
midwifery staff should not hesitate to seek advice from senior
colleagues, particularly at night and weekends, when on-site
cover may be limited. Consultant to consultant referral should
Bryn Kemp MRCOG DPhil is at the National Perinatal Epidemiology

Unit, University of Oxford, Oxford, UK. Conicts of interest: none
declared.
Marian Knight MA MBChB MPH DPhil FFPH FRCPE is at the National
Perinatal Epidemiology Unit, University of Oxford, Oxford, UK.
Conicts of interest: none declared.
26
ETHICS/EDUCATION
be undertaken in cases where specialist advice is required to

minimize delays when assessing and treating women.
SIRS screening and evaluation for Red Flag Sepsis (UK

Sepsis Trust Primary Care Toolkit 2014)
Clinical service configuration: almost three quarters of women

who died from both direct and indirect causes had pre-existing
medical problems, including a wide range of different conditions across all body systems. Such women represent a high-risk
group and need to receive the appropriate individualized multidisciplinary evidence-based care pre-pregnancy, during pregnancy and after delivery.
a. Screening for SIRS

SIRS is confirmed if ANY TWO of the following are present:
Immediate
C
New onset of Confusion or Altered Mental State
C
Temperature >38.3 C or <36 C
C
Heart Rate >90 beats per minute*
C
Respiratory Rate (counted over 60 seconds) >20 breaths per
minute
Point of Care Test (commonly available)
C
Blood Glucose >7.7 mmol/L in the absence of known diabetes
Point of Care Test (not yet widely available)
C
White cell count >12 or <4 109/L
b. Evaluation for Red Flag Sepsis
Act immediately if ANY ONE of the following are present:
C
Systolic BP <90 mmHg (or >40 mmHg fall from baseline)
C
Heart rate >130 per minute
C
Oxygen saturations <91%
C
Respiratory rate >25 per minute
C
Responds only to voice or pain/unresponsive
Point of Care test (not yet widely available)
C
Lactate >2.0 mmol/L
*Note the guidelines are not specific for pregnancy and these
observations should be interpreted in the context of the normal
physiology for the pregnant woman. RCOG guidance suggests
using a threshold of 100 beats per minute in pregnancy (RCOG
Green-top Guideline 64a). (Reproduced with permission from
Saving Lives, Improving Mothers Care 2014).
Topic specic messages

1) Think sepsis
Sepsis refers to an infection with coexisting features of the systemic inflammatory response (SIRS) (see Box 1). Eighty-three
women died of sepsis related causes (maternal mortality rate
2.04 per 100,000 maternities).
Whilst there were examples of excellent care being provided
to women, delays in the diagnosis and management of sepsis was
a recurring theme. Repeated non-specific presentations to nonobstetric services, may be indicative of sepsis and women
should be evaluated for red flag sepsis (Box 1). Where sepsis is
suspected, a sepsis care-bundle should be initiated with urgency.
National guidance requires that obstetric units have a protocol in
place outlining a locally agreed sepsis bundle, along with relevant clinical governance and audit pathways necessary to the
monitor implementation and efficacy of sepsis care pathways.
2) Prevent and treat haemorrhage
Obstetric haemorrhage accounted for 10% of direct maternal
deaths in the UK. Seventeen women died (maternal mortality
rate 0.49 per 100,000 maternities) with an estimated case fatality
rate for massive obstetric haemorrhage of 1 per 1200 episodes.
Two deaths followed placental abruption, one was in association
with placenta praevia, seven deaths followed uterine atony and
seven following genital tract trauma including uterine rupture.
All deaths were related to peri-delivery haemorrhage.
During acute haemorrhage, involvement from senior obstetric, anaesthetic and midwifery staff is essential and concerns
should be escalated if a woman deteriorates. Resuscitation
should not be guided by single point estimates of haemoglobin in
the acute phase of haemorrhage, which can mislead assessments
of the severity of blood loss, but by estimated blood loss as well
as clinical symptoms and signs. Up to four units of fresh frozen
plasma and ten units of cryoprecipitate may be given empirically
in cases of severe bleeding, alongside either O-negative or crossmatched blood while awaiting the results of coagulation studies.
Rapid infusers and fluid warmers should be readily available,
and early recourse to hysterectomy is essential when more conservative interventions prove ineffective.
3) Care for women with amniotic fluid embolism
Amniotic fluid embolism (AFE) has a case fatality rate of 11
e61% and affects 1 in 50,000 pregnant women. Between 2009
and 12, 11 women died from AFE (maternal mortality rate 0.33
per 100,000 maternities); messages for care were similar to those
for women with haemorrhage. In extremis, for women in cardiac
arrest, perimortem caesarean section should be carried out
within 5 minutes of diagnosis; remembering that it is performed
Box 1
for maternal reasons alone, with no need to confirm fetal

viability beforehand.
4) Women with epilepsy
Epilepsy affects 1% of the population and was responsible for
14 maternal deaths (maternal mortality rate 0.40 per 100,000
maternities), more than any single direct cause of death with the
exception of thrombosis; and unchanged from the previous triennium. Pregnant women with epilepsy should have their
treatment optimized before conception and should have access to
joint obstetric and neurological assessment. Multi-agency
guidelines for the care of pregnant women with epilepsy are
urgently needed; an RCOG national guideline is currently under
development.
5) Women with stroke and sub-arachnoid haemorrhage
Between 2009 and 2012, 26 women died with intracranial
haemorrhage (maternal mortality rate 0.75 per 100,000 maternities). Women presenting with headache should have a full
neurological examination, including fundoscopy and an assessment for the presence of neck stiffness. Where stroke is
27
ETHICS/EDUCATION
subsequently diagnosed, care should be within a hyperacute

stroke unit, and pregnancy, caesarean delivery or the immediate
postpartum state should not be considered absolute contraindications to treatment with thrombolysis.
6) Other medical complications
Amongst women who died from other medical complications,
reviewers identified a number of common themes. These included
a general absence of preconception care or treatment optimization
for women with chronic disease. There was also a tendency for
women to alter treatment plans and to stop medication when
pregnant. It was considered essential that women requiring input
from multiple specialities should have a lead clinician nominated
to be responsible for joined-up care across teams.
FURTHER READING
Heslehurst N, Rankin J, Wilkinson JR, Summerbell CD. A nationally
representative study of maternal obesity in England, UK: trends in
incidence and demographic inequalities in 619 323 births, 1989
e2007. Int J Obes (Lond) 2010; 34: 420e8.
on behalf of MBRRACE-UK. In: Knight M, Kenyon S, Brocklehurst P,
Neilson J, Shakespeare J, Kurinczuk JJ, eds. Saving lives,
improving mothers care e lessons learned to inform future maternity care from the UK and Ireland condential enquiries into
maternal deaths and morbidity 2009e12. Oxford: National Perinatal
Epidemiology Unit, University of Oxford, 2014.
Nair M, Kurinczuk JJ, Brocklehurst P, Sellers S, Lewis G, Knight M.
Factors associated with maternal death from direct pregnancy
complications: a UK national case-control study. BJOG 2015; 122:
653e62.
National Institute for Health and Care Excellence. CG62: antenatal
care. 2008. Retrieved 15/04/2015, from: http://www.nice.org.uk/
guidance/cg62.
Royal College of Obstetricians and Gynaecologists. Green-top
guideline 52: postpartum haemorrhage, prevention and management. 2011, http://www.rcog.org.uk/womens-health/clinicalguidance/prevention-and-management-postpartum-haemorrhagegreen-top-52.
guideline No. 64a. Bacterial sepsis in pregnancy. 2012, http://www.
rcog.org.uk/les/rcog-corp/25.4.12GTG64a.pdf.
guideline No. 64b. Bacterial sepsis following pregnancy. 2012,
http://www.rcog.org.uk/les/rcog-corp/25.4.12GTG64a.pdf.
guideline 37a: reducing the risk of thrombosis and embolism during
pregnancy and the puerperium. 2015, http://www.rcog.org.uk/
womens-health/clinical-guidance/reducing-risk-of-thrombosisgreentop37a.
UK Sepsis Trust. Clinical tools. 2013, http://sepsistrust.org/info-forprofessionals/clinical-tools/ (accessed 02 Jul 2014).
United Kingdom Blood Services. Handbook of transfusion medicine.
5th edn. London: TSO, 2013.
Conclusion
The latest UK Confidential Enquiry into Maternal Deaths and
Morbidity clearly identified improvements in care, particularly in
relation to the increasingly complex needs of pregnant women
with medical co-morbidities in the UK. As clinical services
continue to be restructured, and as clinical staff become increasingly sub-specialized, maternity care providers should focus on
developing multidisciplinary care pathways including prepregnancy, during pregnancy and post-delivery, with an
emphasis on early involvement of appropriate senior clinical staff.
Funding
The Maternal, Newborn and Infant Clinical Outcome Review
programme, delivered by MBRRACE-UK, is commissioned by the
Healthcare Quality Improvement Partnership (HQIP) on behalf of
NHS England, NHS Wales, the Health and Social Care division of
the Scottish government, the Northern Ireland Department of
Health, Social Services and Public Safety (DHSSPS), the States of
Jersey, Guernsey, and the Isle of Man.
BK is funded by an NIHR Academic Clinical Lectureship, MK
is funded by an NIHR Research Professorship (NIHR-RP-011032). The views expressed are those of the author(s) and not
necessarily those of the NHS, the NIHR or the Department of
Health.
A
28
SELF-ASSESSMENT
Self-assessment questions
Questions
(iii) Which drug is proven to improve neonatal outcomes in

the setting of preterm labour?
Question 1 (SBA)
A 33-year old woman who is 30 weeks into her first ongoing
pregnancy presents with abdominal pain and ruptured membranes. She is admitted and steroids administered. Which of
the following defines preterm prelabour rupture of the membranes (PPROM)?
A) Preterm spontaneous rupture of the membranes at least 1
hour before the onset of contractions
B) Spontaneous rupture of the membranes prior to 30 weeks
in the absence of any uterine activity
C) Watery vaginal loss in the absence of bleeding at any
gestation prior to 37 weeks at least 1 hour before the onset
of contractions
D) Preterm spontaneous rupture of the membranes at least 24
hours before the onset of contractions
E) Preterm spontaneous rupture of the membranes in the
absence of current contractions or abdominal pain
Question 4 (SBA)
Hysteroscopy is increasingly provided on an outpatient basis
for selected patients. Which of the following patients would
not be suitable to undergo hysteroscopy in an ambulatory
outpatient setting?
A) A 43-year old woman who attends for investigation of
intermenstrual bleeding, having previously undergone
three LLETZ treatments to the cervix
B) A 28-year old woman who is undergoing investigations for
infertility. She has never had a pregnancy in the past
C) A 52-year old woman who is being investigated for perimenopausal bleeding. She is very anxious about the procedure and requests a female doctor only
D) A 73-year old woman who attends with post-menopausal
bleeding. She has COPD and has had a myocardial
infarction in the past
E) A 46-year old woman who has had bleeding on tamoxifen
since her treatment for breast cancer. An attempt to take a
pipelle biopsy in the clinic was unsuccessful due to
discomfort
Question 2 (SBA)
Which of these factors is NOT associated with an increased
risk of preterm labour?
A) Maternal smoking
B) High maternal BMI
C) Decidual haemorrhage
D) Maternal age >40
E) Maternal Afro-Caribbean ethnicity
Question 5 (EMQ)
Each of the following are potential complications of outpatient
hysteroscopy. Match each of the stems below (ieiii) to the
most likely complication in each case (AeH)
A) Infection
B) Uterine perforation
C) Cervical stenosis
D) Bleeding
E) Pain
F) Incomplete procedure
G) Vasovagal attack
H) Cervical damage
Question 3 (EMQ)
Match each of the stems below (ieiii) to one of the following
options (AeJ)
A) Atosiban
B) Nifedipine
C) Calcium gluconate
D) Sulindac
E) Co-amoxiclav
F) Erythromycin
G) Progesterone
H) Indometacin
I) Betamethasone
J) Clindamycin
(i) A 52-year old woman attends for investigation of postmenopausal bleeding. The uterus is acutely retroverted
and retroflexed, making entry difficult. Polyp removal is
attempted by the clinician from a difficult position
(ii) A 32-year old woman with Von Willebrands disease attends for outpatient hysteroscopy. The clinician attempts
resection of a small fibroid polyp
(iii) A 78-year old woman with a history of low blood pressure undergoes outpatient hysteroscopy, during which
the operator chooses to distend the cavity with carbon
dioxide
(i) Which drug has been shown to increase the rate of

necrotizing enterocolitis when administered in the
context of preterm prelabour rupture of membranes?
(ii) Which drug used for the treatment of threatened preterm
labour is the only one licensed for this use in the UK?
Question 6 (SBA)
Which one of the following statements relating to maternal
mortality in the UK is true:
A) A quarter of women who die during or after pregnancy
have co-existing medical complications
Alec McEwan MRCOG is a Consultant in Fetal and Maternal

Medicine at the Division of Obstetrics and Gynaecology, Queens
Medical Centre, Nottingham, UK.
29
SELF-ASSESSMENT
A 2003 Cochrane Database systematic review into antibiotic use in women experiencing preterm prelabour rupture of
membranes showed that babies in the co-amoxiclav group had
a higher incidence of necrotizing enterocolitis than those in
the placebo group. For this reason, co-amoxiclav is not recommended in this context.
(ii) A
While nifedipine is widely used in the treatment of
threatened preterm labour, it is used outside of license and the
only drugs currently licensed for this use are atosiban and
ritodrine.
(iii) I
Corticosteroids give proven improvements in neonatal
outcomes in terms of reducing neonatal death, respiratory
morbidity, necrotizing enterocolitis, cerebrovascular haemorrhage and neonatal intensive care admissions. Magnesium
sulphate has also been recently shown to provide neuroprotection for preterm infants delivered prior to 32 weeks.
Tocolytic agents indirectly assist but their main function is to
provide sufficient time for steroid dose to be completed.
Therefore caution should be exercised if considering prolonging tocolytic therapy once the steroid course is complete
as this runs the risk of maintaining the baby within a hostile,
potentially infected, environment which has been shown to
increase the risk of cerebral palsy.
B) Maternal deaths from indirect (medical and psychiatric)

causes are twice as common as deaths from direct (obstetric) causes
C) Genital-tract sepsis is the cause of almost a quarter of
maternal deaths
D) Women should be advised against influenza vaccination
during pregnancy
E) Haemorrhage is the leading cause of direct maternal death
in the UK
Question 7 (SBA)
You are asked to see a woman who underwent caesarean
section 24 hours ago under general anaesthesia because of
failed spinal anaesthetic. She had a history of prolonged
membrane rupture and failure to progress in first stage. She
has a high pyrexia (38.9 C), tachycardia, BP of 85/45 and a
respiratory rate of 24/minute. Which one of the following
important actions do not form part of the sepsis six bundle?
A) Performing a lactate level
B) Commencing intravenous fluid resuscitation
C) Organizing a chest X-ray
D) Taking blood cultures
E) Starting immediate broad spectrum antibiotics
Question 8 (SBA)
A new screening test is introduced during pregnancy for
condition X which has an incidence of 50 per 10,000 pregnancies. 50,000 women accept screening. In total, 5000
women are told they are screen positive and in this group,
200 cases are actually diagnosed. Which one of the following
statements is true regarding this screening test?
A) The sensitivity is 70%
B) The specificity is 95%
C) The positive predictive value is 4%
D) The false positive rate is 1%
E) The false negative rate is 1%
Answer 4
E
If the patient has found a speculum or pipelle biopsy in
clinic too uncomfortable, it may not be appropriate to manage
them in the outpatient setting for hysteroscopy. The patient
who is anxious may tolerate the procedure well with appropriate reassurance and a suitable attendant to help her. Previous treatment on the cervix such as a large loop excision of
the transformation zone (LLETZ), being nulliparous, or previous myomectomies are not contraindications for outpatient
hysteroscopy. For the patient who has multiple co-morbidities,
avoidance of a general anaesthetic is important if possible.
Answers
Answer 2
B
Risk factors for preterm labour are wide ranging. Maternal
ethnicity has been shown to have a significant impact on
preterm labour. The reasons behind this are poorly understood. High BMI is not known to be associated with the risk of
preterm labour, but there is a higher risk in women with low
BMI (<19.8).
Answer 5
(i) B
Uterine perforation is a rare complication, occurring in less
than 1% of cases. Risks factors include severe uterine retroflexion. There is also an increased risk of perforation in therapeutic hysteroscopy.
(ii) D
Bleeding may occur during the procedure, particularly
secondary to fibroid resection. In this case, the patient has a
pre-existing condition that makes bleeding more likely.
(iii) G
Carbon dioxide and normal saline can both be used as
distention medium and should be left up to the discretion of
the operator, however normal saline is associated with fewer
vasovagal reactions.
Answer 3
(i) E
Answer 6
B
Answer 1
A
PPROM is defined as preterm spontaneous rupture of
membranes, at least 1 hour before the onset of contractions. In
addition to prematurity, PPROM is particularly associated with
maternal sepsis and chorioamnionitis.
30
SELF-ASSESSMENT
Take blood for haemoglobin and lactate levels

Measure urine output hourly
Three-quarters of women who died during pregnancy or in

the 6 weeks after the end of pregnancy had co-existing medical
problems. On a population basis, medical co-morbidities
contribute almost 50% of the increased risk of fatality in
women with specific severe obstetric complications. Two
thirds of maternal deaths are due to indirect (medical and
psychiatric causes) and only one third are due to direct (obstetric) causes. Almost a quarter of all maternal deaths are due
to sepsis, but genital-tract sepsis is only a small proportion of
all maternal deaths due to sepsis. In 2009e12, maternal deaths
from influenza-related sepsis formed the largest group, with a
substantial number of women dying from other respiratory
causes. Maternal deaths from influenza are preventable, and
women should be offered influenza vaccination regardless of
the stage of pregnancy. Thrombosis is the leading cause of
direct maternal death, emphasizing the importance of assessing thrombosis risk and hence the need for
thromboprophylaxis.
Answer 8
C
The positive predictive value is 4%
It helps to construct a 4 3 4 table;

Screen negative Screen positive
Normal pregnancies 44950
4800
49,750
Affected pregnancies
50
200
250
45,000
5000
50,000
There are 50,000 women in total who are screened. The

incidence of the condition is 50 per 10,000, meaning there
should be 250 affected pregnancies in this population. We
know that 200 are detected through screening, meaning that
the sensitivity is 80% (200/250 100). Five thousand women
are screen positive, meaning that 4800 must be false positives,
giving a rate of 10% (4800/49,750 100). The specificity is
the proportion of unaffected pregnancies where the screening
result is negative and with this test it is 90% (44950/49750
100). The false negative rate is the proportion of all affected
pregnancies receiving a screen negative result (50/250 100
20%). The positive predictive value is the proportion of all
screen positive cases that actually have the condition (200/
5000 100 4%).
Answer 7
C
Once sepsis is suspected, a sepsis bundle should be initiated immediately. Several sepsis bundles exist; the following
are the elements of the sepsis six care bundle from the UK
Sepsis Trust:
Take an arterial blood gas and give high flow oxygen if
required
Take blood cultures
Commence intravenous antibiotics
Start intravenous fluid resuscitation
31

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Obstetrics,

Fiona Reid MD MRCOG

Shreelata Datta BSc(Hons) MBBS MRCOG LLM

Mahmood I Shafi MB BCh MD DA FRCOG

Tahir A Mahmood MD FRCOG FRCPI MBA FACOG(Hon)

restriction and certain genetic as well as structural anomalies in

The concept of screening

Keywords non-invasive fetal testing; ovarian cancer; pre-eclampsia;

The use of cervical cytology for the early detection of cervical

In the UK, screening programmes such as cervical cytology were

Lara Morley MBChB BSc PgC is an Academic Clinical Fellow and

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

2016 Elsevier Ltd. All rights reserved.

Current standard NHS antenatal care package

Dating USS, nuchal translucency, triple or quadruple test (depending on gestation)

the rapid advances in genomics may lead to large public health

ensure appropriate regulation, education, counselling and

Screening for adverse pregnancy outcomes

The 10 Wilson-Jungner principles of early disease

10 Case-finding should be a continuing process and not a once

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

2016 Elsevier Ltd. All rights reserved.

up to 90%. In this paper, prediction rate of up to 100% could be

Risk factors for pre-eclampsia

placental gene expression and single nucleotide polymorphisms

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

Screening for Downs syndrome

2016 Elsevier Ltd. All rights reserved.

testing with amniocentesis or chorionic villus sampling (CVS) as

Non-invasive prenatal testing

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

2016 Elsevier Ltd. All rights reserved.

However, cost and implementation burdens are limitations

addition of serum markers was likely to reduce the false positive

Screening in ovarian cancer

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

New advances in ovarian cancer research

Future direction of screening

2016 Elsevier Ltd. All rights reserved.

affordable and more accurate. The result is the availability of

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

Newer screening tests may be combined with the known risk

2016 Elsevier Ltd. All rights reserved.

in the OP setting or if a procedure has previously failed in the

Procedure for diagnostic hysteroscopy

Hysteroscopy is a common procedure used in gynaecology to

Anna Graham BA(Hons) MBBS is an ST2 in Community Sexual and

Shreelata Datta BSc(Hons) MRCOG LLM is a Consultant in Obstetrics

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

There are many different types of hysteroscope available and the

2015 Elsevier Ltd. All rights reserved.

Once inside the uterus the ostia should be identified for

Indications for a diagnostic hysteroscopy

Indications for hysteroscopy

Subfertility and recurrent

TVUSS endometrial thickness >5 mm

All of the techniques outlined below for operative hysteroscopy

Indications for operative hysteroscopy

The patient should be cleaned and draped in lithotomy to

Diagnostic hysteroscope with

OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 26:1

2015 Elsevier Ltd. All rights reserved.

Figure 1 Hysteroscopic polyp forceps.

Hysteroscopic resection and morcellation