Prenatal Screening-Biochemical markers

By

Dr. Sreekumari

Birth of babies with congenital defects is the most traumatic experience to the expectant parents. The incidence of neural tube defects and chromosomal aneuploidy are quite high. Since a positive correlation was found with maternal age, early workers offered the choice of amniocentesis to detect a defective fetus.  Amniocentesis posed a risk for the fetus which was as high as the chance of having an affected child, several groups worked on the development of non invasive prenatal screening tests.

All three types of aneuploidy have a strong correlation with maternal age above 35 years. Since the changing lifestyle has increased the maternal age above 35, reliable markers with high detection rate and low false positive are found to be essential.

Thus several biochemical markers were measured in maternal serum and have now been identified as reliable indices of neural tube defects and chromosomal aneuploidy. Most of these markers are normally present in maternal serum and their level varies with gestational age. Hence these markers are said to have temporality. So both the patient and requesting physician must have a clear idea that the result of a screening test is different from that of a diagnostic test. In order to confirm the diagnosis of a chromosomal disorder, invasive procedures like Chorionic villous sampling or amniocentesis should be done and cytogenetic studies on the cells to be carried out.

Unlike markers used in other diseases, the levels of biochemical markers used in prenatal diagnosis are expressed by the statistical term Multiple of Median (MOM). The markers are quantitated by any of the modern techniques like RIA/EIA/CLIA and then converted to MOM.  MOM values normalize results for purposes of comparison between laboratories .Each laboratory has to use its own data to establish Median values for each marker (analyte) for each week (day) of gestation. Ideally the median is to be calculated with results from 200 samples. MOM values are obtained by dividing the actual value with the lab Median. Kit specific and population specific median values increase reliability and the MOM should be updated.

Since the 1990’s prenatal screening has become standard obstetric practice in all pregnancies at risk. Since maternal age is associated with errors in meiosis an increase in maternal age increased the risk of having children with chromosomal aneuploidy. This is one of the primary indications for prenatal screening.

The Triple Test (Triple screen)

The triple screen is done during the second trimester between 14 and 18 weeks. The markers used are AFP, uE3 and HCG. The pattern of changes and detection rates for Neural tube defects, Trisomy 21 and trisomy 18 are given in table.

Alpha fetoprotein is the major serum protein of the fetus synthesized by the fetal liver and yolk sac. There is a steady increase in AFP level in maternal serum from 10th week of gestation and reaches a peak by   25 weeks of gestation in unaffected pregnancy. Then the maternal serum alpha feto protein (MSAFP) steadily declines until term. In fetal serum and amniotic fluid, the AFP level reaches a peak by 9^th week of gestation and then slowly falls till term. In NTD, the AFP is increased but in chromosomal aneuploidy it is decreased.

Human Chorionic Gonadotrophin is a glycoprotein hormone produced during normal pregnancy by the trophoblast and placenta. HCG appears in maternal serum by 6 to 8 weeks and reaches a peak by 10 weeks. By the second trimester it falls to a constant level by 18 to 20 weeks.

A marked increase about twice the normal was found in pregnancies with trisomy 21 during the second trimester. It was also noted that free beta HCG was increased during the 1^st trimester in DS (MOM 2.4) even though total HCG remained normal (MOM 1.33). Both were increased during the second trimester in Trisomy 21(MOM 2 to 2.5). A hyperglycosylated variant (produced by cytotrophoblasts) was also found in Down’s syndrome. This is referred to as Invasive Trophoblast Antigen (ITA). The higher level of ITA is believed to be due to the defect in the conversion of cytotrophoblast to syncytiotrophoblasts. In trisomy18 the HCG levels remained lower than normal.

Unconjugated Estriol (uE3) is a steroid hormone produced by the fetoplacental unit .It is produced by the placenta but the fetal liver completes the synthesis. It is an estrogen with 3 hydroxyl groups and 3 organs –fetal adrenal, fetal liver and maternal liver are involved in the synthesis. Initially estriol was used as a measure of fetal wellbeing especially at term. Maternal serum uE3 levels rise by 8weeks of gestation and continue to increase through out pregnancy. A 25 % reduction in uE3 levels was found in maternal serum when the fetus had chromosomal aneuploidy.

Even though the Triple screen has a high detection rate, temporalities of the markers have to be emphasized. During the second trimester, AFP and uE3 increase in unaffected pregnancies, where as that of HCG declines. Yet another point which can give false positive results is the method of calculation of gestational age- by ultrasound or by LMP. This fallacy can be corrected using the USG results at 6 weeks of gestation for calculating correct gestational age.

In spite of these limitations, the triple screen has a high detection rate, 80% for neural tube defects and 55-60% for chromosomal aneuploidy and a false positive less than 5 %. When the cut off is around 1:270,false positive rises to 7 to 9%.The increase in maternal age with the changing lifestyle, career options and work pressure in educated and employed women have increased the need for additional markers.

The Quadruple Test (Quad screen)

Includes AFP.uE3, HCG and an additional marker Inhibin-A

Dimeric Inhibin A (DIA) is a glycoprotein produced by the placenta. It is a Dimer, but with dissimilar subunits alpha and beta. Inhibin A has the subunit make up A and inhibin B  .Inhibin A is measurable in maternal serum and has a feed back effect on FSH secretion.

The level increases in the first trimester until 10 weeks and then remains stable upto 25 weeks of gestation. Thereafter it increases to reach a peak by term. The DIA levels are increased in DS and remains elevated through out the second trimester unlike AFP and uE3 that increase and hCG that decreases during the testing period.

It is the least stable of the four analytes, since decomposition can occur during storage. Serum should be promptly separated and assay completed within 3 days. Whole blood should not be transported. 0.7 –2.5 microgram/L in unaffected pregnancy at second trimester.

Statistical modeling of different combinations of AFP, uE3, hCG and DIA indicates that the highest detection rates and lowest false positive rates are achieved when using all four markers corrected for maternal weight. DIA is an independent variable having no correlation with maternal age, race or Insulin dependent diabetes mellitus. The only factor which has a significant effect on DIA levels is maternal weight. There was no correlation with AFP and uE3, but significant correlation was found with hCG

Factors affecting the level of the Quad screen markers

v  Maternal Weight was found to have an inverse relation with the levels of all four markers.

v  Diabetes- Insulin dependent (not GDM)  AFP was found to be 40% lower than non diabetics

v  Twin pregnancy- MSAFP higher than those having single fetus.  MOM > 4 significant.

v  Racial differences were also noted, but not significant in our set up.

Screening during the First trimester

Several workers suggested that a screening test done between 10 and 14 weeks of pregnancy (1^st trimester) may be as accurate as that done during the second trimester. In this screening method, AFP, hCG and Pregnancy associated plasma protein-A(PAPP-A) are measured along with ultrasound examination for Nuchal Translucency(NT) This screening pattern is referred to as an OSCAR(One Stop Clinic for Assessment of Risk) .All the markers are measured in a single serum sample.

PAPP-A is a high molecular weight zinc containing metalloglycoprotein. It is produced by the trophoblast and its biological function is still unclear. In addition to being a marker of chromosomal aneuploidy, it is an indicator of early pregnancy failure and complications, Cornelia de Lange syndrome and acute coronary syndrome.

The level of PAPP-A was found to be significantly lower in pregnancy with Trisomy 21 compared to unaffected pregnancy (MOM 0.27 as against 1.01 in normal pregnancy)But PAPP-A levels when measured in second trimester  the results are found to be normal. Persistently lower levels of PAPP-A in second trimester was indicative of Trisomy18.

Similarly total hCG was found to be a poor marker in the first trimester with an MOM of 1.33, but an adequate marker during the second trimester. Free beta hCG on the other hand is higher and has a relatively stable MOM (2) from 10 to 18 weeks.

The detection rate was 89% with 5% false positive.

Hence the present suggestion is to combine the markers of first and second trimester in maternal serum. The suggested protocol is given

ü  Measurements of NT and PAPP-A are made in the first trimester, but not interpreted or acted upon until the second trimester.

ü  In the second trimester a second serum sample is drawn and quadruple test performed.

ü  Results for all the six tests, NT, PAPP-A, AFP, uE3, hCG and DIA are combined into a single risk estimate for interpretation in the second trimester.

ü  85% detection rate for DS with only 1% false positive is achieved

 Information to be provided by Physician

1.     Specimen collection date

2.     1^st or second specimen

3.     date by LMP or gestational age by USG

4.     maternal age and weight

5.     relevant family and obstetric history

6.     presence of maternal Diabetes mellitus

7.     Maternal race if indicated

8.     Whether multiple pregnancy is present/suspected

Reporting

The report should contain

1.     MOM values for the measured analyte

2.     DS risk estimate along with risk for NTD or trisomy 18

3.     an interpretation as screen positive or screen negative

4.     information that suggests possible further action.

Interpretation of screen results and calculation of risk

It is seen that about 5% test screen positive, for DS, 3% for NTD and 0.2 % for Trisomy 18, but inaccurate dating can give an abnormal screening result. Ultrasound dating gives the best dating accuracy. The MOM values are adjusted according to the patient’s gestational age, maternal weight, insulin dependent diabetic status and twin pregnancy.

The AFP, hCG, uE3 and DIA values are then compared to known data for affected and unaffected pregnancies and a likelihood ratio is calculated for each marker. The likelihood ratios are then combined with the patient’s age related risk for DS. The resulting number is the patient’s specific risk for DS. There are no reference intervals for each analyte.

The detection rate and false positive rate are determined by the screen positive cut off level. Maternal serum marker levels are used to modify a pregnant woman’s age related risk (priori risk) to calculate the patient specific risk. A test is said to be positive if a woman’s fetal DS risk by maternal serum screening is the same as or greater than the fetal DS risk of a 35 year old woman. At 35 years, the risk during second trimester is 1/270 (with 1/350 at term). Using a risk of 1/270 as a cut off level, four marker screening will achieve a detection rate of 75 to 80% which is 15 to 20% above the DR of Triple screen with same false positive rate of 5%. However if the cut off is fixed at 1/150 then the false positive falls to 3%. This would ensure less patient anxiety and fewer amniocenteses.

False positive rate signifies the proportion of women with test results falling at or above a specified MOM for AFP .But since several women are True positive, at present the term Initial positive rate (IPR) is used instead of FPR. The IPR can be used to assess whether Medians are appropriate since it will be shifted upward or downward if medians are incorrect.

Follow up of Patients with Screen positive results:

Ø  Genetic counseling if patient is screen positive

Ø  For moderately elevated results (MOM 2-3 ) a second test

Ø  If second test is negative – Screen negative

Ø  If second test also gives elevated results, further testing

Ø  USG, Amniocentesis and analysis of AF for Acetyl Choline esterase to confirm NTD

Ø  Amniotic fluid AFP results may give false positive due to contamination by fetal blood, hence confirmed by Acetyl choline esterase .Ach-E is not normally present in AF, but appears in open neural tube defects since fetal  CSF contains the enzyme

Ø  In cases of suspected Chromosomal aneuploidy, Fetal karyotyping.

Medicolegal Aspects of Sterilization Operation:  What is New?

DR.    PRAKASH PAWAR

Associate Professor, Terana Medical College, Navi Mumbai

Obstetrician & Gynaecologist & Medico Legal Consultant

Sterilization Operation ---- What is new?                          

Sterilization operation in a Male or Female is one of the oldest procedures. India is the first country that launched a National Family Planning Programme in 1952. With view to encourage people to adopt permanent method of family planning, Government has been implementing a centrally sponsored scheme since 1981 to compensate the acceptors of the sterilizations for the loss of wages for the day on which he/ she attended medical facility for undergoing sterilization. Some state Government used to give ex-gratia payment to the acceptor of sterilization on his / her death or incapacitation or for treatment of postoperative complications. 

The Honorable Supreme Court of India in its order dated 1/3/2005 in Civil Writ Petition no. 209 / 2003 [ Ramakant Rai v/s Union of India ] has directed the Union of India & States for ensuring enforcement of Union Government Guide lines regarding sterilization procedures. 

Sterilization Procedures and Norms :  For bringing out uniformity with regard of sterilization procedure by

1] Creation of panel of doctors / health facilities for conducting sterilization procedures and laying down the criteria for empanelment of doctors for conducting sterilization procedures.

2] Laying down of checklist to be followed by every doctor before carrying out sterilization procedure.

3] Laying down of uniform proforma for obtaining of consent of persons undergoing sterilization.

4] Setting up of Quality Assurance Committee [QAC] for ensuring enforcement of pre and post operative guide lines regarding sterilization procedures.

5] Bringing into effect an Insurance Policy uniformly in all states for acceptors of sterilization. 

New Initiative: Family Planning Insurance Scheme.

Under the existing Government Scheme no compensation was payable for failure of sterilization and no indemnity cover was provided to Doctors / health facilities providing professional services for conducting sterilization procedures. Now Government has done away with ex-gratia payment & introduced present Family Planning Insurance Scheme. This scheme will not only take care of the cases of failure of sterilizations, medical complications  or death resulting from sterilization, but would also provide indemnity cover to doctors / health facility performing sterilization procedures , as follows : w.e.f. January 1^st, 2008. 

Section I

I A – Death following sterilization in hospital or within 7 days from the day from the date of discharge from the hospital    -----------     Rs. 2 Lakh/-

I B – Death following sterilization within 8 – 30 days from the date of discharge from the hospital---------------------------------------------Rs. 50,000/-

I C – Failure of sterilization ---------------------Rs. 30,000/-

I D – Cost of treatment up to 60 days arising out of complications from the date of discharge -------------------------------------------Actual not exceeding Rs. 25,000/- 

Section II   

Indemnity Insurance per Doctor / facility --  Up to  2 Lakh per claim

but not more than 4 cases in a year.

Total liabilities of the Insurance Company shall not exceed Rs. 9 crores in a year under each section. 

Government of India has paid the premium to Insurance company [ ICICI Lombard General Insurance Company]. Doctors individually do not have to pay any premium to get the insurance cover for sterilization procedures but what is required under this scheme is that doctor must be empanelled and the authority must accredit the health facility where sterilization procedures are carried out. Empanelment & accreditation is applicable to all the doctors whether they are working in Government, semi Government, corporate, Municipal or in private practice. The consent form filled by the person at the time of enrolling himself / herself for sterilization operation shall be proof of coverage under the scheme. QAC [if formed] at District level or C.M.O.  [Chief Medical Officer of District] will be responsible for all formalities of insurance.   

It is strongly recommended that each & every one of you must get empanelled and get your maternity & nursing home accredited from the authority.

It is not possible to give format of application forms for empanelment, accreditation, check list to be filled before sterilization and consent format in this small article due to constrain of space. It is available on the net, on the site of Government of India, Health & Family Welfare Department and hard copy with me. 

DR. PAWAR PRAKSH V:  drpvpawar@hotmail.com Cell - 9869007292 

Protocols for Induction of Ovulation by Jaideep malhotra (Agra)

THE USE OF MESHES IN PELVIC RECONSTRUCTIVE SURGERY

By  Nandita Maitra

Gynecologic surgeons have used graft materials in pelvic reconstructive procedures since centuries. Meshes have been composed of a multitude of materials including silver, nylon, silastic, polyester, polytetrafluoroethylene, and polypropylene. Mesh use for sacrocolpopexy, has been the gold standard for the repair of vaginal vault prolapse. 

The options available for reconstructive pelvic floor surgery include the vaginal, transanal, abdominal, or laparoscopic approaches. The use of biological and synthetic grafts for the transabdominal and transvaginal treatment of pelvic organ prolapse (POP) or stress urinary incontinence (SI) has improved long-term support and function after surgery. However, the potential benefits of using grafts need to be carefully balanced against the risks of using materials foreign to the patient’s body. Huebner et al. suggested that there was limited data available to support the use of graft materials in pelvic reconstructive surgery [1]. 

TYPES OF GRAFT MATERIALS 

1. Autologous grafts: derived from patient’s own body
2. Allograft: from post-mortem tissue banks (dura mater, rectus sheath, fascia lata)
3. Xenograft: from animals (modified porcine dermis, porcine small intestine, bovine pericardium)
4. Synthetic grafts: absorbable or non-absorbable

Synthetic grafts 

The mesh may be absorbable or nonabsorbable, mono or polyfilament. The pore size

and interstices distance  are important mesh characteristics that determine whether host inflammatory cell and fibrocollagenous tissue can penetrate the mesh construct (figure1). The diameter of the open spaces is the pore size, greater than 75 μm is defined as macroporous [2] (figure 2). Polypropylene mesh is usually a type I macroporous (Amid classification, 1997 [2]) and monofilament graft and is the most frequently used synthetic non-absorbable mesh in reconstructive pelvic surgery. This type of mesh is found to have less chances of infection as the large pore size allows penetration by leucocytes and macrophages. It also allows connective tissue in-growth and collagen deposition around the fibers. Type 2 materials are totally microporous (pore size <10 μm expanded polytetrafluoroethylene [ePTFE). In this type there is encapsulation of the graft with collagen but no in-growth and higher chances of infectious complications. Type 3 mesh is made of macroporous materials with either microporous components or a multifilament structure. They have the same problems as the type 2 implants. Type 4 materials have submicroscopic pore size. They are not used in gynecologic surgery [2, 3]. 

Xenograft 

Xenografts, are bovine or porcine acellular collagen bioprostheses derived from dermis, pericardium, or small intestine submucosa. There are eight commercially available xenografts. These were introduced to overcome synthetic mesh related complications such as erosion, infection and fistula formation. The chemical cross-linking used in the preparation of xenografts determines the host response. In grafts that are cross-linked, the prosthesis becomes encapsulated in a manner similar to that of type 2 synthetic mesh. Cross-linked materials that are fenestrated are functionally porous and allow fluid and cells to traverse through, become encapsulated and behave like the Type 3 synthetic mesh. Non-cross-linked materials (sheep intestinal submucosa or SIS) are resorbed by the host tissue at varying rates (usually 4 to 12 weeks) and replaced by endogenous collagen tissue. Thus they act as a scaffold for host cell colonization. A clinical concern for their use is the loss of strength over time, a concern which has heretofore not been addressed in human trials [4]. Otherwise it has a clear theoretical advantage over synthetic material in that the graft is replaced by host connective tissue and, hence, has decreased long-term complications. 

Allografts 

Allografts can have an unpredictable resorption and integration process with 20% of the graft being autolysed over time. Although fastidious steps are taken in the preparation, concerns about the potential risk of viral particles, but more particularly prion transmission, remain. The risk of HIV transmission is estimated to be one in eight million [5].  

HOST RESPONSE TO THE MESH 

Most synthetic materials induce a relatively vigorous foreign body response [6]. After

implantation, the host immediately reacts to the injury and covers the material with a biofilm. Host proteins are adsorbed at the interface and a complex host-to-implant material interaction sets off. It follows a fixed and hierarchical pattern referred to as the Vroman effect [7]. First, low-molecular weight proteins, such as albumin, and, later, more complex proteins, like fibrinogen, immunoglobulins, kininogen, and extracellular matrix molecules are adsorbed. These later undergo conformational changes making them immunogenic and this is necessary for the adequate tissue incorporation of the implant. This immunogenic biofilm, triggers a typical inflammatory response, including leading to activation of the complement system, binding of antibodies, leukocytes, and blood clotting and fibrinolysis activation [8]. This is followed by formation of granulation tissue with fibroblasts, macrophages and eventually foreign body giant cells, with the occurrence of neovascularization as well as fibrosis. As capillaries and inflammatory cells get less in number, fibroblasts become increasingly predominant and deposit collagen and other matrix proteins, causing more fibrosis and mechanical stabilization of the implant. The amount of foreign body reaction increases with the surface of the foreign material being exposed to the host [9]. Based on all the above, there is now a consensus in surgical literature that improved results will be achieved by using a low weight, large pore, monofilament mesh, with an elasticity between 20 and 35% [9]. 

The “biofilm” will allow the bacteria to remain quiescent, but they may multiply if an intercurrent event happens such as alteration of host immune defences. Chronic infections thus can show up several months or even several years after the prosthetic device has been fixed. 

GRAFT USE IN RECONSTRUCTIVE PELVIC SURGERY 

Prolapse Surgery 

In gynecology, the two most common procedures involving the use of synthetic mesh are the abdominal sacrocolpopexy and the suburethrat sling. However, the high rate of failure with conventional colporrhaphy for pelvic organ prolapse has led to an increasing use of synthetic and biological grafts to augment vaginal repair procedures to obtain more durable results. Synthetic grafts are also being used in the treatment of prolapse, post-hysterectomy vaginal vault prolapse and the repair of cystocoele, enterocoele and rectocoele. This approach employs the interposition of a prosthesis (synthetic, autologous, allograft or xenograft) between vaginal epithelium and the underlying fascia. 

The use of synthetic mesh in abdominal sacrocolpopexy is better established than its use in vaginal surgery. Vaginal mesh erosion has been reported to occur in approximately 2% of cases using polypropylene mesh [10] and up to 11% of cases with polytetraflourethylene (Gore-Tex), a microporous multifilament mesh (type II) [11], and polyethylene tetraphalate mesh (Mersilene) (type III). Polypropylene monofilament macroporous mesh erosion, even in the presence of infection, can be successfully treated by transvaginal excision and repair with antibiotics [12]. The incidence of dyspareunia decreased after transvaginal repair with mesh from 20% preoperatively to 7% at 24 months, similar to the results with abdominal mesh colpopexy [13,14].  

According to a report by Maher et al [15] the use of mesh overlays has not improved the outcome of the rectocele repair (level 1) and was associated with significant complications (level 3). Further, Level 2 evidence suggests that the midline fascial plication may offer a superior anatomic and functional outcome compared to the discrete site-specific fascial repair. A recent Cochrane Review by the same authors mentions that for the anterior vaginal wall prolapse, standard anterior repair was associated with more recurrent cystoceles than when supplemented by polyglactin mesh inlay (RR 1.39, 95% CI 1.02 to 1.90) or porcine dermis mesh inlay (RR 2.72, 95% CI 1.20 to 6.14), but data on morbidity, other clinical outcomes and for other mesh or graft materials were too few for reliable comparisons. Meta-analysis on the impact of pelvic organ prolapse surgery on continence issues was limited and inconclusive, although about 10% of women developed new urinary symptoms after surgery [16]. 

Stress Urinary Incontinence 

Amongst the anti-incontinence procedures, only the Tension Free Vaginal Tape (TVT) was extensively studied in Europe before being sold in the USA after 510k FDA approval [17]. When TVT was first introduced into clinical practice in the mid- to late-1990s, the gold standard surgical procedure in the treatment of stress urinary incontinence was the Burch colposuspension. Subsequently, several randomized controlled trials have compared the efficacy and safety of these two procedures and shown that TVT has a lower morbidity rate and equal or superior efficacy at mid-term follow-up. TVT has gradually replaced colposuspension as the first choice procedure, especially now that the long-term results are known (81.3% and 82% cure rate respectively) [18, 19]. However there are concerns with its safety, with complications such as vascular injuries, bowel and bladder injuries being reported. This led to a further modification of technique and the introduction of the Transobturator Tape or TOT. A recent randomized controlled trial (TORP study) [20] found that the TVT group was significantly more likely to be complicated by bladder injury (7 TVT, 0 Monarc TOT, p<0.05), while the incontinence impact was similar in the two groups.  

Ethical Issues for Mesh use and the Liability of the surgeon  

Before 1992, all of the incontinence procedures had physician’s names attached to them, whereas after this date, all procedures have corporate nomenclature to identify the procedures, thus making the practice of medicine to be ‘industry driven’ and not ‘physician driven’. A key point to note is that the FDA 510K approval is only for the device (e.g. graft) and not for the surgical procedures and does not ensure efficacy or safety [17]. FDA approval does not mean that the FDA has evaluated the material for effectiveness and safety nor has it evaluated and approved the surgical procedures. 

Physicians have a fiduciary responsibility to protect their patients by having sufficient data to justify the performance of a new procedure. With innovative therapies being marketed all the time, the doctor would do well to ask industry for 1- year success and adverse event rates published in a peer reviewed journal. It is not advisable to use any graft material, new diagnostic technique, or new surgical procedure for sale in the absence of this information.  

Conclusion 

The role of synthetic or biological grafts in reconstructive pelvic floor surgery is controversial and awaits clarification by further prospective randomized studies. The transvaginal approach needs to be standardized by investigators before prospective studies can occur. The ideal synthetic mesh material for pelvic surgery, one that induces minimal foreign-body reaction with minimal risk of infection, rejection and erosion, has yet to be developed. Until more evidence is available, these graft materials should be restricted to clinical trials or to women with recurrent pelvic organ prolapse.  

REFERENCES

1. Huebner M, Hsu Y, Fenner DE  The use of graft materials in vaginal pelvic floor surgery. Int J Gynaecol Obstet 2006;92:279–288
2. Amid PK. Classification of biomaterials and their related complications in    abdominal wall hernia surgery. Hernia 1997;1:15–21
3. Birch C, Fynes MM The role of synthetic and biological prostheses in reconstructive pelvic floor surgery. Curr Opin Obstet 2002;14:527-535
4. Trabuco EC, Klingele CJ, Gebhart JB. Xenograft use in reconstructive pelvic surgery: a review of the literature. Int Urogynecol J (2007) 18:555–563
5. Deprest J, Zheng F, Konstantinovic M, Spelzini F, Claerhout F, Steensma A, Ozog Y et al. Int Urogynecol J 2006 17: S16–S25
6. Klosterhalfen B, Klinge U, Hermann SB, Schumpelick V Pathology of traditional surgical nets for hernia repair after long-term implantation in humans. Chirurg 2000;71:43–51
7. Vroman L, Adams AL. Identification of absorbed protein films by exposure to antisera and water vapor. J Biomed Mater Res 1969;3:669–671
8. Tang L, Eaton JW.  Inflammatory responses to biomaterials. Am J Clin Pathol 1995;103:466–471
9. Rosch R, Junge K, Hölzl F et al 2004. How to construct a mesh. In: Schumpelick V, Nyhus LM (eds) Meshes: benefits and risks. Springer, Berlin Heidelberg New York, pp 179–184
10. Fynes M, Goh JTW, Chong C, Murray C, Rosamilia A, Dwyer PL, Carey M .    Abdominal sacral colpopexy for vaginal vault prolapse. Int Urogynecol J Pelvic Floor Dysfunct  2001;12:14
11. Gandhi S, Kubba LM, Abramov Y, Botros SM, Goldberg RP, Victor TA et al   Histopathologic changes of porcine dermis xenografts for transvaginal suburethral slings. Am J Obstet Gynecol 2002; 192:1643–1648
12. Burger JW, Luijendijk RW, Hop WC, Halm JA, Verdaasdonk EG, Jeekel J (2004)      Long-term follow-up of a randomized controlled trial of suture versus mesh repair of incisional hernia. Ann Surg 2004;240:578–583
13. Dwyer PL, O’Reilly BA  Transvaginal repair of anterior and posterior compartment prolapse with Atrium polypropylene mesh. Br J Obstet Gynaecol 2004; 111(8):831–836
14. Dwyer PL. Evolution of biological and synthetic grafts in reconstructive pelvic surgery. Int. Urogynecol J 2006;17:S10- S15
15. Maher C, Baessler K. Surgical management of posterior vaginal wall prolapse: an evidence based literature review. Int Urogynecol J 2005;17:84-88.
16. Maher C, Baessler K, Glazener CM, Adams EJ, Hagen S. Surgical management of pelvic organ prolapse in women. Cochrane Databse of Syst Rev 2007; 18 (3):CD004014.
17. Ostergaard DR. Lessons from the past :directions for the future. Do new marketed surgical procedures and grafts produce ethical personal liability and legal concern for physicians? Int Urogynecol J (2007) 18:591–598
18. Ward KL, Hilton P. UK and Ireland TVT Trial Group. A prospective multicenter randomized trial of tension free vaginal tape and colposuspension for primary urodynamic stress incontinence: two year follow-up. Am J Obstet Gynecol 2004;190:324-31

19. Nilsson CG, Falconer C, Rezapour M. Seven-year follow-up of tension-free vaginal tape procedure for treatment of urinary incontinence. Obstet Gynecol 2004;104:1259–62.
20. Barry C, Lim YN, Muller R, Corstiaans A, Foote A et al. A multi-centre, randomized clinical control trial comparing the retropubic (RP) approach versus the transobturator approach (TO) for tension-free, suburethral sling treatment of urodynamic stress incontinence: the TORP study. Int Urogynecol J (2008) 19:171–178

FIGURES

Figure 1: Terminology used to classify synthetic implants. Magnified view of a part of a polypropylene tape as used for TVT procedure (Gynecare, Johnson and Johnson) with identification of filament, interstitium, and pore.Taken from: Deprest J, Zheng F, Konstantinovic M, Spelzini F, Claerhout F, Steensma A, Ozog Y et al. Int Urogynecol J 2006 17: S16–S25  

 Figure 2: Electron micrograph of Type 1 mesh (Gynemesh)

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