8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

Preterm Premature Rupture of the Membranes

M. Gjoni
Albania

Tutor
J. Villar
HRP - UNDP/UNFPA/WHO/World Bank Special Programme

Introduction

Preterm premature rupture of the membranes (pPROM) is the classic case when a normal pregnancy becomes suddenly a high-risk one for mother and fetus/neonate. This complication has been and is still considered as one of the most serious events.

There are many studies dealing with this complication and yet there is no final general agreement on the assessment of fetal well-being, management and follow-up of the pregnancy up to the decision when to interrupt it.

During the last five years there seems to be enormous progress concerning the outcome of pregnancies complicated by pPROM.

Looking at the literature concerning pPROM there are different opinions revealed by several studies. Especially the smaller the gestational age of a pregnancy is, the bigger is the diversity of opinions of managing the problem.

Several authors advice obstetric services to build up their own protocol, based on the population’s specifications and socio-economic status as well as on the level of the health care offered by the hospital.

Definitions and abbreviations

PROM	Premature rupture of the membranes before labour contractions begin, whatever the age of the pregnancy.
pPROM	Pre-term premature rupture of the membranes, meaning rupture of the membranes before labour contractions begin in a pre-term pregnancy.
Latent period	Time from rupture of the membranes up to delivery.
Latent interval	Time from rupture of the membranes to the beginning of the active phase of labour.
AFI	Amniotic fluid index
AGA	Adequate for gestational age
AL	Amniotic liquid
BPP	Biophysical profile
CST	Contraction stress test
FBM	Fetal breathing movement
FM	Fetal movement
FRH	Fetal heart rate
GA	Gestational age
IAI	Intra-amniotic infection
IUGR	Intra-uterine growth retardation
IVH	Intra-ventricular haemorrhage
MP	Multifetal pregnancy
NST	Non-stress test
RDS	Respiratory distress syndrome
SGA	Small for gestational age

Epidemiology

Most of the authors show an incidence of 2-3% (1;12) for pPROM. About 30% of pre-term deliveries are anticipated by pPROM. Different numbers found in the literature are due to:

• demographic characteristics of the population studied;
• methods used for diagnosis;
• age of pregnancy at the moment of pPROM;
• type of study (retrospective or prospective);

In table 1, data from several studies between 1940 - late '80 are shown, including a large number of cases.

Table 1. Frequency of PROM

(from Anthony R. 12)

Table 2. Frequency of pPROM*

Author	Age-group / weight	pPROM	Year - Country
Veber	> 32 weeks	2	1989 - London
Veber	28 - 31 weeks	28	1989 - London
Veber	< 28 weeks	33	1989 - London
Tejani	< 2.500 gr	17	1988 - California
Tejani	< 2.500 gr	29	1988 - California

* In both studies more than 6.000 cases were surveyed.

Etiology

The etiology of pPROM is multifactorial (3; 13). Three items are involved in its etiology:

• the special anatomy of the membranes
• risk factors for their rupture
• protecting factors against pPROM

Few words on anatomy

The amnion is a mono-cellular epithelial layer, 0.02 - 0.05 mm thick and not vascularised. The connective tissue underneath contains dense filaments of collagen (25,47,62). Chorion is a 2 - 10 mm layer of cuboid cells, adherent to the decidua and perfused by dense vascularisation. This special structure makes the membranes more resistant to damage. If they are locally damaged by any factor which disappears later on, the membranes will probably restore their integrity.

Risk factors

The membranes may resist to a pressure higher than the intrauterine one (7,24,28) They rupture if damaged by any risk factor, as those listed below:

• infection (cervico-vaginitis);
• cervical incompetence;
• smoking;
• invasive procedures in the cervix;
• low placental insertion;
• Ehlers Danlos syndrome;

In more than 50% of the cases, pPROM occurs during physical rest of the women. This fact indicates once the membranes are damaged, they loose their resistance and rupture spontaneousely. Infection is the major cause of membrane damage (5;26). The micro-organisms produce proteolytic enzymes and are often isolated in pregnancies complicated by pPROM. The use of antibiotics to prevent pre-term delivery has been successful in reducing the incidence of pPROM too.

The most frequent germs isolated in cases complicated by pPROM are: Chlamydia, Mycoplasma, group B Streptococcus (30; 31; 32). The same micro-organisms are often found to cause pre-term birth with intact membranes. In both cases, the level of immuno-globulins in the AL is high.

During normal pregnancy, collagen content of the membranes decreases gradually with increasing gestational age. It has been proven that in pregnancies complicated by pPROM, collagen content decreases earlier than in normal ones. This is one of the reasons that the membranes loose their mechanical resistance and rupture easily, even at rest.

The membranes are not damaged uniformly. The common place of rupture is the lower pocket because this is the locus where ascending infections attack.

Increased intrauterine pressure, especially acute, may be an adjuvant cause of pPROM (polihydramnion, multifetal pregnancy, etc.). On the other hand, this pressure reduces the utero-decidual perfusion of the membranes. Physical effort doesn’t seem to have any impact on preterm rupture (6, 27).

Protecting factors

A healthy vagina and a competent cervix are defined as good barriers to ascending infections. Cervical mucus plays also an important anti-bacterial role as well as the pH of a healthy vagina itself.

Diagnosis

There are no real prodroms of pPROM but amniorrhoea is in some cases preceded by lower pelvic pain (35%) and increased vaginal discharge (30%).

The leakage of amniotic fluid is the most common symptom of pPROM. In 1929, Phillip and Williams used to look through the microscope at samples from the posterior fornix, in order to distinguish lanugo. In 1942, Bourgeois coloured foetal fat cells, confirming the diagnosis of pPROM. In 1933, Temesvary found that the vaginal pH changes from 5 to 7 due to amniorrhoea. It was in 1944 when arborisation was used for the first time to diagnose pPROM with a low failure rate, a sensibility of 96-99% and specificity of 98-99%. The results may be misleading in the presence of blood, urine or meconium in the fornix (65).

A normal vaginal pH (3,5-4) is altered by the leakage of LA (pH = 7).

A very important tool for the diagnosis is ultrasound examination (66). Measuring the deepest pocket or calculating ALI, amniorrhoea can be diagnosed and the quantity of amniotic liquid can be followed throughout the pregnancy, thus confirming if oligo-amnios is still present or recovered. The presence of an anterior pocket is a valuable parameter of the pregnancy outcome. a -feto protein is also an important diagnostic marker f found in the posterior vagina.

Management

Dealing with pregnancies complicated by pPROM, one has to keep two risks in mind:

• pre-term delivery, surviving rates and long-term complications for the baby;
• infection risk for mother and fetus

Treatment

Several studies achieve better results by using antibiotic prophylaxis. Infection rates are closely related to the duration of latent period, vaginal examination or manipulation and to pre-existing cervico-vaginal infections. Microbiological examination of the vagina must be performed with the help of a speculum, measuring the pH and performing the arborisation test at the same time. The antibiogram will reveal the most efficient antibiotic which may be continued up to the end of pregnancy.

It is not suitable to use bacteriolytic antibiotics because of the toxins' induction of pre-term contractions. Fetal outcome is far better if prophylactic antibiotics are used (52).

On the other hand, some authors suggest to use antibiotics only when clinical signs appear and laboratory data confirm infection. They are concerned that antibiotic use would lead to microbial resistance in the neonate.

In 1972, Liggins used for the first time steroids to prevent the neonatal RDS, which is nowadays part of routine care for women in preterm labour. It is confirmed that the best results are achieved after the first treatment, beginning after 24 hours up to one week after. The second cycle of treatment gives a lower rate of RDS prevention. Intra-muscular rather than oral administration is suggested. Steroids appear to be successful to prevent RDS when administered in pregnancies between 27-30 weeks with prevention rates up to 50%. One has to keep in mind that steroids might increase the risk of infection (59).

It has been proven that steroid treatment is associated with a lower rate of long-term complications of pre-term born babies, matched for GA. Among babies receiving steroids in utero neurological impairment is less frequent compared to new-borns with higher birth weight.(2;33). Patricia C. refers to a follow up for a two to six year period (17).

The conclusions of the majority of studies reveal that in pregnancies complicated by pPROM the pulmonary maturation is accelerated compared to uncomplicated pre-term births of the same gestational age (41; 42; 56).

Table 3. Steroid effect on preventing RDS in pPROM pregnancies

Nowadays, the use of tocolytic agents is no longer recommended as routine care for women with pPROM. Different studies observed a higher rate of neonatal infection when long-term tocolysis was used (8; 63). The main indication for still using it is to gain time to:

• to give the possibility of using intra-muscular steroid treatment for 24 hours;
• to transfer the patient to a tertiary intensive care unit.

Assessment of fetal well-being

Up to ten years ago, amniocentesis was routinely performed as a routine for the detection of IAI. Recent studies have shown that amniocentesis at the time of recovery gives low diagnostic results (11; 15). Also, it is invasive and may be the cause of infection. Romero et al. in the early '90, have suggested that BPP has the same diagnostic accuracy as amniocentesis to detect IAI. In general, a score of 8 BPP is a good predictor for fetal well-being.

For example, normal foetal respiratory movements exclude IAI. For accurate assessment of fetal well-being, BPP should be performed once every 24 hours (43).

The assessment of AL quantity is also very important. If the greatest pocket is more than 2 cm, the risk of harm for the fetus is low. But for better accuracy, AFI should be calculated. If exposed for a long time to oligoamnios (9; 23), the fetus is at risk of developing non-renal agenesia (Potter syndrome). The duration of exposure may be as little as six days. (10; 29).

As the pregnancy progresses to term, NST is always more sensitive to assess fetal well-being. A reactive NST is associated with 93% fetal survival within one week.

It is currently recommended to perform amniocentesis if two or more of the following indications exist:

• fetal lung maturation diagnosis;
• amnio-infusion;
• micro-biological investigation;
• local use of antibiotics;
• diagnostic confirmation by a dye;

Infection risk for the mother

There is a general agreement for the follow up of maternal infection. The classic screening implies: body temperature, which is regarded positive if more than 38° C for a duration of 24 hours or more, a heart rate of 100 or more / min, elevated WBC count, odorous vaginal secretion and uterine tenderness (48).

Table 4. Frequency of symptoms associated with IAI

Symptoms		Frequency (%)
Temperature	> 37.8 C	100
Maternal Heart Rate	> 100 / min	20 - 80
Fetal Heart Rate	> 169 / min	40 - 70
White Blood Cells / cc	> 15.000	70 - 90
White Blood Cells /cc	> 20.000	3 -10
Odorious AL		5 - 22
Uterine Tenderness		4 - 25

If two or more of the above mentioned tests are positive, chorioaminionitis is considered to be present and interruption of pregnancy is advised. Several data confirm strong relationships regarding the time of first vaginal examination till delivery and maternal infection. Therefore, speculum use instead of a gloved hand is strongly advised when a vaginal approach is needed.

Evidence that IAI is caused by ascending germs was first shown by Knix and Hoerner in 1950. They proved that infection will attack membranes and make them susceptible to rupture. The first treatment goes back to 1966, when vagina was irrigated by non-specific antiseptics. The histopathology of the placenta, AL and membranes revealing the presence of germs were associated with pre-term birth at a rate of 23% (45; 48).

Decision for interruption of pregnancy

• Interruption of pregnancy is considered when the risk of infection overcomes the risk of prematurity. There are three major indications, which obviously suggest the interruption of pregnancy:
• fetal lung maturation;
• fetal distress;
• maternal and/or fetal infection;

The decision to interrupt the pregnancy varies from different countries and hospitals (18). It mostly depends on neonatal survival rates matched for gestational age as it appears in the following table:

Table 5. Neonatal survival rate of pregnancies complicated by pPROM

Gestational age (weeks)	Survival rate (%)
24	36
25	55
26	65
27	76
28	85
29	90

p.s. Surfactant has been used postnatally (Jonathan M, 14)

One also has to consider the specific situation for every pregnancy, e.g. age of the pregnant woman, obstetric history, other current risk factors, IUGR, diabetes, PIH, etc.

Many studies advise decision making according to the gestational age:

• 20-24 weeks of pregnancy: the survival rate is very low (less than 20-25%), with a very accurate expectant management of the pregnancy. Infection risk is very high and the long-term complications are very common and need an expensive follow-up. Therefore, termination of pregnancy is more often offered to the parents (60).
• 24-26 weeks of pregnancy: most of the studies suggest active management, checking for infection or fetal distress. In case of clinically apparent symptoms and positive laboratory results for chorio-amnionitis, it is advisable to interrupt the pregnancy by induction of labour (64). Caesarean section should be avoided if possible, being associated with a high rate of puerperal infection (39).
• 26-30 weeks of pregnancy: observation and follow-up are advisable. Antibiotic prophylaxis and steroids are considered to be of benefit. The risk of prematurity is higher than the risk of fetal/neonatal infection. This age-group has the highest benefits from the steroids treatment. Tocolysis is indicated if transfer to another health care unit is needed (58).
• 30-36 weeks of pregnancy: survival rate is high in this age-group (95%) (6). Lung maturation is achieved in more than 50% of cases, thus one has to check if steroids are needed. Antibiotics are advisable if the latent period is rather long. Interruption of pregnancy, once the diagnosis of IAI is confirmed, has no better outcome than using a antibiotics before induction is commenced. In this age-group induction failure rate is low and the need of C/S and its puerperal complications are rare (53; 55).

One has to keep in mind that if there is a lower pocket present, the risk of infection is low and expectant policy less risky. In about 10% of case amniotic leakage stops spontaneously and AL quantity is restored. It is suggested to admit the woman to the hospital and asses fetal well-being with daily US for a few days. If there are no abnormalities she may be discharged and re-examined after one week. Otherwise, discharging the patients from the hospital is not advisable.

Amnioinfusion is reserved for the cases where other indications for amniocentesis are also present. It is not advisable as a routine procedure and is useless if leakage continues.

Perinatal and neonatal outcomes are similar in twin and singleton pregnancies (54).

Repeated pPROM

Pre-term birth or pPROM in a previous pregnancy is associated with subsequent pPROM. If a positive history exists, the woman has to be assessed for the possible presence of risk factors (22), e.g. cervix incompetence, smoking. The two most frequent risk factors are: multifetal pregnancy and hydramnion. Infection and its inadequate treatment are the most common causes for repeated pPROM (22). A vaginal pH up to 4.5 or more, is associated with high risk for pPROM. Low genital tract cultures provide poor prediction of IAI and pPROM (50; 57).

References

1. Steven R. Epidemiology of premature rupture of the fetal membranes. Clin Obstet Gynecol 1991; 34 (4): 685-694
2. Nancy R. The role of corticosteroids in the management of patient with preterm premature rupture of membranes. Clinical Obstet Gynecol 1991; 34(4): 694-702
3. William J. Mecanical factors in the ethiology of pPROM. Clinical Obstet Gynecol 1991; 34(4): 702-714
4. Kim M. Dtection of the pPROM. Clinical Obstet Gynecol 1991; 34(4): 715-723.
5. Patrick D. Management of pPROM in term patients. Clinical Obstet Gynecol 1991; 34(4): 723-730
6. Tamerou A. Mnagement of pPROM. Clinical Obstet Gynecol 1991; 34(4): 730-743
7. Rosemary T. Antibiotic therapy in pPROM. Clinical Obstet Gynecol 1991; 34(4): 742-750
8. Frederick E. The use of tocolytics in patients with pPROM. Clinical Obstet Gynecol 1991; 34(4): 751-758
9. Douglas S. Complications of prolonged PROM nad oligoamnios. Clinical Obstet Gynecol 1991; 34(4): 759-769
10. Romero R. Microbial invasion of the amniotic cavity in pPROM. Clinical Obstet Gynecol 1991; 34(4): 769-778
11. Anthony M. Antepartum surveillance in patients with pPROM. Clinical Obstet Gynecol 1991; 34(4): 779-793
12. Anthony R. Introduction to pPROM. Obstet Gyne Clinics of North America 1992; 19(2): 241-247
13. Philip J. Ethiology of pPROM. Obstet Gynecol Clinics of North America 1992; 19(2): 251-263
14. Jonathan M. Neonatal morbidity and mortality secondary to pPROM.. Obstet Gyn Clinics of North America 1992; 19(2): 265-277
15. Anthony M. Test of fetal well-being in pPROM. Obstet Gynecol Clinics of North America 1992; 19(2): 281-305
16. Maureen P. Expectant and active management of pPROM. Obstet Gyn Clinics of North America 1992; 19(2): 309-315
17. Patricia C. Corticosteroids after pPROM. Obstet Gyn Clinics of North America 1992; 19(2): 217-225
18. James A. Use of antibiotics for pPROM. Obstet Gyn Clinics of North America 1992; 19(2): 327-337
19. Brian M. Management of pPROM before 26 weeks of gestation. Obstet Gyn Clinics of North America 1992; 19(2): 339-349
20. Franc J. Mnagement of pPROM at term. Obstet Gyn Clinics of North America 1992; 19(2): 353-364
21. Motoharu I. New technologies for the management of pPROM. Obstet Gyn Clinics of North America 1992; 19(2): 365-385
22. Anne C. Antenatal care of the patients with previous pPROM. Obstet Gyn Clinics of North America 1992; 19(2): 387-393
23. Katherine D. Pulmonary hypoplasia and deformations related to pPROM. Obstet Gyn Clinics of North America 1992; 19(2): 397-407
24. Harger J. Risk factors for pPROM. Am J Perinatol 1994; 7: 374
25. Skinner S. Collagen content of human amniotic membranes. Obstet Gyn 1981; 57:487
26. Riedvald S. Vaginal and cervical pH in normal pregnancy and in pregnancies complicated by labour. J Perinatol Med 1990; 18:181
27. Clapp I. Endurance exercise and pregnancy outcome. Med Sci Sport Exer 1984; 16:557
28. Mc Gregory. Antibiotic inhibition of bacterially induced fetal membrane weakening. Obstet Gyn 1990; 76:124
29. Edward R. Chorioamnionitis and intraamniotic infection. Clinical Obstet Gynecol 1993; 36(4): 795-807
30. J Chris Carey. The vaginal infection and prematurity study: an overview. Clinical Obstet Gyn 1993; 36(4) : 809-819
31. Vern I. Management of group B strept disease in pregnancy. Clinical Obstet Gyn 1993 ; 36(4) : 832-842
32. Hedstorm S. Antibiotics in pregnancy. Clinical Obstet Gyn 1993 ; 36(4) : 886-892
33. Bauer C. Prolonged pPROM associated with a decreased incidence of RDS. Pediatrics 1974 ; 53 :7
34. Richard H. Non-stress test. Clinical Obstet Gyn 1995 ; 38(1) : 3-10
35. David C. The contraction stress test. Clinical Obstet Gyn 1995 ; 38(1) : 11-25
36. Frank A. Dynamic ultrasound based fetal assessment : the fetal biophysical profile score. Clinical Obstet Gyn 1995 ; 38(1) : 26-44
37. Anthony M. Fetal biophysical assessment in pPROM. Clinical Obstet Gyn 1995 ; 38(1) : 45-58
38. William F. Fetal movement monitoring. Clinical Obstet Gyn 1995 ; 38(1) : 59-67
39. Assessment of amniotic fluid volume in at-risk pregnancies. Clinical Obstet Gyn 1995 ; 38(1) : 79-90
40. Morales WJ. The effect of antenatal dexamethasone administration on the prevention of the RDS in preterm gestations with Pprom. Am J of Obstet Gyn 1986 ; 154 :591
41. Crowley P. Corticosteroids prior to preterm delivery. Oxford, 1992 ; disk 7 ; record 2955.
42. Liggins G. A controlled trial of antepartum glucocorticoide treatment for prevention of the RDS in premature infants. Pediatrics 1972 ; 50 :515
43. Dev. Maulik. Doppler ultrasound velocimetry for fetal surveillance. Clinical Obstet Gyn 1995 ; 38(1) : 1-111
44. Jens Svare. Uro-genital microbial colonisation and threatened preterm delivery. Acta O/G Scandinavia 1994 ; 73 : 460-464
45. Michael J. Urinary tract infection in pregnancy. Clinical Obstet Gyn 36(4) : 855-868
46. Mercer B. Erythromycin therapy in Pprom : a prospective randomised trial of 220 patients. Am J of Obstet Gyn 1992 ; 166 : 794-802
47. Lockwood C. Fetal fibronectin in cervical and vaginal secretions as a predictor of preterm delivery. N Engl J Med 1991 ; 325 : 669-674
48. Romero R. Infection and labour : microbial invasion of the amniotic cavity in spontaneous rupture of membranes at term. Am J Obstet Gyn 1992 ; 166 : 129-133
49. Garland SM. Group B strept. (GBS) and neonatal infection : the care for intrapartum chemioprophylaxis. Aust N Z Obstet Gyn 1991 ; 31 : 119-122
50. Carroll SG, Ppaioannou S, Ntumazah IL, Philpott-Howard J, Nicolaides KH. Lower genital tract swabs in the prediction of intrauterine infection in pre-term pre-labour rupture of membranes. Br J Obstet Gynaecol 1996 Jan; 103(1): 54-59.
51. Vintzileos AM. Antepartum surveillance in pre-term rupture of membranes. J Perinatal Med 1996; 24(4): 319-326.
52. Egarter C, Leitich H et al. Antibiotic treatment in preterm premature rupture of membranes and neonatal morbidity: a metaanalysis. Am J Obstet Gynaecol 1996 Feb; 174(2): 589-597.
53. van Heerden J, Steyn DW. Management of premature rupture of membranes after 34 weeks' gestation--early versus delayed induction of labour. S Afr Med J 1996 Mar; 86(3): 264-268.
54. Bianco AT, Stone J et al. The clinical outcome of prterm premature rupture of membranes in twin versus singleton pregnancies. Am J Perinatol 1996 Apr; 13(3): 135-138.
55. Roztocil A, Novotna M, et al. An active approach in membrane rupture before the 32nd week of pregnancy and perinatal results. Ceska Gynecol 1996 Jun; 61(3): 157-161.
56. Imseis HM, Iams JD. Glucocorticoid use in patients with preterm premature rupture of the fetal membranes. Semin Perinatol 1996 Oct; 20(5): 439-450.
57. Doody DR, Patterson MQ et al. Risk factors for the recurrence of pPROM. Paediatr Perinat Epidemiol 1997 Jan; 1: 96-106.
58. Eroiz-Hernandez J et al. Conservative management of pPROM in pregnancy of 28-34 weeks. Aleatory clinical trial. Ginecol Obstet Mex 1997 Feb; 65: 43-47.
59. Chen B, Basil JB et al. Antenatal steroids and intravascular hemorrhage after pPROM at 24-28 weeks'gestation. Am J Perinatol 1997 Mar; 14(3): 171-176.
60. Nourse CB, Steer PA. Perinatal outcome following conservative management of mid-trimester pre-labour rupture of membranes. J Paeditr Child Health 1997 Apr; 33(2): 125-130.
61. Vergani P, Locatelli A et al. Amnioinfusion for prevention of pulmonary hypoplasia in second-trimester rupture of membranes. Am J Perinatol 1997 Jul; 14(6): 325-329.
62. Hampson V, Liu D et al. Amniotic membrane collagen content and type distribution in women with pPROM in pregnancy. Br J Obstet Gynaecol 1997 Sep; 104(9): 1087-1091.
63. Decavalas G, Mastrogiannis D et al. Short-term versus long-term prophylactic tocolysis in patients with preterm premature rupture of membranes. Eur J Obstet Gynecol Reprod Biol 1995 Apr; 59(2): 143-147.
64. Tan BP, Hannah ME. Abstract of review: Oxytocin for prelabour rupture of membranes at or near term. The Cochrane Library.
65. Atterbury JL, Groome LJ, Hoff C. Methods used to diagnose pPROM: a national survey of 812 obstetric nurses. Obstet Gynecol 1998 Sep; 92(3): 384-389.
66. Frigo P, Lang C, Sator M, Ulrich R, Husslein P. Mmebrane thickness and PROM--high-frequency ultrasound measurements. Prenatal Diagn 1998 Apr; 18(4): 333-337.