16. Obstetric outcomes after recurrent pregnancy loss

Howard JA Carp

INTRODUCTION

Most work on recurrent pregnancy loss (RPL) has concentrated on the causes, prognosis, treatment, and subsequent live birth rate. However, a question arises as to whether this group of patients is at a higher risk for obstetric complications such as bleeding, fetal anomalies, preeclampsia, intrauterine growth restriction (IUGR), preterm labor, and perinatal mortality, and whether prenatal care has to be modified to seek these complications. The question then arises as to whether these complications are associated with specific conditions associated with RPL. Antiphospholipid syndrome (APS) and hereditary thrombophilias are two such conditions that have been described to be associated with recurrent pregnancy loss and late obstetric complications. Various interventions have also been reported to affect the incidence of later obstetric complications. These interventions include paternal leukocyte immunization and intravenous immunoglobulin (IVIG) for unexplained RPL, anticoagulants and aspirin or IVIG for APS, and anticoagulants for hereditary thrombophilias. This chapter assesses some of the obstetric complications associated with different forms of RPL and the treatment modalities that have been used.

METHOD OF STUDY

Publications describing the obstetric complications in RPL were sought by a thorough literature search including online databases, MEDLINE and EMBASE. The original database of the Recurrent Miscarriage Trialists Group is held by the author as one of the data contributors to that database. Figures were also

obtained from one of the author’s own databases, which contains information on 1800 patients attending the Recurrent Miscarriage Clinic of the Sheba Medical Center, Tel Hashomer, Israel. The figures were entered into a computerized database (SPSS, Chicago, Ill) and analyzed.

STATISTICAL ANALYSIS

Odds ratios (OR) with 95% confidence intervals (CI) were calculated for developing obstetric complications such as vaginal bleeding, anomalies, preeclampsia, IUGR, and perinatal mortality. When true incidences were available from cohort studies, the relative risks (RR) were calculated. These figures were also compared in subgroups of patients and after various treatment interventions.

INCIDENCE OF OBSTETRIC

COMPLICATIONS AFTER RPL

Most of the literature on obstetric complications comes from an era after APS had been defined but before hereditary thrombophilias had been defined. Reginald et al,1 in a retrospective observational cohort study, assessed the results of 175 pregnancies in 97 recurrently miscarrying women whose subsequent pregnancy progressed beyond 28 weeks. However, the underlying causes of RPL in this group of women were not documented. The results were not compared with a control group attending the same hospital, but with standard figures from Scotland between 1973 and 1979. A significantly higher incidence of preterm deliveries, perinatal deaths, and IUGR was found. In contrast, Hughes et al2 examined the obstetric

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RECURRENT PREGNANCY LOSS: CAUSES, CONTROVERSIES AND TREATMENT

outcome in 88 women with a past history of three or more consecutive pregnancy losses and compared the results with a control group drawn from their local obstetric population. The incidences of small-for-gestational-age infants (3.4%), preterm delivery (12.5%), and perinatal mortality (0%) were no different to those in the control group. As in the study by Reginald et al,1 there was no mention of APS. However, an increased incidence of gestational diabetes and pregnancy-induced hypertension was found. Tulppala et al3 conducted a prospective study of 32 deliveries in 63 women with RPL and presented the results of a detailed investigative protocol, including APS. The incidences of IUGR (20%), preterm delivery (9.7%), and impaired glucose tolerance (22.8%) appeared to be increased. Unfortunately, the results were not compared with any control population. Jivraj et al4 studied a cohort of 162 women with RPL compared with local controls, and found an increased incidence of the same complications as Reginald et al,1 but also an increased incidence of cesarean sections, which were performed for the above obstetric conditions. Although that study did define the causes of pregnancy loss in the control group, the figures were too small to allow comparisons to be drawn between different groups of patients. Seidman et al5 reported the same complications in 338 women with pregnancy losses compared with 13 338 parous women in a multicenter study in four large hospitals in Jerusalem. In the survey by Seidman et al,5 there was a statistically significant 14% prevalence of preterm labor, compared with 7.5% in control women (OR 2.32; 95% CI 1.67–3.22). The different prevalence of IUGR was even more significant: 14% in aborting women, compared with 5% in control women (OR 3.02; 95% CI 2.17–4.18). However, the study by Seidman et al5 included patients with one pregnancy loss and was not restricted to patients with RPL. A more recent population-based study has been reported by Sheiner et al,6 in which all singleton pregnancies were assessed in women with and without two or more consecutive recurrent abortions. Between 1988 and 2002, 154 294 singleton deliveries occurred. Of these deliveries, 7503 occurred in

patients with RPL. The following complications were found to be associated with RPL: advanced maternal age, cervical incompetence, diabetes mellitus, hypertensive disorders, placenta praevia and abruptio placentae, malpresentations, and premature rupture of the membranes (PROM). A higher rate of cesarean section was also found in patients with previous RPL compared with controls: 15.9% and 10.9%, respectively (OR 1.6; 95% CI 1.5–1.7).

An attempt was made to determine the common OR for various late complications of pregnancy after RPL compared with controls. The series of Reginald et al1 could not be included as there was no relevant control group. The series of Seidman et al5 was not included as it only described patients with one previous miscarriage. The series of Tulppala et al3 could not be included as there was no control group. The other three publications were combined in a meta-analysis.

VAGINAL BLEEDING

The incidence of bleeding was only described in the series of Reginald et al quoted by Beard,7 and in that of Seidman et al.5 Hence no common OR could be calculated. Vaginal bleeding seems to be increased in pregnancies that develop. Vaginal bleeding is a common complication, occurring in 50 of 162 women in the series of Reginald et al7 and in 50 of 102 patients in the author’s series.8 The reason for this bleeding remains unclear. Seventyfive percent of habitual abortions are blighted ova.8 However, when the pregnancy succeeds and there is a live embryo within the uterus, bleeding still occurs in 40–50% of patients. Seidman et al5 also reported a 13.7% incidence of first-trimester bleeding, compared with a 13.8% incidence in the standard population.

ANOMALIES

Little information is available on anomalies. The study by Sheiner et al6 reports 2 anomalies in 29 patients. Although this is a very small series, the figures are higher than expected. Analysis of the figures in the RMITG trial9 showed an anomaly rate

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Study	Statistics for each study					OR and 95% Cl
		Lower	Upper
Hughes et al2	OR	limit	limit	p
	7.001	3.977	12.323	0.000
Jivraj et al4	2.335	0.739	7.379	0.149
Sheiner et al6	2.233	2.073	2.406	0.000
Common OR	2.277	2.116	2.451	0.000
				0.1		1			10						100

Figure 16.1 Odds ratio (OR) for gestational diabetes in recurrent pregnancy loss.

of 4%. In the author’s series, there were three anomalies in 99 developing pregnancies in non-treated patients. However, in the RMITG series and the author’s series, no control group is available.

DIABETES

Three papers have described the prevalence of diabetes: Hughes et al,2 Jivraj et al,4 and Sheiner et al.6 As a control group was available, their common OR could be determined for 7753 patients with RPL and 172 490 control patients. The prevalence of diabetes was 11.75% and 4.95% in recurrently miscarrying and control patients, respectively. The OR are summarized in Figure 16.1. As can be seen, there was a common OR of 2.27 for gestational diabetes in RPL. This figure was statistically

significant (95% CI 2.1–2.45). Tulppala et al3 also found a prevalence of 22.6% (7 of 31 patients tested).

PREGNANCY-INDUCED HYPERTENSION

Hughes et al,2 Jivraj et al,4 and Sheiner et al6 quoted the incidence of pregnancy-induced hypertension (PIH). The figures are summarized in Figure 16.2. In order to obtain significant numbers, the figures for preeclampsia and other forms of PIH were analyzed as a whole. The common OR was 1.89 (95% CI 1.74–2.06), which was statistically significant. The total number of patients was identical to those with gestational diabetes. The prevalence of PIH was 671 of 7753 patients (8.6%) of recurrently miscarrying patients, compared with 5.7% of control women (9921 of 172 490 control patients).

Study	Statistics for each study						OR and 95% Cl
		Lower	Upper
Hughes et al2	OR	limit	limit	p
	1.941	0.783	4.814	0.152
Jivraj et al4	0.728	0.412	1.285	0.274
Sheiner et al6	1.933	1.778	2.102	0.000
Common OR	1.894	1.743	2.057	0.000
				0.1			1				10				100

Figure 16.2 Odds ratio (OR) for pregnancy-induced hypertension in recurrent pregnancy loss.

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Study	Statistics for each study						OR and 95% Cl
		Lower	Upper
Hughes et al2	OR	limit	limit	p
	2.433	0.762	7.768	0.133
Jivraj et al4	6.885	4.318	10.978	0.000
Sheiner et al6	1.000	0.847	1.181	0.998
Common OR	1.257	1.076	1.467	0.004
				0.1			1			10				100

Figure 16.3 Odds ratio (OR) for intrauterine growth restriction in recurrent pregnancy loss.

Neither Reginald et al1 nor Tulppala et al3 quoted figures for PIH.

INTRAUTERINE GROWTH RESTRICTION

The same three papers as above give figures for IUGR. The common OR for developing IUGR is 1.25 (95% CI 1.08–1.47) (Figure 16.3). Reginald et al1 reported a 33% incidence in 344 pregnancies prospectively followed up, and reported that this showed a relative risk of 3 compared with the standard Scottish population. Tulppala et al3 also reported a 20% incidence (6 out of 30 pregnancies).

PRETERM LABOR

Comparative figures are only available for preterm labor from the series of Hughes et al2 and Jivraj et al.4

Figure 16.4 summarizes the results. Again, there was a statistically significant association between preterm labor and RPL. The common OR was 2.84 (95% CI 1.96–4.1). In the series of Reginald et al,1 there was a 28% incidence of preterm labor. The relative risk was 3.3 when compared with the Scottish data for the equivalent period. Tulppala et al3 quoted a 9.7% incidence in their series.

PERINATAL MORTALITY

Again, there was an increased tendency for mortality after RPL, loss with a common OR of 1.25 (95% CI 1.05–1.49). This is summarized in Figure 16.5. However, the perinatal mortality may be artificially low due to obstetric intervention for other complications in pregnancy. Reginald et al1 reported 19 perinatal deaths in 118 infants (16.1%), which

Study	Statistics for each study					OR and 95% Cl
		Lower	Upper
	OR	limit	limit	p
Hughes et al2	1.530	0.811	2.887	0.189
Jivraj et al4	3.890	2.470	6.126	0.000
Common OR	2.837	1.961	4.104	0.000
				0.1		1					10						100

Figure 16.4 Odds ratio (OR) for preterm labor in recurrent pregnancy loss.

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OBSTETRIC OUTCOMES AFTER RECURRENT PREGNANCY LOSS

Study	Statistics for each study							OR and 95% Cl
		Lower	Upper
Hughes et al2	OR	limit	limit	p
	1.103	0.060	20.305	0.947
Jivraj et al4	2.506	0.922	6.814	0.072
Sheiner et al6	1.222	1.021	1.464	0.029
Common OR	1.250	1.047	1.492	0.014
				0.1				1		10			100

Figure 16.5 Odds ratio (OR) for perinatal mortality in recurrent pregnancy loss.

was considerably higher than the standard figures for England and Wales in the same period of time, when the perinatal mortality was 10.1/1000. Tulppala et al3 did not quote perinatal mortality.

It seems, therefore, that the currently available literature on the obstetric and neonatal outcome of pregnancies from women with a history of RPL shows a consistently worse prognosis. However, it is unclear whether the worse prognosis is only found in patients with predisposing causes such as APS and hereditary thrombophilias or is also present in patients with unexplained pregnancy losses.

ANTIPHOSPHOLIPID SYNDROME

Most series on APS have concentrated on the subsequent live birth rate and ignored the late obstetric complications. The present author published a series10 in which the outcome of 24 pregnancies in patients with lupus anticoagulant (LA) and five or more first-trimester abortions was compared with 22 pregnancies in women with no antiphospholipid antibodies (aPL), and 5 or more miscarriages. Although the subsequent number of first-trimester miscarriages and the live birth rate were similar in both groups of patients, the incidences of secondor third-trimester fetal deaths, IUGR, and need for premature induction of labor or preterm cesarean section were significantly higher in the APS patients. The similar live birth

rate was only obtained by early obstetric intervention to prevent intrauterine fetal deaths. A number of other publications have attested that the risk of obstetric complications is high in APS.11,12 The incidence of preeclampsia is particularly high in APS.13,14 IUGR has been reported with a frequency ranging from 30% to 12% in different series. Some series show a significant increase in the incidence of IUGR,15,16 whereas others have not confirmed the increased incidence.17,18 The different results on the association of obstetric complications with aPL might have various explanations. None of the results has been correlated with β2-glycoprotein I(β2GPI)-dependent antibodies. None has corrected for fetal chromosomal aberrations, in which the aPL may just be an epiphenomenon. Alternatively, the obstetric complications may be dependent on other factors associated with RPL rather than aPL. No series has compared the incidence of obstetric complications in RPL due to APS and in RPL without APS. The incidence of preterm labor is increased in APS patients,16 but again has not been compared with patients with RPL and no APS.

The currently accepted optimal treatment regimen for APS is heparin or low-molecular-weight heparin (LMWH) with the addition of low-dose aspirin. However, anticoagulants do not seem to lower the incidence of obstetric complications associated with this syndrome.19 IVIG may have a beneficial effect in APS, as the action and production of aPL are inhibited by IVIG. The F(ab′) fragment of IVIG

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inhibits binding of anticardiolipin antibody (aCL) to cardiolipin in a dose-dependent manner.20 The F(ab′) fragment of IVIG inhibits LA activity.21 IVIG lowers levels of aCL after each infusion.22 IVIG may contain anti-idiotypic antibodies to aPL, or may inactivate B-cell clones, leading to decreased autoantibody production.23 In the late 1980s and early 1990s, IVIG was used to improve the live birth rate in APS.24-27 However, these were small series, and showed IVIG to have no apparent benefit over anticoagulants in terms of live births. However, when the obstetric complications are considered, a different clinical picture emerges. Vaquero et al28 compared IVIG with prednisone and aspirin. The prevalence of IUGR and preterm labor was similar in both groups, but the prevalences of PIH and gestational diabetes were significantly lower (p<0.05) after IVIG (5% of 41 patients and 14% of 22 patients, respectively). Branch et al29 compared IVIG with placebo: there were fewer cases of IUGR after IVIG (14% of 7 patients, compared with 33% of 9 patients, respectively), and fewer admissions to the neonatal intensive care unit (14% of 7 patients after IVIG, compared with 44% of 9, respectively). Harris and Pierangelli30 reported that preeclampsia, IUGR and prematurity were reduced when IVIG was compared with prednisone and aspirin or heparin and aspirin.

HEREDITARY THROMBOPHILIAS

There have recently been numerous publications associating genetic predispositions (hereditary thrombophilias) to thrombosis with pregnancy loss. The hereditary thrombophilias include protein C, protein S, and antithrombin III deficiencies, activated protein C resistance (APCR), factor V Leiden mutation, methylenetetrahydrofolate reductase (MTHFR) mutation, the prothrombin gene mutation (G20210A) and excessive factor VIII. The features of hereditary thrombophilias and the effects on obstetric complications are discussed in Chapter 10. Suffice it to say here that Kupferminc et al31 have reported an association between

thrombophilias and severe preeclampsia, placental abruption, IUGR, and stillbirth. However, theirs was a case–control study looking at the prevalence of hereditary thrombophilias in women with obstetric complications. Additionally, these findings have beeen disputed by Infante-Rivarde et al,32 who also performed a case–control study. Alfirevic et al33 have published a systematic review of the various reports and have described the strengths of association between hereditary thrombophilias and preeclampsia, placental abruption, stillbirth, and IUGR. Sheiner et al6 have drawn attention to the fact that the other publications on obstetric complications in RPL were written at a time when the hereditary thrombophilias had not yet been recognized. In their series, higher rates of IUGR, cesarean section, low Apgar scores and perinatal mortality were found among the 22 patients with known thrombophilia as compared with the controls, although the differences did not reach statistical significance. There are no cohort studies assessing the true incidence of obstetric complications in the presence of thrombophilia and RPL. In the present author’s series of 21 pregnancies with factor V Leiden which were followed up prospectively, there was one case of HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), but no other obstetric complications, and no deep vein thrombosis or pulmonary embolus.

The LMWH enoxaparin has been shown to be associated with a significantly increased chance of a live birth, both overall and when corrected for the number of miscarriages34 (RR 0.53; 95% CI 1.07–3.28), in women with RPL and hereditary thrombophilia. There are isolated reports35–37 of the use of anticoagulants in the presence of thrombophilias to reduce the late obstetric complications, and this approach has been endorsed by the American College of Chest Physicians.38 However, there is as yet insufficient evidence that anticoagulants actually reduce the incidence of late obstetric complications. Further trials need to be performed in order to determine whether anticoagulants do indeed reduce the incidence of obstetric complications.

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	OBSTETRIC COMPLICATIONS AFTER		Table 16.1 Preterm labor, IUGR, perinatal
			mortality, and anomalies with paternal leukocyte
	ALLOIMMUNIZATION		immunization compared with controlsa
	Some 20 years ago, alloimmunization had become			Immunized		Controls
				(n = 979)b		(n = 483)b	Relative riskc
	the treatment of choice for patients with RPL.
	Two methods of alloimmunization had been used		Preterm labor	39 (3.9%)		52 (10.8%)	0.63 (0.49–0.79)
	in order to improve the subsequent live birth rate in		IUGR	17 (1.7%)		59 (12.2%)	0.32 (0.21–0.49)
	recurrently aborting women: active immunization		Perinatal mortality	9 (0.9%)		21 (4.3%)	0.44 (0.26–0.47)
			Anomalies	25 (2.6%)		19 (3.9%)	0.84 (0.65–1.10)
	with paternal leukocytes and passive immuniza-
			aFigures include 92 immunized and 175 non-immunized patients from
	tion using IVIG.39 Paternal leukocyte immunization
			7
	became standard management after the double-		Beard’s series , 759 immunized patients and 279 non-immunized
			patients from the RMITG register,9 and 128 immunized patients and 29
	blinded randomized trial by Mowbray et al40 and		non-immunized patients from the present author’s series.
	a subsequent meta-analysis by the Recurrent		bIncidences in parentheses.
			c95% confidence intervals in parentheses.
	Miscarriage Immunization Trialists Group,9 but fell
	out of favor due to the paper by Ober et al,41 which
	claimed lack of efficacy. As with treatment for APS		These figures are summarised in Table 16.2. As can
	and hereditary thrombophilias, most publications
			be seen, the incidence of preeclampsia was lower
	on immunomodulation have assessed the subsequent
			in immunized	women. However,			there	was no
	live birth rate as the primary outcome measure, and
			significant difference		in	the incidence of		vaginal
	have ignored the late obstetric complications of
			bleeding, which remained high: 38% and 34% in
	pregnancy occurring in women with a subsequent
			immunized and control women, respectively.
	live birth.
			Table 16.3	shows	the	obstetric	complications
	In order to summarize the obstetric complica-
			after IVIG in the 136 women in the present author’s
	tions with or without immunotherapy, the various
			series. There is no relevant control group, as some
	series in the literature have been pooled to obtain
			of the patients were administered IVIG after failure
	a sufficient number of patients available for mean-
			of paternal leukocyte		immunization. The			figures
	ingful analysis. The databases of Beard et al,7 the
			were compared with		those for non-immunized
	RMITG meta-analysis9 and the present author’s
			patients in the registers above and those in control
	series have been combined in order to compare the
			patients in other series on IVIG in the literature. The
	obstetric complications after paternal leukocyte
			incidences of IUGR, perinatal mortality, bleeding,
	immunization: 979 immunized patients were avail-
	able for analysis, compared with 483 non-immunized
	patients. The prevalence of IUGR, perinatal mortal-
	ity, and the incidence of anomalies were assessed.		Table 16.2 Bleeding and preeclampsia with
	These figures are summarized in Table 16.1. As can
			paternal leukocyte immunization compared
	be seen, there was a significantly lower incidence of		with controlsa
	preterm labor, perinatal mortality, and IUGR after
				Immunized		Controls
	paternal leukocyte immunization than in controls.
				(n = 216)b		(n = 191)b	Relative riskc
	The incidence of fetal anomalies was not sig-
	nificantly different in the two groups of patients.		Bleeding	83 (38%)		64 (34%)	1.10 (0.92–1.33)
	As the RMITG meta-analysis9 did not assess bleed-		Preeclampsia	27 (13%)		57 (30%)	0.55 (0.40–0.76)
	ing and preeclampsia, data could only be obtained		aFigures include 88 immunized and 162 non-immunized patients from
	from Beard’s7 series and the present author’s series.		Beard’s series7 and 128 immunized patients and 29 non-immunized
	Two hundred and sixteen immunized patients		patients from the present author’s series.
			bIncidences in parentheses.
	and 191 control patients are available for analysis.		c95% confidence intervals in parentheses.

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Table 16.3 Obstetric complications after

IVIG compared with controlsa

	IVIGb	Controlsb	Relative riskc
Preterm labor	15/136 (11%)	52/483 (10.8%)	1.02 (0.53–1.96)
IUGR	6/136 (4%)	59/483 (12.2%)	0.39 (0.18–0.86)
Perinatal	2/136 (1.5%)	21/483 (4.3%)	0.39 (0.10–0.47)
mortality
Bleeding	5/136 (3.7%)	64/191 (34%)	0.14 (0.06–0.33)
Preeclampsia	4/136 (2.9%)	57/191 (30%)	0.13 (0.05–0.34)
Anomalies	1/136 (0.7%)	19/483 (3.9%)	0.22 (0.03–1.51)

aFigures show the incidence of anomalies as a function of the total number of patients in the sample. IVIG figures are from the present author’s series. The control figures are pooled data from the literature. bIncidences in parentheses.

c95% confidence intervals in parentheses.

and preeclampsia were all lower after IVIG, but the incidences of preterm labor and anomalies did not seem to be affected. However, these results should be interpreted with caution due to the nature of the control group.

CYTOKINES AS MEDIATORS OF PREGNANCY LOSS AND OBSTETRIC COMPLICATIONS

Cytokines are low-molecular-weight peptides or glycopeptides, which are produced by lymphocytes, monocytes/macrophages, mast cells, eosinophils, and blood vessel endothelial cells. Cytokines seem to influence all stages of pregnancy. Cytokines such as interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and epidermal growth factor (EGF) stimulate placental cell proliferation42 in vitro, and may enable the trophoblast to secrete human chorionic gonadotropin(hCG) and human placental lactogen (hPL). Cytokines such as transforming growth factor β2 (TGF-β2) can inhibit lymphokine activation of natural killer (NK) cells (which may attack the trophoblast). Although cytokines can have pleiotropic actions, these actions of the above cytokines are classified as T-helper 2 (Th2) or anti-inflammatory in nature, and they seem to benefit the development of pregnancy. Other cytokines can have actions that are known as Th1 or proinflammatory, and these may be

detrimental to pregnancy; for example, tumor necrosis factor α (TNF-α) can activate NK cells at the fetomaternal interface,43 leading to apoptosis and trophoblast cell death.44 Wegman23 suggested that appropriate cytokines are necessary in order to confer benefits on the developing fetoplacental unit. In early pregnancy, the conceptus and placental tissues produce a variety of Th1-type cytokines, including interferons, interleukins and TNF.45 In normal pregnancy, the maternal immune system seems to modulate the cytokine pattern to preferential expression of Th2 cytokines, including GM-CSF, IL-3, IL-4, IL-5, IL-10, and IL-13, that may enhance fetal survival.46 Preferential expression of Th1 cytokines (TNF-α, interferon-γ (IFN-γ), and IL-2) may result in abnormal placental and embryonic growth and subsequent fetal demise.

An inappropriate cytokine balance has been reported to act in early pregnancy, causing NK-cell activation,43 placental apoptosis,44 teratogenesis,47 and excessive coagulation, particularly TNF-α and IL-6.48 Hence, cytokine imbalance is among the mechanisms that have been proposed to underlie RPL. The effect of cytokine imbalance on coagulation may explain some of the effects of hereditary thrombophilias. Additionally, APS and most of the late complications of pregnancy have also been shown to have an underlying cytokine basis.

Although it is generally accepted that aPL may act by causing blood coagulation in decidual vessels, cytokines may also be responsible for the action of aPL early in the pathogenesis of the condition. Serum TNF-α is increased in women with APS.49 IL-3 is decreased in APS,50 and fetal loss can be prevented in experimental APS by in vivo administration of recombinant IL-3.51 Alteration of the Th1/Th2 balance may also be involved in the effect of anti-idiotypic antibodies on APS.52

Late obstetric complications have also been shown to be associated with altered cytokine levels. Preeclampsia is associated with reduced IL-10 and higher IL-2 production from peripheral blood mononuclear cells (PBMC),53,54 and high serum IL-8 and TNF-α.55 In preterm births, cytokine involvement has been reported,56 particularly increased amniotic IL-6, IL-8, and TNF-α.57–60

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OBSTETRIC OUTCOMES AFTER RECURRENT PREGNANCY LOSS

In IUGR, TGF-β in cord blood and mRNA for IL-10 are significantly reduced, whereas IL-8 mRNA is significantly higher61,62 and placental TNF-α secretion is enhanced.62

The various interventions used for improving the live birth rate in RPL may exert their effects by modulating cytokine balance, and this modulation may also influence the incidence of later obstetric complications. As stated in Chapter 10 it is possible that heparin or enoxaparin may work by antiinflammatory mechanisms rather than anticoagulation. Heparin increases serum TNF-binding protein, hence protecting against systemic harmful manifestations.63 LMWH inhibit TNF-α production.64 Thrombosis results in an inflammatory response of the vein wall. Both heparin and LMWH limit the anti-inflammatory response, but in the series of Downing et al,65 LMWH was more effective than heparin in limiting neutrophil extravasation and was the only intervention to decrease vein wall permeability. In addition, heparin has been shown to prevent the accumulation of proliferating vascular smooth muscle cells encroaching on the lumen of arteries injured at angioplasty, hence enlarging the lumen.66

The mode of action of paternal leukocyte immunization (PLI) is unclear. The two most plausible explanations seem to be that PLI may downregulate the numbers and killing activity of NK cells,67 which may attack the trophoblast when activated by cytokines. PLI may also alter the balance between Th1 and Th2 cytokines. (PLI has been reported to reduce IFN-γ and increase the secretion of IL-10 and TGF-β,68 and has also been shown to lower the serum IL-6 and soluble IL-6 receptor (sIL-6R) levels to the values observed in normal pregnancy.69)

IVIG has numerous actions. The actions of IVIG in pregnancy, including its effects on APS, have been summarized elsewhere.70 In addition to various other mechanisms, IVIG, like PLI, depresses NK-cell function71 and enhances the action of Th2 cytokines.72

CONCLUSIONS

Patients with RPL seem to comprise a high-risk group for later obstetric complications. Late obstetric

complications have been described in APS and hereditary thrombophilias. However, there is insufficient evidence at present to determine whether the late obstetric complications occur exclusively in these two conditions, or whether they are associated with RPL per se. Immunomodulation seems to reduce the incidence of some of these complications. The role of anticoagulants in reducing obstetric complications is more doubtful. However, careful surveillance is required in pregnancies following RPL, in order to detect obstetric complications. Further prospective cohort studies are necessary in order more accurately define the patient at risk, the role of APS and hereditary thrombophilia, and the effect of treatment modalities.

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