Table 5.

The use of intravenous immunoglobulins in gyneco-obstetric diseases

Disease	Ref.	Study design	Intervention including dose and IVIg preparation used	Number of patients	Results/response
Perinatal hemochromatosis	[211]	Case–control study; previous patients' pregnancies used as their own controls	IVIg 1 g/kg weekly since week 18	15 patients (16 pregnancies) with previous pregnancies resulting in perinatal hemochromatosis	Good outcome (survived with or without medical therapy) in 15 gestations treated with IVIg; in historical controls of the same mothers, 2 pregnancies had good outcome and 13 had poor outcome (fetal or neonatal death, or liver failure necessitating liver transplantation), p = 0.0009
Recurrent pregnancy loss excluding antiphospholipid syndrome	[212]	Meta-analysis	IVIg	442 women with recurrent spontaneous miscarriages (at least 3) from eight RCTs; secondary recurrent miscarriages are defined as those in women that had at least a previous successful birth	No significant difference (p = 0.21) between women with primary recurrent miscarriages treated with IVIg or without; however, there was a significant improvement of live births when IVIg was given to women with secondary recurrent miscarriages (p = 0.03)
	[213]	Meta-analysis	IVIg versus placebo or no treatment	303 women with idiopathic recurrent abortions from 8 RCTs	No benefit of IVIg on recurrent pregnancy loss
	[214]	Meta-analysis	IVIg	246 women with recurrent spontaneous miscarriages (at least 2) from 5 RCTs; secondary recurrent miscarriages are defined as those in women that had at least a previous successful birth	No significant difference between women with primary recurrent miscarriages treated with IVIg or without; not enough patients to conclude something about women with secondary recurrent miscarriages but there was a trend towards improvement
	[215]	RCT	29 women received IVIg, 29 placebos; IVIg was administered from weeks 5–10 weekly at 0.8 g/kg every week, from weeks 10–20 at 0.8 g/kg every 2 weeks and from weeks 20–26 at 1 g/kg every 2 weeks; no IVIg as given after week 26	58 women with recurrent spontaneous miscarriages (at least 4); secondary recurrent miscarriages are defined as those in women who had at least a previous pregnancy that progressed to week 26 or more	No benefit in primary recurrent miscarriages but a trend towards improvement among women with secondary recurrent miscarriages
	[216]	Meta-analysis	IVIg in 125 patients, 115 received placebo	240 women with recurrent spontaneous miscarriages	No benefit of IVIg
	[216]	RCT	IVIg (Gammonativ) 20 g every 3 weeks, 5 courses after confirmation of pregnancy	41 women with recurrent spontaneous miscarriages	No benefit of IVIg neither for women with primary or secondary recurrent miscarriage
	[217]	RCT	22 patients received IVIg (Sclavo) 50 g over 2 days upon confirmation of pregnancy (weeks 5–7) and again 25 g 3 weeks later	46 women with recurrent spontaneous miscarriages	No benefit of IVIg
	[218]	RCT	47 patients received IVIg 0.5 g/kg every month starting up to 4 months before pregnancy and until weeks 28–32 of pregnancy; 48 patients received placebo	95 women with recurrent spontaneous miscarriages (2 or more)	More live births in women receiving placebo (p = 0.04)
	[219]	RCT	IVIg (Nordimmun, Novo-Nordisk, Gentofte, Denmark) 25–40 g per dose according to patient weight every 2 weeks until week 34 of pregnancy or placebo	34 women with secondary recurrent spontaneous abortion (subsequent to a birth or including at least one second trimester miscarriage)	More live births but not statistically significant in the IVIg group (52.9% against 29.4%)
	[220]	RCT	IVIg initial dose 30 g, then 20 g every 3 weeks until week 25 (Verum, Immuno GmbH, Heidelberg, Germany) or placebo	64 women with primary recurrent spontaneous abortion	No benefit of IVIg
Recurrent pregnancy loss in antiphospholipid syndrome	[221]	Meta-analysis	IVIg given in addition to heparin and aspirin	58 women with recurrent miscarriages due to antiphospholipid syndrome in 2 RCTs	Increased risk of pregnancy loss or premature birth in the group receiving IVIg
	[222]	Randomized trial	21 women received IVIg (IgVENA N; Sclavo, Siena, Italy) at the dose of 0.8 g/kg over 2 consecutive days as initial dose followed by 0.4 g/kg each month up to week 31; 19 women received aspirin 75 mg/day up to week 34 + heparin 5,700 IU/day up to week 37	40 women with at least 3 abortions due to antiphospholipid syndrome were treated since conception with IVIg or heparin + aspirin	More live births (84% against 57%, not significant difference) in the aspirin + heparin group (p = 0.06)
	[223]	RCT	IVIg 2 g/kg (Gamimune-N, Bayer Corporation, West Haven, CT, USA) over 2 days every 4 weeks through 36 weeks’ gestation	16 pregnant women (no more than 12 weeks' gestation) with recurrent miscarriages due to antiphospholipid syndrome received low-dose aspirin and heparin and received random IVIg or placebo	No benefit of IVIg
	[224]	Prospective two-center trial study	29 were treated with PD and LDA; 53 received IVIg 0.5 g/kg (Alphaglobin, Grifols International, Pisa, Italy) for 2 consecutive days, once a month from the 5th to the 32nd week of pregnancy	82 pregnant women with a history of recurrent fetal loss and APS	Live-birth rates were equivalent between groups (78% vs 76%), mean birth weight was higher in the IVIg group gestational hypertension and diabetes were found significantly more often in the PD group (14% vs 5%), respectively (p < 0.05)
	[225]	Case series	Patients were treated with heparin (15), LDA (18), and CS (6); additionally, they received IVIg 0.4 g/kg for 5 days monthly from the first or early second trimester	19 pregnancies of 15 women with APS and recurrent fetal loss	The live-birth rate was 84%; compared to approximately 70% described in literature without IVIg
	[226]	Controlled trial	In phase III, they received heparin + LDA with or without IVIg	121 women with APS, who failed to achieve live births after 2 IVF attempts with heparin + LDA	The birth rate was 41% when IVIg was added and anti-PS or anti-PE involving IgG or IgM isotypes were present, as compared with 17% when H + A alone was administered; the IVF outcome did not improve when IVIg was administered in association with any other single APS antibodies
	[227]	Controlled trial	IVIg 0.3 g/kg every 3 weeks until the 16th to 17th week of pregnancy	38 women after 3 or more consecutive first trimester spontaneous abortions and APS	Pregnancy proceeded beyond the first trimester in 34 of the patients (89.4%), and 31 patients (81.4%) gave birth to healthy infants at 37 to 42 weeks' gestation
	[228]	Case control	IVIg 0.5 g/kg for 2 days from the fifth week of pregnancy and repeated every 4 weeks until the 33rd week of gestation	14 women with a history of recurrent spontaneous abortion and APLA	No significant biometrical differences between the groups were seen; no fetal or neonatal growth retardation was seen
			Data were compared to 70 matched uneventful pregnancies
Premature rupture of membranes	[229]	RCT	IVIg (Pentaglobin, Biotest, Frankfurt/Main, Germany) 20 g, 24–48 h after premature rupture of membranes; thereafter, 10 g was administered in weekly intervals	18 women with premature rupture of membranes	Infants in treated group showed less laboratory and clinical signs compatible with prenatally acquired infection (p < 0.002); less chorioamnionitis in treatment group (p < 0.036)
Failure of in vitro fertilization	[230]	Meta-analysis	IVF along with or without IVIg	Women with IVF failure	Improvement in live-birth rate (p = 0.012)
	[231]	RCT	IVIg (Gamimune 5%, Bayer Canada Inc., Etobicoke, Canada) 0.5 g/kg or placebo (saline), first infusion on the day of embryo transfer or during preceding 72 h, second infusion 4 weeks later upon evidence of embryonic heart activity	51 women after IVF failure	No significant improvement in implantation, pregnancy, or live birth rate