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Glomerular Diseases in Pregnancy

Friederike Susanne Quittnat-Pelletier, Arrti Bhasin, andMichelle A. Hladunewich

AbstractAlthough the primary glomerulonephritides(GN) often affect young patients, these areoverall rare diseases within the general popu-lation. A major concern for generations ofnephrologists has been and continues to bethe impact that these rare renal diseases haveon pregnancy outcomes. Little literature isavailable to guide counseling and treatmentduring pregnancy, and experience is oftenbased on case reports and single-center studies.Disease-specific outcome data and treatmentstrategies are even more limited, hamperingindividualized counseling. In primary GN, dis-ease activity must be under control or in remis-sion before conception since risk factors foradverse outcomes include impaired renal func-tion, uncontrolled hypertension, and signifi-cant or nephrotic-range proteinuria. As ageneral approach, experts in the field recom-mend multidisciplinary pre- and perinatal careto optimize treatment of hypertension and pro-teinuria as well as to facilitate early diagnosisof preeclampsia, flares of the underlying

glomerulonephritis, or impaired developmentof the fetus, thereby assuring the best possibleoutcome for mother and her baby.

KeywordsPregnancy • Glomerulonephritis • Preeclamp-sia • Prematurity

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

General Management Principles . . . . . . . . . . . . . . . . . . . 2It Takes a Health-Care Team . . . . . . . . . . . . . . . . . . . . . . . . . . 2Fertility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Control of Underlying Primary GN and Proteinuria . 4Renal Dysfunction and Adverse Pregnancy Outcomes 4Clinical Visits During Pregnancy . . . . . . . . . . . . . . . . . . . . . 7Laboratory Evaluations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Supportive Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Immunosuppression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8Management of Hypertension . . . . . . . . . . . . . . . . . . . . . . . . 10Assessment and Management of Nephrotic Syndrome 11Safety of Kidney Biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12Diagnosing Superimposed Preeclampsia . . . . . . . . . . . . . 13

Disease-Specific Pregnancy Outcomes . . . . . . . . . . . . . 14Lupus Nephritis in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . 14Systemic Vasculitis, Antineutrophil Cytoplasmic

Autoantibody-Associated Vasculitis . . . . . . . . . . . . . . 16Antiglomerular Basement Membrane Antibody

Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16IgA Nephropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Hereditary Nephritis/Alport Syndrome . . . . . . . . . . . . . . . 17Thin Basement Membrane Nephropathy . . . . . . . . . . . . . 18Other Primary Glomerular Diseases . . . . . . . . . . . . . . . . . . 18

F.S. Quittnat-Pelletier • A. Bhasin •M.A. Hladunewich (*)Divisions of Nephrology and Obstetric Medicine,Department of Medicine, Sunnybrook Health SciencesCentre, University of Toronto, Toronto, ON, Canadae-mail: [email protected];[email protected];[email protected]

# Springer International Publishing AG 2017H. Trachtman et al. (eds.), Glomerulonephritis,DOI 10.1007/978-3-319-27334-1_49-1

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mailto:[email protected]

mailto:�arti.�[email protected]

mailto:�michelle.�[email protected]

Atypical Hemolytic Uremic Syndrome and ThromboticThrombocytopenic Purpura (TTP) . . . . . . . . . . . . . . . . 19

Summary Statements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20

Introduction

Pregnancies in women with chronic kidney dis-ease (CKD) are associated with an increased riskof adverse maternal and fetal outcomes. As theprimary glomerulonephropathies encompass onlya small percentage of renal diseases in the overallpopulation with an incidence estimated between0.2–2.5/100,000/year (McGrogan et al. 2011),data is scarce on the primary glomerulonephriti-des (GN) and pregnancy, making these pregnan-cies anxiety-provoking for most clinicians. Theliterature on primary GN during pregnancy iscomprised of single-center experiences or casereports. Even in the nonpregnant population,treatment of primary GN presents with chal-lenges, and the best-studied medications areoften contraindicated in pregnancy due toteratogenicity.

In the past, the adverse pregnancy outcomesassociated with renal disease led to recommenda-tions either not to pursue pregnancy or to considerpregnancy termination when an unplanned preg-nancy occurred (Pregnancy and renal disease1975). However, in the last decade, patient-cen-tered care has overtaken this more paternalisticapproach to practicing medicine wherein thesewomen may have been advised to forgo the notionof a family. As such, increased numbers of youngwomen with chronic medical illnesses, includingthose with CKD due to glomerular diseases, arepursuing high-risk pregnancies that require spe-cific counseling on potential adverse outcomes,thorough preparation preconception, strong sup-port, and frequent assessments during pregnancyas well as close follow-up postpartum.

In this chapter, we highlight the considerationsfor preconception, pre- and perinatal care ofwomen with underlying kidney disease (Fig. 1),what effect pregnancy could have on maternalhealth and kidney function, and what effect

chronic kidney disease could have on the preg-nancy outcome.

General Management Principles

Due to the paucity of data, following patients withGN during pregnancy is more an art than a sci-ence. The potential for acute disease flares, pro-gressive renal function loss, and potential sideeffects of treatments to mother and fetus have tobe explored thoroughly, and a dedicated multi-disciplinary team should follow the majority ofpregnancies in this patient population. Carefulassessment of the health status of the mother,activity of underlying disease, treatment availabil-ity, and response to treatment as well as previouspregnancy outcomes should all be consideredwhen counseling on pregnancy risk and potentialoutcomes. The time of observation should ideallystart before conception and should continue post-partum for ongoing support. Pregnancies inpatients with kidney disease also involve complexmedical, ethical, and psychosocial considerationsthat if not considered can introduce feelings ofworthlessness and disengagement (Tong et al.2015). Opposing rather than supportive counsel-ing may jeopardize trust and willingness to workwith the health-care professional to achieve thebest outcome for mother and baby.

It Takes a Health-Care Team

In addition to availability of a neonatal intensivecare unit (NICU) care for the neonate if necessary,pre- and perinatal care should involve a multi-disciplinary team. In addition to the obstetrician,nephrologist and neonatologist, nurses, dietitians,social workers, and pharmacists may make up theteam caring for the pregnancy. Depending on pre-existing and developing comorbidities, variousother specialists may also need to be involved incare as the underlying disease dictates (e.g., rheu-matology for systemic lupus). Hereditary diseasesmay benefit from preconception genetic counsel-ing to ensure understanding of the inheritancepattern of their condition and the potential

2 F.S. Quittnat-Pelletier et al.

implications to their unborn child. Reproductivemedicine specialists cannot only assist with fertil-ity issues, but are expanding the field of preim-plantation genetic diagnosis, which may preventthe birth of a child with a genetic disorder. Finally,these pregnancies are very emotionally taxing,and the need for psychological support cannot beunderstated. Having a newborn while managing achronic medical condition has been shown to beassociated with increased rates of postpartumdepression (Katon et al. 2014), so regular screen-ing for inadequate coping or bonding along withprompt mental health support is often necessary.

Fertility

While primary GN does not cause infertility initself, various mechanisms related to diseaseactivity may contribute to difficulties in concep-tion. For example, in patients with systemic lupuserythematous (SLE), autoimmune oophoritis andchronic inflammation causing dysfunction of thehypothalamic-pituitary axis both may contributeto infertility (Oktem et al. 2015). Further, changesto the hypothalamic-pituitary-ovarian axis inadvanced CKD can result in impaired ovulationor anovulation through absence of preovulatory

estradiol and LH peaks, increased prolactin levels,and dysfunctional uterine bleeding (Holley et al.1997; Hou et al. 1985; Lim et al. 1980). Enhancedclearance for patients with ESRD by either inten-sive dialysis or renal transplantation can reversethe altered hormonal milieu, increasing the ratesof successful conception (Barua et al. 2008; vanEps et al. 2012; Saha et al. 2002).

Another source for infertility can be the phar-macological treatment of the underlying disease.Irreversible primary ovarian failure after exposureto cyclophosphamide has been reported as cumu-latively dose-dependent and increasing with agewith rates as high as 12% reported in females<25 years of age, 27% in women 26–31 years ofage, and 62% in women >30 years old (Boumpaset al. 1993). Also, the route of administration canimpact fertility with oral cyclophosphamideinducing a more sustained amenorrhea than IVadministration (Mok et al. 2006). To potentiallylimit ovarian damage from cyclophosphamide,leuprolide acetate, a synthetic GnRH analog, hasbeen studied, but results are mixed. Of threerecent meta-analyses conducted in women withmalignancies and other rheumatological diseases,two found a significant benefit with regard toresumption of menses and ovulation with GnRHanalog co-treatment (Bedaiwy et al. 2011; Del

Pre-conception Pregnancy Postpartum

Diagnosis of GN, Biopsy, Genetic testing

Control of hypertension

Control of proteinuriaImmunosuppression RAS blockade

Pre-conception counselingRisk of loss of kidney functionRisk of adverse fetal outcomes

Pregnancy-safe medications

Initiation of pregnancy supportivemedications (eg. Folic acid, calcium, vitamin D)

Initial routine lab work includingRenal functionProteinuria (24h-urine),Repeat GN defining serology (eg ANA, ENA, APLA, complement levels, ANCA)

Q4 weekly or as indicated routinelabwork,urine albumin-to-creatinine ratio, serology, tacrolimus or cyclosporine level

Blood pressure monitoring

ASA (initiate prior to 16 weeks and D/C at 34 weeks GA),Vitamin D, calcium, anticoagulation as needed

Fetal/placental ultrasound qmonthly

Assessment for preeclampsia

Involvement of a multidisciplinary team, Center with neonatal intensive care services

Routine lab work, proteinuria

Repeat Tacrolimus/Cyclosporine levels

Blood pressure monitoring

Reintroduction of ACE-inhibitor (enalapril, captopril) for reduction of proteinuria

Emotional support

Fig. 1 Pregnancy counseling and management

Glomerular Diseases in Pregnancy 3

Mastro et al. 2014), while another found no ben-efit (Elgindy et al. 2015).

Control of Underlying Primary GN andProteinuria

Most evidence for pursuing a remission of theunderlying GN prior to embarking on a pregnancyderives from data in SLE, wherein lupus activity,particularly active nephritis, is linked to higher ratesof preeclampsia, increased premature delivery,small for gestational age births, and acceleratedloss of renal function (Koh et al. 2015; Smyth etal. 2010). From this, we deduce that other types ofglomerulonephritis when poorly controlledwill potentially contribute to adverse pregnancyoutcomes, and control of the glomerulardisease with pregnancy-safe immunosuppression isrecommended where possible. Potentially terato-genic medications should be stopped in additionto those medications with limited long-term neo-natal safety data (Table 1). Cyclophosphamideand mycophenolate mofetil should bediscontinued at least 6 weeks prior to a pregnancyattempt, while current recommendations forrituximab is to wait at 6–12 months after exposureper the manufacturer’s guidelines, but more clin-ical data is required. A reasonable approachincludes treatment with pregnancy-safe immuno-suppression to attain remission for at least3–6 months prior to a pregnancy attempt(Cabiddu et al. 2016). A repeat kidney biopsymay prove necessary in select cases wherein it isdifficult to clinically confirm absence of activenephritis on pregnancy-safe immunosuppression.

In patients without immunological treatmentoptions, control of urine protein with agents thatblock the renin angiotensin system (RAS) is themainstay of treatment (Table 1). Although clearlyteratogenic in the second and third trimesters ofpregnancy (see Management of Hypertension),data for teratogenicity with only early pregnancyexposure is no longer supported, and unintentionalfirst trimester exposure does not require termination(Diav-Citrin et al. 2011). Again the potential use ofthese agents in pregnancy planning is not derivedfrom data published in the management of GN, but

comes from small, uncontrolled studies in patientswith diabetic nephropathy wherein intensive treat-ment with angiotensin-converting enzyme inhibi-tion in addition to optimization of glucose controlprior to conception has been shown to stabilizeproteinuria during pregnancy (Hod et al. 1995; Baret al. 1999) and, compared to older preexistingliterature, prolong gestation and improve birthweights (Nielsen et al. 2009). A pragmatic approachmay be to intensify RAS blockade prior to preg-nancy in women with renal diseases wherein thereare no immunosuppressive treatment options, stop-ping at the time of conception, which is our practicein women with significant proteinuria. Thisapproach, however, requires careful counselingwith respect to associated risks and aggressive sur-veillance for a potential pregnancy in order to min-imize the risk of fetal exposure. Other practitionersmay choose to discontinue these agents whenattempts at conception begin. Significantly worsen-ing proteinuria prior to conception though is alsoassociated with worse pregnancy outcomes. Assuch, these decisions should be individualized, andthis is an area that requires further study in womenwith GN.

Renal Dysfunction and AdversePregnancy Outcomes

The risk of loss in renal function and poor preg-nancy outcome increases with severity of renaldysfunction; however, even stage 1 CKD seemsto pose a higher risk for adverse pregnancy out-comes as compared to the general population,including preterm delivery, small for gestationalage babies, requirements for admission to theneonatal intensive care, and increased rates ofcaesarian section (Piccoli et al. 2010, 2015).This was confirmed by a population-based studyfrom Norway (HUNT II) when there is concurrenthypertension with CKD stage 1, but not micro-albuminuria (Munkhaugen et al. 2009).

Moderate renal dysfunction is currentlydefined as a creatinine clearance between 40 and70 ml/min or CKD stage 2–3, whereas severerenal insufficiency is defined as a creatinine clear-ance below 40 ml/min or CKD stages 3–4 (Piccoli


Table

1Com

mon

lyused

drug

sin

glom

erulon

ephritis,consideringpregnancy

Medications

FDA

class*

Maternaladv

erse

effects,du

ring

pregnancy

Placental

passage

Hum

anteratogenicity

Fetal/neonataleffects

Excretedin

breastmilk

Breastfeeding

Corticosteroids

CGestatio

nal

diabetes

Hyp

ertension

Preeclampsia

Perinataladrenal

supp

ression

Deactivated

by11beta-H

SD2

(except

betamethasone,

dexamethasone)

Possibleorofacialcleftlip

and

palate

Possibleintrauterine

grow

threstriction

Prematureruptureof

mem

branes

Trace

Acceptableexcept

athigh

doses

Azathioprine

DMyelosupp

ression

inTMPTdeficient

wom

en

Yes,b

utno

tactiv

ated

dueto

lack

ofIPPase

Non

eNon

eLow

levels

Acceptable

Cyclosporine

CGestatio

nal

diabetes

Hyp

ertension

Decreased

plasma

drug

levelsdu

eto

increased

distribu

tion

volume

Yes

Non

ePossibleintrauterine

grow

threstriction

Hyp

erkalemia

Reversiblerenal

impairment

Low

levels

Acceptable

Tacrolim

usC

Gestatio

nal

diabetes

Hyp

ertension

Decreased

plasma

drug

levelsdu

eto

increased

distribu

tion

volume

Yes

Non

ePossibleintrauterine

grow

threstriction

Hyp

erkalemia

Reversiblerenal

impairment

Low

levels

Acceptable

Ritu

ximab

CNon

eYes

Non

eLeuko

penia,increased

peri-/po

stpartum

infectious

risk

Unk

nown

Not

recommended

Hyd

roxy

chloroqu

ine

CNon

eYes

Non

eNon

eTrace

Acceptable

Cycloph

osph

amide

DNon

eYes

Abn

ormalities

ofcraniofacial

structures,ears,lim

bs,and

visceral

organs

Impaired

neurolog

ical

developm

ent

Decreased

hematop

oiesisGrowth

restriction

Yes

Not

recommended

(con

tinued)


Table

1(con

tinue

d)

Medications

FDA

class*

Maternaladv

erse

effects,du

ring

pregnancy

Placental

passage

Hum

anteratogenicity

Fetal/neonataleffects

Excretedin

breastmilk

Breastfeeding

Mycop

heno

late

mofetil

CNon

eYes

Cleftlip

andpalate,m

icrotia

with

atresiaof

theexternal

auditory

canals,m

icrogn

athia,

andhy

pertelorism

Neonatalanemiaand

hydrop

sfetalis

Unk

nown

Not

recommended

Eculizum

abC

Non

eYes

Non

erepo

rted

Non

erepo

rted

No

Use

with

caution

ACEinhibitors/

ARB

XOlig

ohyd

ramnios

Yes

Atrial/v

entricular

septal

defects,microceph

aly,and

pulm

onaryhy

poplasia

Peripartum

renal

failu

reNo,

buto

nly

stud

iedin

ahand

fulo

fACE

inhibitors

Enalapril,

captop

ril,qu

inapril

acceptable,

otherw

ise

contraindicated

FDAclass:A=

Generally

acceptable,studies

show

noevidence

offetalrisk;

B=

May

beacceptable,animalstud

iesshow

edno

triskandhu

man

stud

iesno

tavailable,or

anim

alstud

iesshow

edminor

risks,hu

man

stud

iesdidno

tconfi

rmrisk;C=

Use

with

cautionifbenefitou

tweigh

srisk,animalstud

iesshow

risk,o

rno

stud

iesdo

ne;D=

Use

inlife-

threateningem

ergencieswhenno

saferdrugsavailable,

evidence

ofhuman

fetalrisk;X

=Risks

outweigh

benefits,andsaferalternatives

exist.11beta-H

SD2=

11beta-

hydrox

ysteroid

dehy

drog

enasetype

2,IPPase=

Inosinatop

yrop

hoph

orylase,TPMT=

Thiop

urinemethy

ltransferase


et al. 2015). Progressive renal dysfunction isfound in these pregnancies at a higher rate thanwomen who have similar renal dysfunction, butdo not become pregnant. A study with 82 preg-nancies in 74 patients from 1996 reported overallrenal function stability in 79% during pregnancybut a decrease of 25% in renal function in 20% ofwomen (Jones and Hayslett 1996). In 23% (16pregnancies) renal function declined directlyafter delivery and eight women progressed toend-stage renal disease by 6 months postpartumdespite stability of renal function during preg-nancy. A such, a significant loss of renal functionduring pregnancy or postpartum occurred in 43%,while recovery of pregnancy-related renal func-tion decline was seen in only 8% of pregnanciesby 6 months postpartum. The progression of renaldysfunction was not necessarily linear. Somewomen with severely reduced creatinine clear-ance did not progress, while others with lesssevere disease had a more significant renal func-tion loss, suggesting that other factors contributeto the deterioration of renal function, namely,hypertension, proteinuria, or the underlying etiol-ogy of renal dysfunction.

Support for the impact of proteinuria on renalfunction decline comes from a prospective studythat assessed 49 women with a calculated eGFR<60 ml/min stratified by the degree of proteinuria(Imbasciati et al. 2007). Only women with aneGFR <40 ml/min and >1 gram of proteinuriashowed significantly hastened renal functiondecline postpartum (0.21 � 0.20 increased to1.17� 1.23 ml/min/month prior to and after preg-nancy, respectively). The study was limited by asmall sample size particularly in the group with ahigher eGFR (>40 ml/min) and >1 gram of pro-teinuria (n = 6), which is unfortunate as thiswould represent the largest group of women withglomerular disease that require pregnancycounseling.

Perhaps as a consequence of this progressiveloss of renal function during pregnancy, remark-ably worse pregnancy outcomes are noted inwomen with advanced CKD with much higherrates of cesarean section (70%), preterm delivery<37 (89%) and <34 (44%) weeks, and small forgestational age babies [<10% (50%) and <5%

(25%)] as well as an increased need for NICUcare (70%) (Piccoli et al. 2015). The aforemen-tioned prospective cohort noted a stepwise declinein gestational age and birth weight with succes-sive worsening in eGFR and amount of protein-uria. Women with >40 ml/min and <1 gram ofproteinuria delivered their babies at36.7 � 2.5 weeks of gestation, weighing2519 � 670 grams, while women with <40 ml/min of eGFR and >1 gram per day of proteinuriahad shorter gestations and smaller babies, deliveringtheir babies at 33.5� 3.5 weeks gestation, weighing1864 � 806 grams (Imbasciati et al. 2007).

Clinical Visits During Pregnancy

Follow-up visits should be scheduled regularlyevery 4–6 weeks after conception and then morefrequently as the pregnancy progress or as thepatient’s condition dictates (Cabiddu et al.2016). These visits include both an assessmentof the mother and baby and are, therefore, likelybest provided in multidisciplinary clinics attendedby both nephrologists and high-risk obstetricianstogether. Nephrologists can carefully assess themother’s well-being including blood pressure,volume status, and signs or symptoms of a diseaseflare, while obstetrical staff can carefully assessfetal well-being and growth as well as placentalintegrity to assist with the diagnosis of super-imposed preeclampsia.

Laboratory Evaluations

Blood work should include routine laboratoryvalues including CBC, electrolytes creatinine,blood urea nitrogen, uric acid, iron stores, liverfunction tests, and serum albumin. A urine albu-min or protein to creatinine ratio should be mea-sured and, if abnormal, a 24 h urine collection forprotein for quantification. Patients with SLEshould have monthly anti-dsDNA and comple-ment levels checked, especially if these markershave been concordant with past disease activity.Of note, pregnancy is a state of the acute phaseresponse, so complement levels can be normal or


even high. Falling complement levels, evenwithin the normal range, may suggest that lupusis becoming more active in an individual patient.It is unknown whether monitoring changes to theANCA titer during pregnancy helps to predictrelapses of vasculitides. If on prednisone, randomblood glucose should be checked regularly andbefore the routine oral glucose tolerance test in thesecond trimester. For patients on tacrolimus orcyclosporine, closer monitoring is needed as theincrease in the volume of distribution can cause adecrease in drug levels.

Supportive Medications

Prenatal vitamins are commonly used prior toconception except for women with end-stagerenal disease where supplementation with vitaminE and A is not recommended due to the concern ofaccumulation. Folic acid 5 mg daily has beenadvised for patients with renal dysfunction, aswell as iron supplementation orally or intrave-nously (Khalafallah et al. 2012). For GFR lessthan 30 ml/min, erythropoietin-stimulating agentscan be used and are safe in pregnancy to hopefullyomit the requirement for red blood cell transfu-sions (Breymann et al. 2001). Vitamin D andcalcium should be supplemented for bone healthof the mother and fetus especially if on steroidtherapy. Further, calcium supplementation hasbeen shown to lower the risk of preeclampsia inhigh-risk women and those whose dietary intakeis insufficient (Hofmeyr et al. 2006). Low-doseacetylsalicylic acid (75–100 mg/d) started after8 but, before 16 weeks of gestation, is currentlyconsidered to help placentation and has beenshown to reduce the risk of preeclampsia inhigh-risk patients (Roberge et al. 2013; Hender-son et al. 2014). Initiation prior to conception istypical in women with thrombophilias, includinga positive antiphospholipid antibody. To date,there appears to be no risk of congenitalmalformations (Slone et al. 1976), and low doses(below 100 mg/d) do not hamper closure of theductus arteriosus (Di Sessa et al. 1994). In higherdoses, aspirin may cause perinatal cerebral hem-orrhage and clotting abnormalities when exposed

up to 1 week prior to delivery (Stuart et al. 1982).It is our practice to stop aspirin after 34–36 weeksof gestation in most women wherein preeclampsiaprevention is the only indication for its use.

Immunosuppression

Corticosteroids are a mainstay in induction ther-apy for many GNs and are considered acceptablefor use during pregnancy, as the benefit tends tooutweigh the risks of untreated underlying dis-ease. The placenta poses a natural barrier to mater-nal cortisol by degrading it to inactive cortisonethrough high 11-beta-hydroxysteroid dehydroge-nase type 2 (11-beta-HSD2) activity on the syn-cytiotrophoblasts at the fetal-maternal interface(Hallman 2015), and low doses (5–10 mg/d) arethought to not induce thymic hyperplasia or adre-nal suppression (Transplantation 2002).Betamethasone and dexamethasone bypass thisenzymatic step, and fetal serum levels reachapproximately 30% that of the maternal leveland, as such, are used to accelerate fetal lungmaturation (Hallman 2015). Orofacial cleftshave been reported with corticosteroid use in thefirst trimester (Fraser and Sajoo 1995), but thisfinding was not confirmed by a larger, more recentpopulation-based study from Denmark (Hviid andMolgaard-Nielsen 2011). However, there may bean increased risk of intrauterine growth restrictionand premature rupture of the membranes associ-ated with corticosteroids (Murphy et al. 2008;Guller et al. 1995). Maternal risks include dose-dependent gestational diabetes, pregnancy-inducedhypertension, infections, cataracts, bone necrosis,and, if used chronically, osteoporosis (Ostensen etal. 2006). Adrenal suppression needs to be consid-ered and treated during labor and delivery, if thewoman has been takingmore than 20mg/d for morethan 3 weeks within the 6 months prior to delivery(Lockwood et al. 1996).

Azathioprine, when taken at doses �2.0 mg/kg/day, is considered a pregnancy-safe medication, as itrequires conversion to its active metabolite 6-mer-captopurine by inosinate pyrophosphorylase, anenzyme lacking in the fetal liver. This medicationhas mainly been used in renal transplantation and


non-renal inflammatory conditions, and in thesesmall matched cohort studies, the rate of fetal mal-formation has not been noted to be increased (Bar etal. 2003; Schramm et al. 2006) However, a cohortstudy from a population-based prescription registryin Denmark assessed the use of azathioprine or 6-mercapotpurinol in the first trimester and reportedan increased risk in malformations, prematurity, andperinatal mortality (Norgard et al. 2003). Similarly,another larger retrospective cohort studydocumented an increased risk for premature birthand ventricular and atrial septum defects (Clearyand Kallen 2009), but these findings have not beenconfirmed by data from the National Transplanta-tion Pregnancy Registry with the exception of ahigher prematurity rate that may be related to theunderlying medical condition or the calcineurininhibitors that are typically used in conjunctionwith azathioprine (Armenti et al. 2002). Maternalside effects are more pronounced with low enzymeactivity of thiopurine methyltransferase (TPMT),causing bone marrow suppression with possibleanemia, hepatitis, and pancreatitis. Assessment ofTPMTactivity prior to initiation is recommended toguide dosing.

Most of the data on the calcineurin inhibitors(cyclosporine and tacrolimus) in pregnancy isderived from transplant patients (Armenti et al.1994; Lamarque et al. 1997). Up to 50% of thecyclosporine dose crosses the placenta, and tran-sient immune alterations in neonates have beennoted without renal dysfunction (Shaheen et al.1993). Congenital malformations have not beendocumented to exceed the general population asconfirmed by a meta-analysis analyzing the riskfor preterm delivery, congenital malformations,and low birth weight (Bar Oz et al. 2001). Oneretrospective and one prospective study reportedpregnancy outcomes with tacrolimus use in renal,combined renal/pancreas, and liver transplanta-tions (Jain et al. 2003, 2004). Prematurity andpreterm delivery was seen in about 50% ofwomen, and one neonate presented with congen-ital malformations. A retrospective analysisbetween 1992 and 1998 reported 100 pregnanciesexposed to 12 mg/day of tacrolimus (Kainz et al.2000). Outcomes were available for 95 pregnan-cies with 68 lives births (12 pregnancy

terminations, 12 spontaneous abortions, 1 still-birth, and 2 neonatal deaths), and the mean preg-nancy duration was 35 weeks of gestation with anormal birth weight in 90% of live births.

As mentioned, serum levels of the calcineurininhibitors should be regularly assessed and thedose adjusted as needed. Nephrotoxicity doesoccur, and these medications can exacerbatematernal hypertension. Even though there ismore data available on cyclosporine in pregnancydue to its longer availability on the market,tacrolimus may be preferred when treating lupusnephritis in pregnancy given its efficacy com-pared to cyclophosphamide and mycophenolatemofetil in inducing remission and its lower riskof infectious complications (Lee and Song 2015).Small amounts of cyclosporine are excreted intobreast milk, and although the FDA advises not tobreastfeed when on this medication, most studieshave no documented neonatal side effects(Moretti et al. 2003). Even less tacrolimus isexcreted into breast milk, approximately 0.06%of maternal weight adjusted dose (French et al.2003). As such, the benefits of breastfeeding out-weigh any documented risks.

Rituximab, a monoclonal antibody againstCD20, crosses the placenta, and high concentra-tions have been found in the umbilical cord blood.One case report noted transient complete deple-tion of B-lymphocytes in a neonate after beingexposed multiple times to rituximab in utero upto the 32nd week of gestation for maternalBurkitt’s lymphoma (Friedrichs et al. 2006). At26 months after delivery, the baby had nodocumented immunological complications andresponded normally to vaccinations. Anothercase report of fetal exposure to rituximab earlyin the first trimester for membranous nephropathynoted normal B-lymphocyte counts at deliveryand no short-term complications (Al-Rabadi etal. 2016). Beyond case reports, there is a growingexperience from the rituximab global drug safetydatabase including 90 live births from 153exposed pregnancies (Chakravarty et al. 2011).Among the live births, there were only 2 birthdefects, but hematological abnormalities wereseen in 11 children. Long-term outcome data isnot available. Expert opinion suggests to wait at


least 6–12 months after exposure to rituximab toconceive, but if it is critically important to use thismedication during pregnancy, it should be givenas early on as possible to reduce the risk of neo-natal infections due to B-lymphocyte depletion atdelivery.

Cyclophosphamide andmycophenolate mofetilare both established teratogens that arecontraindicated in pregnancy and whilebreastfeeding. Cyclophosphamide has an incon-sistent and unpredictable teratogenic effect in thehuman fetus when given during the first trimester.Defects of the calvaria, ear and craniofacial struc-ture, limb, and visceral organ abnormalities havebeen reported in case studies, as well as develop-mental delay during childhood has beendocumented (Greenberg and Tanaka 1964; Toledoet al. 1971; Murray et al. 1984; Kirshon et al.1988; Zemlickis et al. 1992, 1993; Enns et al.1999). When administered in the second or thirdtrimester, structural abnormalities were not found,but growth restriction, suppression of hematopoi-esis, and neurological impairments have beendocumented (Zemlickis et al. 1992; Durodola1979). It is excreted into breast milk (Wiernikand Duncan 1971), and breastfeeding while onthis medication is contraindicated for the concernof hematopoietic suppression. Mycophenolatemofetil is a purine biosynthesis inhibitor that iscontraindicated in pregnancy and whilebreastfeeding. A systematic review reported onpregnancy outcomes in 65 women exposed tomycophenolate mofetil, noting miscarriages in31% and congenital abnormalities in 15%(Ostensen et al. 2006). The characteristic pheno-type of these abnormalities includes cleft lip andpalate, microtia with atresia of the external audi-tory canals, micrognathia, and hypertelorism(Perez-Aytes et al. 2008).

Management of Hypertension

There are two types of hypertension during preg-nancy: prepregnancy chronic hypertension, whichis often diagnosed in pregnancy prior to 20 weeksof gestation, and transient gestational hyperten-sion often developing as part of the preeclampsia

syndrome after the 20th week of gestation. Withthe initial physiological changes of pregnancy thatinclude systemic vasodilatation, blood pressuremay decrease in women with chronic hyperten-sion, necessitating temporary cessation or a reduc-tion in dose of antihypertensive medications.However, toward the end of the second trimester,re-initiation of antihypertensive medication maybe necessary. Significant hypertension in the firsttrimester is associated with poor pregnancyoutcomes.

For decades, the target for blood pressure con-trol has been debated. Recently the Control ofHypertension in Pregnancy Study (CHIPS) trialconcluded that tighter control of maternal bloodpressure is preferable (Magee et al. 2015). Thislarge, international, multicenter, randomized, con-trolled trial enrolled 987 women between 14+0

and 33+6 weeks with chronic hypertension or ges-tational hypertension and randomized them toeither “less tight” (target diastolic BP100 mmHg) or “tight” blood pressure control(target diastolic BP 85 mmHg). No differencewas noted in the primary composite perinatal out-come (pregnancy loss, high level neonatal care),which was 31.4% in the “less tight” versus 30.7%in the “tight” control group. Further, there was nosignificant difference in the size of the babies. Themost significant finding, however, was that severehypertension (>160/110 mmHg) was signifi-cantly more common in women receiving “lesstight” (vs. “tight”) control at 40.6 vs. 27.5%,respectively. Although women with renal diseasewere not represented in the CHIPS trial, intui-tively controlling blood pressure in this popula-tion is likely to be even more critical, and the goalis to achieve blood pressure values consistently<140/90 mmHg. Blood pressure should bechecked on a regular basis during follow-up visitsand at home by the patient herself to assure earlydetection of potential preeclampsia. For this thepatient’s cuff should be assessed for accuracyearly in the pregnancy.

Safe medications for blood pressure controlduring pregnancy include methyldopa, extended-release dihydropyridine calcium channelblockers, and hydralazine. Labetalol crosses theplacenta and conflicting findings on perinatal


effects on the neonate, including bradycardia andhypoglycemia, have been reported (Bateman et al.2016; Thewissen et al. 2016) A subanalysis of theCHIPS trial also noted that women prescribedmethyldopa at randomization instead of labetalolhad was fewer babies with birthweight <10thpercentile (adjusted odds ratio 0.48; 95% CI0.20–0.87) (Magee et al. 2016). Finally, anotherstudy found higher rates of hospitalization forrespiratory distress syndrome, sepsis, and seizuresin the babies of mothers prescribed labetalol onlycompared to those prescribed only methyldopa(Xie et al. 2014). Although labetalol is still widelyprescribed and considered a safe alternative forthe management of hypertension in pregnancy,more definitive randomized controlled trials arelikely required.

Blockade of the renin angiotensin system(RAS) is contraindicated in pregnancy, andwomen planning to conceive should be on alter-native antihypertensive agents, unless the indica-tion for use is to reduce proteinuria, in which casethese medications should be discontinued as soonas the pregnancy is detected and preferably within8 weeks of gestation. An earlier retrospectiveanalysis of Medicaid data of 29,507 childrenborn between 1985 and 2000 in Tennessee ofwhich 209 were exposed to ACE inhibitors and202 to other antihypertensive medicationssuggested the potential for teratogenicity withfirst trimester exposure that included major con-genital malformations such as atrial/or ventricularseptal defects and patent ductus arteriosus (2.9versus 0.8% neonates) (Cooper et al. 2006). How-ever, a larger subsequent study that was better ableto control for potential confounders includingmaternal age, ethnicity, parity, and obesity didnot find an increased risk of teratogenicity afterfirst trimester exposure to drugs that block theRAS compared to other antihypertensive agents(Li et al. 2011). In addition to cardiac and renalmalformations, exposure to ACE inhibitors in thesecond and third trimester can reduce fetal GFRthrough changes in fetal hemodynamics, whichcan lead to oligohydramnios through decreasedfetal urine production, which in turn may lead tofetal pulmonary hypoplasia and potentially death(Shotan et al. 1994; Tabacova et al. 2003).

Peripartum fetal renal failure can be seen, whichmay slowly improve over time (Schubiger et al.1988). In the postpartum period, enalapril, capto-pril, and quinapril have not been noted to pass intobreast milk in significant quantities, andbreastfeeding while on these medications forreduction in proteinuria and blood pressure con-trol is acceptable (Beardmore et al. 2002; Begg etal. 2001).

Assessment and Management ofNephrotic Syndrome

De novo presentation of idiopathic nephrotic syn-drome during pregnancy is rare. A thoroughwork-up includes medical history, clinical symp-toms, physical examination, urinalysis, and sero-logical testing to assess for systemic andsecondary causes. After excluding secondarycauses and preeclampsia, the most important dif-ferential diagnosis (often associated with hyper-tension in the late second or third trimester), denovo idiopathic nephrotic syndrome can be diag-nosed. Early in gestation, a renal biopsy isrecommended to determine the underlying etiol-ogy. As gestation progresses, delivery should beconsidered, and renal biopsy considered postpar-tum, unless marked improvement of the nephroticsyndrome is seen. Treatment depends on presen-tation timing and severity of the nephrotic syn-drome. If diagnosis is not possible, and treatmentneeds to be administered on speculation, eithersteroids or calcineurin inhibitor, alone or in com-bination, can be considered.

Due to the physiological changes that accom-pany pregnancy, including a lower serum albu-min, a higher tendency to develop edema, andhypercoagulabity (Abbassi-Ghanavati et al.2009; Kamel et al. 2014), the symptoms thataccompany the nephrotic syndrome can be par-ticularly severe in pregnancy, and supportivetherapy is often needed while awaiting aresponse to treatment or when diagnosis andtreatment are delayed due to the inability to per-form a biopsy during pregnancy. Conservativetreatment for edema includes elevation of theextremities and compression stockings, but


often diuretics are required, and furosemide isappropriate for severe edema when conservativemeasures fail. Case reports also describe the useof albumin infusions in women with severenephrosis (Sebestyen et al. 2008; Ope-Adenugaet al. 2015).

Nephrotic syndrome with severe hypo-albuminemia (albumin <25 g/L) is associatedwith an increased risk of venous thromboembolicdisease (Barbour et al. 2012), and pregnancyitself is a prothrombotic state (Kamel et al.2014). Presently, there is no data to guide thepractice of prophylactic anticoagulation forsevere hypoalbuminemia from nephrotic syn-drome in pregnancy. In the nonpregnant popula-tion, nephrotic syndrome from membranousnephropathy with an albumin level < 28 g/Lwas found to be the most significant risk factorfor venous thromboembolism (Lionaki et al.2012), and expert opinion suggests considerationfor prophylactic anticoagulation when serumalbumin levels drop below 25 g/L after consid-ering the risk of bleeding (Alfaadhel and Cattran2015); a risk-benefit calculation tool is availableonline (gntools.com (Lee et al. 2014)), but theextrapolation to the pregnant state is unclear, andlikely the indications for anticoagulation shouldbe even more aggressive. In our practice, werecommend that any women with severe protein-uria and serum albumin <20 g/L should receivethromboprophylaxis throughout pregnancy, butanticoagulation should also be considered inthose with less severe nephrotic syndrome withadditional risk factors, e.g., obesity, immobility(including prescribed bed rest), membranousnephropathy, or vasculitis. Treatment with hepa-rins (unfractionated and low-molecular-weightheparin) during pregnancy is considered safe(Singh et al. 2013). Warfarin crosses the placentaand is contraindicated due to associations withhigher rates of fetal loss (Soma-Pillay et al. 2011)and teratogenicity, including skeletal and centralnervous system defects (Basude et al. 2012).Thromboprophylaxis should be held prior to deliv-ery, but resumed as soon as possible postpartum andcontinued for at least 6 weeks, as the postpartumperiod carries a particularly high risk of thrombosis(Kamel et al. 2014).

Safety of Kidney Biopsy

Renal disease can be found in approximately 3%of pregnancies, but in most cases the pathologicaldiagnosis is known prior to conception or can bediagnosed without tissue (such as diabeticnephropathy, lupus nephritis, vasculitis, etc.),and only a small subset will prompt the discussionfor requirement of a biopsy during pregnancy toobtain a tissue diagnosis. Indications for this inter-vention include a sudden and severe decline inrenal function or to obtain the diagnosis in casesof de novo nephrotic syndrome.

Severe complications from renal biopsies inthe nonpregnant population have been reportedto be as low as 0.1%, but there is less safety datain pregnancy. A systematic review of 30 years ofdata (1980–2012) compared outcomes of 243biopsies performed during pregnancy to 1236performed postpartum, mostly within the first2 months (Piccoli et al. 2013a). Overall, 2% ofinterventions developed adverse outcomes,including need for transfusion, embolization ofthe renal artery, early preterm delivery, and pre-sumed related fetal death. Significantly morecomplications were observed in biopsiesperformed during pregnancy compared to thepostpartum period (7 vs. 1%, respectively;p = 0.001). With respect to timing, only minorhemorrhage occurred between 0 and 20 weeks ofgestation, whereas severe biopsy-related compli-cations occurred between 23 and 26 weeks ofgestation. However, it should be noted that theindication for biopsy in many of the older studieswas to diagnose preeclampsia, which is particu-larly precarious. In fact, once preeclampsia entersthe differential diagnosis, delivery should be con-sidered as opposed to a kidney biopsy, which canbe performed more safely in the postpartumperiod should there be no improvement in therenal parameters. As such, we agree with otherauthors with respect to the judicious use of renalbiopsy in pregnancy (Chen et al. 2001;Lindheimer and Davison 1987). There is no abso-lute contraindication to perform a kidney biopsy;however, it should be considered only whenmaternal well-being is at risk and knowledge ofthe underlying pathology will change or help


http://gntools.com

guide the most appropriate and safe treatmentapproach and when waiting until after delivery isnot an option. Further, the earlier the better, as thegrowing uterus will further complicate correctpositioning for the procedure.

Diagnosing SuperimposedPreeclampsia

Proteinuria is a common finding in GN anddistinguishing the etiology of proteinuria duringpregnancy is of paramount importance to dictatefollow-up and plan further treatment and timedelivery. Preeclampsia rarely presents before20 weeks of gestation and is, therefore, unlikelyto be the reason for worsening proteinuria early inpregnancy. However, the onset or worsening ofproteinuria after 20 weeks of gestation includespreeclampsia in the differential diagnosis in addi-tion to de novo presentation or a flare of glomer-ulonephritis. At this point, the work-up shouldproceed as in the nonpregnant patient, includingurinalysis and serological assessment. In patientswith preexisting diseases like lupus nephritis andvasculitis, it is helpful to have baseline serologyavailable for comparison. However, in somecases, superimposed preeclampsia occurs alongwith a flare of underlying renal disease, and thepresentation may be severe (ACOG practice bul-letin. Diagnosis and management of preeclampsiaand eclampsia. Number 33, January 2002. Amer-ican College of Obstetricians and Gynecologists2002). As already mentioned, kidney biopsy hasno role in the diagnosis of superimposed pre-eclampsia, but fortunately an enhanced under-standing of its pathophysiology as a placentallymediated disease can assist with this difficult diag-nostic dilemma, including the assessment ofangiogenic and antiangiogenic markers, theassessment of placenta morphology and bloodflow patterns through the uterine and umbilicalarteries, and finally the assessment of fetal growthand well-being.

The pathophysiology of preeclampsia includesan ischemic placenta that releases antiangiogenicfactors including soluble fms-like tyrosine kinase1 (sFlt-1), which binds and removes from the

maternal circulation vascular endothelial growthfactor (VEGF) and placental growth factor(PlGF), while soluble endoglin (sEng), a trun-cated tumor growth factor (TGF) beta co-receptor,antagonizes the action of TGF-beta and augmentsthe effects of sFlt-1 on the endothelium. Cumula-tively, this results in maternal endothelial dys-function producing the usual signs andsymptoms associated with preeclampsia, theHELLP (hemolysis, elevated liver enzymes, andlow platelets) syndrome, and eclampsia.

Although not as yet widely available, there ismounting evidence to suggest that the measurementof these angiogenic factors will prove useful diag-nostically, especially in women with preexistingrenal disease. The prognosis study noted that asFlt-1/PlGF ratio of 38 or less predicted short-termabsence of preeclampsia in singleton pregnancies inwomen without other comorbidities (Zeisler et al.2016). In the PROMISSE study, after adjusting forclinical risk factors, sFlt-1 was the strongest predic-tor of severe adverse outcomes in pregnancies inpatients with systemic lupus at 12–15 weeks ofgestation, while the combination of elevated sFlt-1and depressed serum levels of PlGF were predictiveof adverse pregnancy outcomes between 16 and19 weeks (Kim et al. 2016). In a cohort of hyper-tensive pregnant women, sFlt-1, sEng, and thesFlt-1/PlGF ratio were found to be significantlyhigher, while PlGF was significantly lower inwomen with superimposed preeclampsia (Perniet al. 2012). Also, in women with chronic kidneydisease, preeclamptic patients demonstratedhigher sFlt-1, lower PlGF, and a higher sFlt-1/PlGF ratios (Rolfo et al. 2013; Masuyama et al.2012) with a low PlGF having the highest diag-nostic accuracy for superimposed preeclampsiarequiring delivery within 14 days (Bramham etal. 2016).

Until these markers are better studied inwomen with different forms of GN at differentlevels of CKD, assessment of the placenta can bevery helpful in diagnosing superimposed pre-eclampsia. High resistance patterns and lowvelocity waveforms in uterine and umbilical arter-ies can distinguish chronic kidney disease (normalflow waves) from preeclampsia (high resistanceflows with a pulsatility index >1.4) (Piccoli et al.


2013b). If not available, poor fetal growth is alsoindicative of poor placentation, which can helpdiagnostically to make appropriate treatmentdecisions.

Disease-Specific Pregnancy Outcomes

Lupus Nephritis in Pregnancy

Unlike other rheumatologic diseases, systemiclupus erythematous (SLE) is well described andstudied in pregnancy due to its predominant dis-ease onset in young females (Pons-Estel et al.2010). Overt renal disease develops in about30% of lupus patients over 10 years with Eastand South Asians having the highest occurrenceof lupus nephritis, followed by Afro-Caribbeanand Europeans (Morais and Isenberg 2016). Thede novo presentation of lupus during pregnancyhas been reported (Ergin 2014; Patel et al. 2012),but pregnancy as a risk factor for a flare of sys-temic lupus has been debated for years (Bramhamet al. 2012). A newer hypothesis is that pregnancyin itself is not the risk factor, but that a bluntedincrease in T-lymphocyte-2-helper cells inducedcytokine levels along with lower levels of estro-gen and progesterone leads to amplification ofinflammatory effects (Iaccarino et al. 2012;Doria et al. 2004).

Overall outcomes of pregnancies affected bySLE have significantly improved in developedcountries in recent years, but in developing coun-tries ongoing poor outcomes is a concern(Chandran et al. 2005), reflecting that there is aneed for medical resources to appropriately pre-pare these women for pregnancy. There are sub-sets of SLE patients who have higher risks ofpregnancy-related complications. Women withactive disease, especially nephritis, at the time ofconception, have worse outcomes, and pregnancyshould be delayed until their disease is controlled(Imbasciati et al. 2009; Saavedra et al. 2012).Endocapillary proliferative lupus nephritis (classIII and IV) may present more frequently withpreeclampsia and lower birth weight babies thanmesangioproliferative (class II) or membranous

(class V) lupus nephritis (Carmona et al. 2005),while women with antiphospholipid antibodiescan develop pregnancy-related thrombosis, pre-eclampsia, and fetal loss (Ruiz-Irastorza andKhamashta 2005).

A comprehensive systematic review of the lit-erature summarized results for 1842 patients and2751 pregnancies from 37 smaller studies andnoted the most common maternal risk was a dis-ease flare, occurring in 26% with a flare of nephri-tis occurring in 16% of pregnancies (Smyth et al.2010). Predictors for renal flares during preg-nancy and the long-term outcome of these flareshave been retrospectively studied in 183 patientswith SLE and preexisting lupus nephritis (Koh etal. 2015). In this retrospective analysis, there wasa high rate of renal flares in patients with pre-existing lupus nephritis (50.7%). Predictors ofrenal flare were preexisting lupus nephritis (OR17.7; 95% CI, 5.77–54.48), active disease precon-ception (OR 2.74; 95% CI, 1.07–7.00), and aprepregnancy eGFR of less than 90 ml/min/1.73m2 (OR 11.15; 95% CI, 3.29–37.77). Patientswere followed for a median of 5.9 years postpar-tum, and 33% of those who flared during preg-nancy had persistent renal disease activity 1 yearafter delivery with high rates of progression tochronic kidney disease when proteinuria couldnot be reduced �50% of the presenting protein-uria within 6 months postpartum. Other fearedmaternal complications include the development ofgestational hypertension (16.3%), preeclampsia(7.5%), and eclampsia (0.8%), while fetal risksinclude spontaneous abortion (16%), intrauterinefetal death or stillbirth (3.6%), intrauterine growthrestriction (12.5%), premature rupture of mem-branes and premature delivery (39.4%), and neona-tal lupus and perinatal mortality (2.5%) (Smyth et al.2010; Warren and Silver 2004; Clowse 2007).

There is new evidence though to support thefact that careful preconception counseling andclose observation during pregnancy can minimizematernal risk and improve perinatal morbidity andmortality. The recently published PROMISSEstudy is a large prospective study of 385 womenfrom multiple ethnic and racial backgrounds(Buyon et al. 2015). It included only women


with largely quiescent disease at conception byexcluding women with a urine protein to creati-nine ratio >1000 mg/g, creatinine level greaterthan 1.2 mg/dL, and daily prednisolone use>20 mg/day. Overall, 81% of 236 women haduncomplicated pregnancies, and fetal and infantdeaths were very rare. Severe maternal flares inthe second and third trimesters occurred only in2.5% and 3.0%, respectively. Risks for adversepregnancy outcomes included being positive forlupus anticoagulant (OR 8.32 [CI, 3.59 to 19.26]),use of antihypertensive medications (OR, 7.05[CI, 3.05 to 16.31]), a physician global activityscore that exceeded 1 (OR, 4.02 [CI, 1.84 to8.82]), and a low platelet count (OR, 1.33 [CI,1.09 to 1.63] per decrease of 50 x 109 cells/L). Ofnote, the vast majority of these women receivedspecialized care and oversight. As such, mostpatients with SLE, especially those with normalrenal function and controlled proteinuria, willhave minimal maternal or fetal complicationsand overall good pregnancy outcomes, if the preg-nancy has been carefully planned, monitored, andmanaged.

As already mentioned, monitoring includes theregular assessment of anti-dsDNA titers, comple-ment levels, CBC, liver enzymes and renal func-tion including urinalysis for hematuria andquantification of proteinuria by microalbumin-to-creatinine ratio, and when increasing by 24 hurine collection. It is our practice to monitor theseparameters once monthly or more frequentlywhere indicated. As anti-dsDNA and decreasedC3 and C4 complements have been associatedwith poor pregnancy outcome, knowledge of thebaseline values and whether the patient presentswith concordant or discordant serology duringflares is helpful when trying to judge diseaseactivity during pregnancy. The usual clinical pre-sentation of a lupus flare should be also noted andused as reference for the clinical assessment dur-ing pregnancy. Other serology that should be eval-uated at least once before or in the first trimesterinclude antiphospholipid antibodies, which mayinform anticoagulation, as well as Anti-SSA (anti-Rho) and Anti-SSB (anti-La) to assess the risk ofneonatal lupus with congenital heart block (Jaeggi

et al. 2010). Pregnancies with positive Anti-Rhoand anti-La titers should be monitored with serialfetal echocardiography. Blood pressure monitor-ing in office and at home when elevated should bean ongoing part of assessment to pick up the firstsigns of gestational hypertension or preeclampsia.As mentioned, a low sFlt-1 and elevated PlGFwere effective in predicting severe adverse preg-nancy outcomes in patients with SLE as noted inthe PROMISSE study and may very well becomethe standard of care in the not too distant future(Kim et al. 2016).

Treatment of SLE should ideally have led todisease quiescence for at least 6 months prior toconception, and the patient should be switchedand stable on pregnancy-safe medications(Bertsias et al. 2012). Azathioprine shouldreplace mycophenolate mofetil for at least3 months before conception, while biologicagents such as rituximab should not be adminis-tered closer than 3–6 months prior to conceptionwhenever possible (Bertsias et al. 2012). Gener-ally safe medications for use during pregnancyinclude prednisone, which could be used as pulseand maintenance therapy, calcineurin inhibitors,and azathioprine. Hydroxychloroquine is a main-stay of therapy in this disease. Although thisantimalarial medication crosses the placenta,there is no evidence of fetal toxicity in doses of200–400 mg/d. Hydroxychloroquine has beendemonstrated to maintain remission of extrarenalmanifestations of lupus, and decrease neonatallupus when anti-Rho and anti-La antibodies arepresent (Tsakonas et al. 1998; Abarientos et al.2011; Clowse et al. 2006). Hydroxychloroquinediscontinuation during pregnancy has also beenreported to promote lupus flares, resulting in ahigher exposure to prednisone (Clowse et al.2006). Ideally, it should be started prior to preg-nancy, but we will also start it at the first preg-nancy visit before the end of the first trimesteralong with low-dose ASA for preeclampsia pre-vention. Anticoagulation with low-molecular-weight heparin may also be required in womenwith positive antiphospholipid antibodies or asignificant flare accompanied by nephrotic-range proteinuria.


Systemic Vasculitis, AntineutrophilCytoplasmic Autoantibody-AssociatedVasculitis

Antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is fortunately rare in pregnancyas, unlike SLE, these diseases lack a female pre-ponderance, and the peak onset is after 65 years ofage. As such, little data is available on these dis-eases in pregnancy with respect to renal functiondecline and the potential for a pregnancy-associatedrelapse as well as adverse maternal and fetal out-comes. As such, the principles of management arelargely extrapolated from studies on lupus nephritis.

Active vasculitis at time of conception canresult in spontaneous abortions, and disease dete-rioration has led clinicians to recommend thera-peutic abortions in the attempt to maintainmaternal health given the teratogenicity of first-line therapies. De novo disease during pregnancyis rarely reported, so it is difficult to determine ifthere is a predilection for any particular trimester.In a retrospective review of 65 pregnanciesfollowed by specialists in 8 institutions between1995 and 2014, only 2 presented for the first timeduring pregnancy (Fredi et al. 2015). In anotherreview of published cases, 8 of 21 patients devel-oped relapse during pregnancy (Koukoura et al.2008), but other studies have documented fewerrelapses with only 18% of patients reporting wors-ening of vasculitis symptoms during pregnancy(Clowse et al. 2013).

Pregnancy outcomes are worse than the gen-eral population, and these pregnancies are notwithout significant risk to both mother and baby.In the aforementioned review of 65 pregnancies,vasculitis-related complications occurred in 23pregnancies (35.4%), including 3 cases of tran-sient ischemic attack (TIA). Further, early pretermdelivery (<34 weeks) was significantly more fre-quent than in the general population (11.3% vs5.0%, p= 0.049). Postpartum flares also occurredin 21.4% of pregnancies (Fredi et al. 2015). Asurvey of participants in the Vasculitis ClinicalResearch Consortium Patient Contact Registrythat compared pregnancy outcomes prior to andafter diagnosis of vasculitis reported higher ratesof pregnancy loss and preterm delivery in those

who conceived after diagnosis, especially amongthose wherein vasculitis activity worsened duringpregnancy (Clowse et al. 2013).

Given the low number of cases and the highpotential for reporting bias, it is important toclosely observe these pregnancies within a multi-disciplinary team in a tertiary health center toadjust the treatment approach on an individualbasis. There is limited data to suggest well-man-aged patients that enter pregnancy in a remissiondo better. A small case series from the UnitedKingdom reported on 15 pregnancies noting thatall were successful given that all, but one, wereplanned following a minimum of 6 months ofclinical remission (Croft et al. 2015). The singleflare was successfully treated with increased doseof azathioprine and corticosteroids, intravenousimmunoglobulin, and plasma exchange therapy,all safe in pregnancy. IVIG crosses the placenta insignificant amounts (Hockel and Kaufmann1986), but no side effects have been reported inneonates (Bellisai et al. 2004). Transplacentaltransmission of anti-MPO antibodies does occur.One case described neonatal pulmonary renal syn-drome, which was successfully treated with ste-roids and exchange transfusions (Bansal andTobin 2004), but antibodies have been detectedin fetal blood after delivery without causing vas-culitis-related symptoms (Alfhaily et al. 2009).

Antiglomerular Basement MembraneAntibody Disease

The experience with antiglomerular basementmembrane (anti-GBM) antibody disease in preg-nancy is minimal with only a handful of casereports in the literature that were recently summa-rized (Thomson et al. 2014), and overall outcomesare very poor. Renal biopsies were obtained inseven of eight women, three of them during theearly second trimester (14–18 weeks). Dialysiswas required in seven of eight patients duringand in most chronically after pregnancy. Onlytwo recovered renal function after treatment, oneof which underwent therapeutic abortion at gesta-tional age of 15 weeks. Significant pregnancy-related maternal morbidity was reported (2/


8 preeclampsia, 2/8 hyperemesis gravidarum, 3/8 gestational diabetes, and 1/8 severe infectiondue to immunosuppressive pharmacotherapy).Treatments varied significantly and were partiallystarted during pregnancy, and more aggressivelypursued after delivery, including plasmapheresisand steroids in all pregnancies, cyclophosphamidein two cases during pregnancy with three delayeduntil after delivery. In the absence of cyclophos-phamide during pregnancy, azathioprine was usedfor induction treatment. Fetal demise was seen intwo of eight pregnancies. Prematurity was univer-sal in all live-born babies (6/6) of which one wasseverely premature (26.5 weeks). Growth restric-tion and small for gestation age babies were alsofrequent. Congenital abnormalities were found intwo of six live births. Anti-GBM antibodies couldbe found in some of the newborn’s blood (2/5),but none were symptomatic with renal or pulmo-nary disease.

IgA Nephropathy

IgA nephropathy is the commonest primarynephropathy in the developed world so it is com-mon in pregnancy as well. There is a low risk ofdeterioration of renal function in women with IgAnephropathy during pregnancy so long as renalfunction is preserved (Abe 1994). A study thatcompared 62 women who had 69 pregnancies to62 matched nonpregnant controls determined thatpregnancy was not an independent risk factor fordisease progression over 45.7 months, but pro-gression was minimal in both groups (�2.5 vs�2.4 mL/min/1.73m2 per year, respectively,P = 0.7) (Liu et al. 2014). A large Italian studyof patients recruited patients with IgA nephropa-thy and an eGFR>60 ml/min from 1974 to 2003,followed patients for a median of 10 years post-partum and confirmed no difference in progres-sion between pregnant and nonpregnant groups(Limardo et al. 2010). Pregnancy outcomes inthis cohort included 3% perinatal death, 10% pre-mature delivery, and 21% development of hyper-tension with 8.5% superimposed preeclampsia.Shimizu and colleagues followed 67 patientswith IgA nephropathy during pregnancy, and

similarly renal function remained stable, and com-parable to a nonpregnant control group, in theobservation interval of 5 years postpartum, whenentering pregnancy with eGFR >45 ml/min(N = 16) (Shimizu et al. 2015). However,women with eGFR <45 ml/min showed wors-ening renal function, with 91% of the womenentering pregnancy at CKD stage 4 (eGFR 27þ/� 4.2 ml/min; N = 11) reaching end-stage renaldisease within 5 years postpartum, with require-ment of renal replacement therapy after 3.9þ/�0.7 years. Regardless of the eGFR, womenwith proteinuria >1 g/d (N = 10) developedhypertension in 60% and had low birth weightneonates in 30% of pregnancies. In a single-centerretrospective study, proteinuria at conception wasindependently associated with a faster decline inpostpartum maternal eGFR (Oh et al. 2011).Based on this data, proteinuria should be stabi-lized and decreased prior to conception.

Hereditary Nephritis/Alport Syndrome

Type IV collagen mutations in the alpha-3, alpha-4, and alpha-5 chains cause longitudinal splittingand irregular thinning and thickening of the lam-ina densa of the glomerular basement membranein Alport syndrome. It is a familial nephritis,which is passed on, in the majority of cases, as aX-linked trait (gene COL4A5) in the alpha-5chain, and penetrance is widely variable inwomen due to differing degrees of X-genelyonization (Artuso et al. 2012). The autosomal-recessive or more rarely autosomal-dominantforms of Alport syndrome are introduced throughmutations in the alpha-3 chain (gene COL4A3) oralpha-4 (gene COL4A4) type IV collagen. Assuch genetic assessment and counseling isrequired in addition to discussions about potentialpregnancy-associated complications.

Unfortunately, the only data available to guidepregnancy counseling is in form of case reports.The baseline renal function and the extend ofproteinuria at conception seemingly determinesprogression of renal disease during pregnancy.One report documented good maternal and fetaloutcomes in two consecutive pregnancies in a


woman with X-linked Alport syndrome with nor-mal renal function, normal blood pressure, andmild proteinuria at conception (Matsubara andMuto 2012), while women with more advancedCKD or higher grades of proteinuria are at higherrisk for adverse outcomes as one would expect.One woman with Alport and stage 3 CKD (creat-inine 106 umol/l, eGFR 57.8), controlled bloodpressure below <140/90 mmHg, and 0.9 g/24 hproteinuria at conception developed severe pre-eclampsia at 25þ 2 weeks of gestation with renalfailure and severe early-onset fetal growth restric-tion (Matsuo et al. 2007). Two women, both withproven missense mutations in the alpha-5 chain oftype IV collagen, entered pregnancy with normalrenal function and blood pressure at conception(Alessi et al. 2014), but different levels of baselineproteinuria, <1 g/24 h and 3.26 g/24 h, whichincreased in both to overt nephrotic-range protein-uria during pregnancy. The woman with baselinenephrotic-range proteinuria developed hyperten-sion and delivered at 33 weeks of gestation. Herrenal function declined to 42 ml/min postpartumat 22 months of follow-up, and her proteinuriareturned to 3.21 g/24 h, while the woman withnon-nephrotic-range proteinuria preconceptionmaintained her renal function with a GFR 85 ml/min and returned to preconception proteinurialevels of 0.9 g/24 h. One may deduct from thesereports that both a compromised GFR and theseverity of baseline proteinuria impacts nega-tively on renal outcome in pregnancy, and despitethe lack of data, general principles of counselling,already reviewed, apply to this subset of youngwomen.

Thin Basement MembraneNephropathy

Persistent (isolated) hematuria, normal renal func-tion, minimal proteinuria, a family member withhematuria, and an overall benign course clinicallycharacterize thin basement membrane nephropa-thy. Tissue biopsies exhibit diffuse thinning of thelamina densa of the glomerular basement mem-brane. Women and men are equally affected, andthe incidence is about 5–9% in the general

population (Dische et al. 1990). Women seem-ingly come more frequently to medical attentiondue to their thinner glomerular basement mem-branes resulting in more prominent and, therefore,more easily noticed hematuria (Savige et al.2003). Usually, the prognosis is excellent, andthis is equally true for renal and fetal outcomesduring pregnancy.

However, earlier studies noted that isolatedhematuria, which may very well representwomen with thin basement membrane disease ormild IgA nephropathy, increased the risk ofadverse pregnancy outcomes in particular animpressively increased odds ratio for both pre-eclampsia (OR 9.5, 95%CI 3.1–28.2) and pretermdelivery (OR = 3.8, 95% CI 1.5–9.7) (Stehman-Breen et al. 2000). A subsequent analysis by thesame author utilizing data from the trial of Cal-cium for Preeclampsia Prevention (CPEP) studyfound a similar association, but of less magnitudewith an adjusted odds ratio of 1.89, 95% CI1.12–3.18 (Stehman-Breen et al. 2002). This asso-ciation though was not confirmed by a large Aus-tralian study that assessed 1000 women fordipstick-positive hematuria, noting first that dip-stick-positive hematuria in pregnancy was com-mon (20%) and that there was no difference thedevelopment of gestational hypertension, pre-eclampsia, or small for gestational age babiesbetween women with and without microscopichematuria (Brown et al. 2005). This suggeststhat not all hematuria is of glomerular origin andperhaps studies need to look more carefully atpregnancy outcomes in women with microscopichematuria in association with low-gradeproteinuria.

Other Primary Glomerular Diseases

There is limited data on the pregnancy outcomesin women with the other primary causes ofnephrotic syndrome, including minimal changedisease, focal segmental glomerulosclerosis(FSGS), and membranous nephropathy. Furthermany of the larger studies are quite dated. Thelargest study, spanning 1965–1994, assessed dis-ease progression in 360 women with glomerular


disease and preserved renal function (creati-nine � 100 μmol/l) and reported that pregnancywas not associated with accelerated progression,regardless of disease etiology (Jungers et al.1995). Similarly, another study noted no hastenedprogression relative to a nonpregnant population,but higher rates of prematurity and neonatal deathwas documented compared to the general popula-tion, most notably in women with acceleration ofhypertension and proteinuria during pregnancy(Barcelo et al. 1986).

There are a few case reports on de novo mini-mal change disease in pregnancy treated withprednisone, the standard treatment outside preg-nancy. Overall outcomes were quite good with theexception of mild prematurity in one fetus(35 weeks) (Nelson 2003; Hamilton et al. 2014).There is a similar paucity of data available for thetreatment of FSGS in pregnancy, and treatmentchoices are prednisone and/or a calcineurininhibitor.

There are also few reports on pregnancies inidiopathic membranous nephrology describingoverall poor outcome associated with nephrotic-range proteinuria in the first trimester (Aoshima etal. 2013). In an older study of 33 pregnancies,there was a significant increase in proteinuria in55% with nephrotic syndrome in 30%, gestationalhypertension in 46%, and a decrease in renalfunction in 9% (Packham et al. 1987). Fetal lossoccurred in 24%, and 43% of neonates were deliv-ered prematurely (Packham et al. 1987). Idio-pathic membranous nephropathy presents withcirculating M-type phospholipase A2 receptor(PLA2R) antibodies in the nonpregnant popula-tion (Beck et al. 2009). Even though one reportconfirmed that this antibody can be found duringpregnancy (Al-Rabadi et al. 2016), it is not clear ifthis biomarker can be used to reliably diagnoseidiopathic membranous nephropathy. Calcineurininhibitors and low-dose prednisone have beenused for treatment; also a combination of predni-sone and azathioprine was used with variablesuccess (Aoshima et al. 2013; Sebestyen et al.2008). As mentioned there is not as yet enoughexperience with rituximab in pregnancy availableto determine the long-term fetal outcomes afterexposure to this medication.

Atypical Hemolytic Uremic Syndromeand Thrombotic ThrombocytopenicPurpura (TTP)

Atypical hemolytic uremic syndrome (aHUS)and thrombotic thrombocytopenic purpura(TTP) both fall into the spectrum of thromboticmicroangiopathies characterized by microvascu-lar endothelial activation, cell injury, and throm-bosis. Both these conditions pose a significantthreat in pregnancy. As HELLP (hemolysis, ele-vated liver enzymes, low platelets) syndromeand preeclampsia share common features withaHUS and TTP, such as hypertension, protein-uria, microangiopathic hemolysis, and decreasedplatelet count, distinction can be challenging, butis critical as treatment varies significantly.Although TTP can present in any trimester, itmore commonly presents later in gestation asdoes the HELLP syndrome, while aHUS mostcommonly presents in late gestation and the earlypostpartum. The absence of improvement of theplatelet count 3–5 days after delivery may be anindicator that indeed the underlying etiology isaHUS or TTP rather than preeclampsia orHELLP syndrome.

As pregnancy in some way incites the cascadeof endothelial disruption resulting in micro-thrombi, it is a well-described precipitant (Georgeet al. 2004), and a significant percentage of youngwomen with TTP present for the first time duringpregnancy (Wiznitzer et al. 1992; Meti et al.2010). There are a number of theories why preg-nancy might pose a heightened risk for the devel-opment of TTP, including the procoagulant statethat accompanies pregnancy as well as the poten-tial effect of estrogen on the level of ADAMTS13(a disintegrin and metalloproteinase withthrombospondin type 1 motifs 13), which pro-gressively decreases throughout pregnancy tonadir in the early postpartum period. In the largest,most complete patient registry of TTP-HUS fromOklahoma City, pregnancy accounted for 26 ofthe 352 cases collected over approximately15 years, and the vast majority presented in thethird trimester and early postpartum period(George et al. 2004). Plasmapheresis, which isthe mainstay of treatment, inhibits platelet


aggregation, replenishes absent ADAMTS13,and/or removes pathogenic antibodies.

Atypical HUS, secondary to genetic mutationsinvolving the activation or regulation of the alter-native complement pathway, can be induced bypregnancy, presenting clinically with low serumcomplement levels and predominant renalinvolvement. Currently, data is limited, but over-all maternal outcome appears to be quite poor.Documented cases most frequently present in thepostpartum period with only 20% presenting dur-ing pregnancy, without preference for a specifictrimester. Severe renal involvement is typical,necessitating dialysis during the acute phase ofthe disease in 81% with 62% reaching ESRDwithin a month despite therapy, a number thatincreased to 79% on further follow-up (Fakhouriet al. 2010). However, given the late onset ofdisease, fetal outcomes are reasonable with thevast majority proving uneventful (74.7%).Eculizumab, a humanized monoclonal antibody,blocks the terminal step in the formation of themembrane attack complex by inhibiting cleavageof C5a to C5b, and stops with it the uncontrolledalternative complement pathway activation.Eculizumab is likely to improve pregnancy out-comes, as successful pregnancies in women withknown aHUS on maintenance treatment witheculizumab have been reported (Servais et al.2016). However, most of the current experiencewith this drug comes from patients with paroxys-mal nocturnal hemoglobinuria and the PNH reg-istry (75 pregnancies from 61women) (Kelly et al.2015). Although eculizumab was documented in7/20 cord blood samples, the antibody was notfound in breast milk samples (0/10). Reporteddosing of this medication in known aHUS isevery other week; however, the authors suggestto individually dose treatment based on the com-plement level suppression, which may vary dur-ing pregnancy (Servais et al. 2016).

Summary Statements

The rarity of glomerular diseases in general resultsin a challenge in pregnancy due to the paucity ofdata beyond case reports and case series available to

guide counseling and management. However, itmust be remembered that overall live births are therule and that careful prepregnancy counselingand optimization likely improves outcomes. Further,there is a renewed interest in these patientswith large observational cohorts includingNephrotic Syndrome Study Network (NEPTUNE)(NCT01209000) and Cure GN (https://curegn.org),which will also assess pregnancy outcomes and canpotentially guide future collaborative research.

References

Abarientos C, Sperber K, Shapiro DL, Aronow WS, ChaoCP, Ash JY (2011) Hydroxychloroquine in systemiclupus erythematosus and rheumatoid arthritis and itssafety in pregnancy. Expert Opin Drug Saf.doi:10.1517/14740338.2011.566555

Abbassi-Ghanavati M, Greer LG, Cunningham FG (2009)Pregnancy and laboratory studies: a reference table forclinicians. Obstet Gynecol 114(6):1326–1331.doi:10.1097/AOG.0b013e3181c2bde8

Abe S (1994) The influence of pregnancy on the long-termrenal prognosis of IgA nephropathy. Clin Nephrol41(2):61–64

ACOG practice bulletin. Diagnosis and management ofpreeclampsia and eclampsia. Number 33, 2002. Amer-ican College of Obstetricians and Gynecologists(2002). Int J Gynaecol Obstet 77(1):67–75

Al-Rabadi L, Ayalon R, Bonegio RG, Ballard JE, FujiiAM, Henderson JM, Salant DJ, Beck LH Jr (2016)Pregnancy in a patient with primary membranousnephropathy and circulating anti-PLA2R antibodies:A case report. Am J Kidney Dis 67(5):775–778.doi:10.1053/j.ajkd.2015.10.031

Alessi M, Fabris A, Zambon A, Cremasco D, Muraro E,Dosa L, Anglani F, Del Prete D (2014) Pregnancy inAlport syndrome: A report of two differently-evolvingcases. J Obstet Gynaecol 34(1):98–100. doi:10.3109/01443615.2013.834299

Alfaadhel T, Cattran D (2015) Management of membra-nous nephropathy in western countries. Kidney Dis(Basel) 1(2):126–137. doi:10.1159/000437287

Alfhaily F, Watts R, Leather A (2009) Wegener’sgranulomatosis occurring de novo during pregnancy.Clin Exp Rheumatol 27(1 Suppl 52):S86–S88

Aoshima Y, Iyoda M, Nakazawa A, Yamaguchi Y, KurokiA, Shibata T, Akizawa T (2013) Membranous nephrop-athy that first presented in pregnancy. Intern Med 52(17):1949–1952

Armenti VT, Ahlswede KM, Ahlswede BA, Jarrell BE,Moritz MJ, Burke JF (1994) National transplantationpregnancy registry – outcomes of 154 pregnancies incyclosporine-treated female kidney transplant recipi-ents. Transplantation 57(4):502–506


https://curegn.org

Armenti VT, Radomski JS, Moritz MJ, Gaughan WJ,Philips LZ, McGrory CH, Coscia LA (2002) Reportfrom the National Transplantation Pregnancy Registry(NTPR): outcomes of pregnancy after transplantation.Clin Transpl:121–130

Artuso R, Fallerini C, Dosa L, Scionti F, Clementi M,Garosi G, Massella L, Epistolato MC, Mancini R,Mari F, Longo I, Ariani F, Renieri A, Bruttini M(2012) Advances in Alport syndrome diagnosis usingnext-generation sequencing. Eur J Hum Genet 20(1):50–57. doi:10.1038/ejhg.2011.164

Bansal PJ, Tobin MC (2004) Neonatal microscopic poly-angiitis secondary to transfer of maternalmyeloperoxidase-antineutrophil cytoplasmic antibodyresulting in neonatal pulmonary hemorrhage and renalinvolvement. Ann Allergy Asthma Immunol 93(4):398–401. doi:10.1016/s1081-1206(10)61400-7

Bar J, Chen R, Schoenfeld A, Orvieto R, Yahav J, Ben-Rafael Z, HodM (1999) Pregnancy outcome in patientswith insulin dependent diabetes mellitus and diabeticnephropathy treated with ACE inhibitors before preg-nancy. JPEM 12(5):659–665

Bar J, Stahl B, Hod M, Wittenberg C, Pardo J, Merlob P(2003) Is immunosuppression therapy in renal allograftrecipients teratogenic? A single-center experience. AmJ Med Genet A 116A(1):31–36. doi:10.1002/ajmg.a.10817

Bar Oz B, Hackman R, Einarson T, Koren G (2001) Preg-nancy outcome after cyclosporine therapy during-pregnancy: A meta-analysis. Transplantation71(8):1051–1055

Barbour SJ, Greenwald A, Djurdjev O, Levin A,Hladunewich MA, Nachman PH, Hogan SL, CattranDC, Reich HN (2012) Disease-specific risk of venousthromboembolic events is increased in idiopathic glo-merulonephritis. Kidney Int 81(2):190–195.doi:10.1038/ki.2011.312

Barcelo P, Lopez-Lillo J, Cabero L, Del Rio G (1986)Successful pregnancy in primary glomerular disease.Kidney Int 30(6):914–919

Barua M, Hladunewich M, Keunen J, Pierratos A,McFarlane P, Sood M, Chan CT (2008) Successfulpregnancies on nocturnal home hemodialysis. Clin JAm Soc Nephrol 3(2):392–396. doi:10.2215/cjn.04110907

Basude S, Hein C, Curtis SL, Clark A, Trinder J (2012)Low-molecular-weight heparin or warfarin for anti-coagulation in pregnant women with mechanical heartvalves: What are the risks? A retrospective observa-tional study. BJOG 119(8):1008–1013; discussion1012–1003. doi:10.1111/j.1471-0528.2012.03359.x

Bateman BT, Patorno E, Desai RJ, Seely EW, Mogun H,Maeda A, Fischer MA, Hernandez-Diaz S, HuybrechtsKF (2016) Late pregnancy beta blocker exposure andrisks of neonatal hypoglycemia and bradycardia. Pedi-atrics 138(3). doi:10.1542/peds.2016-0731

Beardmore KS, Morris JM, Gallery ED (2002) Excretionof antihypertensive medication into human breast milk:A systematic review. Hypertens Pregnancy 21

(1):85–95. doi:10.1081/PRG-120002912. 120002912[pii]

Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, PowellDW, Cummins TD, Klein JB, Salant DJ (2009) M-typephospholipase A2 receptor as target antigen in idio-pathic membranous nephropathy. N Engl J Med 361(1):11–21. doi:10.1056/NEJMoa0810457

Bedaiwy MA, Abou-Setta AM, Desai N, Hurd W, StarksD, El-Nashar SA, Al-Inany HG, Falcone T (2011)Gonadotropin-releasing hormone analog cotreatmentfor preservation of ovarian function duringgonadotoxic chemotherapy: A systematic review andmeta-analysis. Fertil Steril 95(3):906–914, e901–904.doi:10.1016/j.fertnstert.2010.11.017

Begg EJ, Robson RA, Gardiner SJ, Hudson LJ, Reece PA,Olson SC, Posvar EL, Sedman AJ (2001) Quinapril andits metabolite quinaprilat in human milk. Br J ClinPharmacol 51(5):478–481. doi:bcp1327 [pii]

Bellisai F, Morozzi G, Marcolongo R, Galeazzi M (2004)Pregnancy in Wegener’s granulomatosis: Successfultreatment with intravenous immunoglobulin. ClinRheumatol 23(6):533–535

Bertsias GK, Tektonidou M, Amoura Z, Aringer M,Bajema I, Berden JH, Boletis J, Cervera R, Dorner T,Doria A, Ferrario F, Floege J, Houssiau FA, IoannidisJP, Isenberg DA, Kallenberg CG, Lightstone L, MarksSD, Martini A, Moroni G, Neumann I, Praga M,Schneider M, Starra A, Tesar V, Vasconcelos C, vanVollenhoven RF, Zakharova H, Haubitz M, Gordon C,Jayne D, Boumpas DT (2012) Joint European LeagueAgainst Rheumatism and European Renal Association-European Dialysis and Transplant Association(EULAR/ERA-EDTA) recommendations for the man-agement of adult and paediatric lupus nephritis. AnnRheum Dis 71(11):1771–1782. doi:10.1136/annrheumdis-2012-201940

Boumpas DT, Austin HA, Vaughan EM, Yarboro CH,Klippel JH, Balow JE (1993) Risk for sustained amen-orrhea in patients with systemic lupus erythematosusreceiving intermittent pulse cyclophosphamide ther-apy. Ann Intern Med 119(5):366–369. doi:10.1059/0003-4819-119-5-199309010-00003

Bramham K, Soh MC, Nelson-Piercy C (2012) Pregnancyand renal outcomes in lupus nephritis: An update andguide to management. Lupus 21(12):1271–1283.doi:10.1177/0961203312456893

BramhamK, Seed PT, Lightstone L, Nelson-Piercy C, Gill C,Webster P, Poston L, Chappell LC (2016) Diagnostic andpredictive biomarkers for pre-eclampsia in patients withestablished hypertension and chronic kidney disease. Kid-ney Int 89(4):874–885. doi:10.1016/j.kint.2015.10.012

Breymann C, Visca E, Huch R, Huch A (2001) Efficacyand safety of intravenously administered iron sucrosewith and without adjuvant recombinant human eryth-ropoietin for the treatment of resistant iron-deficiencyanemia during pregnancy. Am J Obstet Gynecol184(4):662–667. doi:10.1067/mob.2001.111717

Brown MA, Holt JL, Mangos GJ, Murray N, Curtis J,Homer C (2005) Microscopic hematuria in pregnancy:


Relevance to pregnancy outcome. Am J Kidney Dis45(4):667–673

Buyon JP, Kim MY, Guerra MM, Laskin CA, Petri M,Lockshin MD, Sammaritano L, Branch DW, PorterTF, Sawitzke A, Merrill JT, Stephenson MD, Cohn E,Garabet L, Salmon JE (2015) Predictors of pregnancyoutcomes in patients with lupus: A cohort study. AnnIntern Med 163(3):153–163. doi:10.7326/m14-2235

Cabiddu G, Castellino S, Gernone G, Santoro D, MoroniG, Giannattasio M, Gregorini G, Giacchino F, Attini R,Loi V, Limardo M, Gammaro L, Todros T, Piccoli GB(2016) A best practice position statement on pregnancyin chronic kidney disease: The Italian study group onkidney and pregnancy. J Nephrol 29(3):277–303.doi:10.1007/s40620-016-0285-6

Carmona F, Font J, Moga I, Lazaro I, Cervera R, Pac V,Balasch J (2005) Class III-IV proliferative lupusnephritis and pregnancy: A study of 42 cases. Am JReprod Immunol 53(4):182–188. doi:10.1111/j.1600-0897.2005.00263.x

Chakravarty EF, Murray ER, Kelman A, Farmer P (2011)Pregnancy outcomes after maternal exposure torituximab. Blood 117(5):1499–1506. doi:10.1182/blood-2010-07-295444

Chandran V, Aggarwal A, Misra R (2005) Active diseaseduring pregnancy is associated with poor foetal out-come in Indian patients with systemic lupuserythematosus. Rheumatol Int 26(2):152–156.doi:10.1007/s00296-004-0540-3

Chen HH, Lin HC, Yeh JC, Chen CP (2001) Renal biopsyin pregnancies complicated by undetermined renal dis-ease. Acta Obstet Gynecol Scand 80(10):888–893

Cleary BJ, Kallen B (2009) Early pregnancy azathioprineuse and pregnancy outcomes. Birth Defects Res A ClinMol Teratol 85(7):647–654. doi:10.1002/bdra.20583

Clowse ME (2007) Lupus activity in pregnancy. RheumDis Clin N Am 33(2):237–252, v. doi:10.1016/j.rdc.2007.01.002

Clowse ME, Magder L, Witter F, Petri M (2006)Hydroxychloroquine in lupus pregnancy. ArthritisRheum 54(11):3640–3647. doi:10.1002/art.22159

Clowse ME, Richeson RL, Pieper C, Merkel PA (2013)Pregnancy outcomes among patients with vasculitis.Arthritis Care Res 65(8):1370–1374. doi:10.1002/acr.21983

Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA,Dyer S, Gideon PS, Hall K, Ray WA (2006) Majorcongenital malformations after first-trimester exposureto ACE inhibitors. N Engl J Med 354(23):2443–2451.doi:10.1056/NEJMoa055202. 354/23/2443 [pii]

Croft AP, Smith SW, Carr S, Youssouf S, Salama AD,Burns A, Pusey CD, Hamilton P, Brown N, VenningM, Harper L, Morgan MD (2015) Successful outcomeof pregnancy in patients with anti-neutrophil cytoplasmantibody-associated small vessel vasculitis. Kidney Int87(4):807–811. doi:10.1038/ki.2014.329

Del Mastro L, Ceppi M, Poggio F, Bighin C, Peccatori F,Demeestere I, Levaggi A, Giraudi S, Lambertini M,D’Alonzo A, Canavese G, Pronzato P, Bruzzi P

(2014) Gonadotropin-releasing hormone analoguesfor the prevention of chemotherapy-induced prematureovarian failure in cancer women: Systematic reviewand meta-analysis of randomized trials. Cancer TreatRev 40(5):675–683. doi:10.1016/j.ctrv.2013.12.001

Di Sessa TG, Moretti ML, Khoury A, Pulliam DA, ArheartKL, Sibai BM (1994) Cardiac function in fetuses andnewborns exposed to low-dose aspirin during preg-nancy. Am J Obstet Gynecol 171(4):892–900

Diav-Citrin O, Shechtman S, Halberstadt Y, Finkel-Pekarsky V, Wajnberg R, Arnon J, Di Gianantonio E,Clementi M, Ornoy A (2011) Pregnancy outcome afterin utero exposure to angiotensin converting enzymeinhibitors or angiotensin receptor blockers. ReprodToxicol 31(4):540–545. doi:10.1016/j.reprotox.2011.02.008

Dische FE, Anderson VE, Keane SJ, Taube D, Bewick M,Parsons V (1990) Incidence of thin membrane nephrop-athy: Morphometric investigation of a population sam-ple. J Clin Pathol 43(6):457–460

Doria A, Ghirardello A, Iaccarino L, Zampieri S, Punzi L,Tarricone E, Ruffatti A, Sulli A, Sarzi-Puttini PC,Gambari PF, Cutolo M (2004) Pregnancy, cytokines,and disease activity in systemic lupus erythematosus.Arthritis Rheum 51(6):989–995. doi:10.1002/art.20837

Durodola JI (1979) Administration of cyclophosphamideduring late pregnancy and early lactation: A case report.J Natl Med Assoc 71(2):165–166

Elgindy E, Sibai H, Abdelghani A, Mostafa M (2015)Protecting ovaries during chemotherapy throughgonad suppression: A systematic review and meta-analysis. Obstet Gynecol 126(1):187–195.doi:10.1097/AOG.0000000000000905

Enns GM, Roeder E, Chan RT, Ali-Khan Catts Z, Cox VA,Golabi M (1999) Apparent cyclophosphamide(cytoxan) embryopathy: A distinct phenotype? Am JMed Genet 86(3):237–241

Ergin RN (2014) Pregnancy-associated systemic lupuserythematosus. Proc (Bayl Univ Med Cent)27(3):221–222

Fakhouri F, Roumenina L, Provot F, Sallee M, Caillard S,Couzi L, Essig M, Ribes D, Dragon-Durey MA,Bridoux F, Rondeau E, Fremeaux-Bacchi V (2010)Pregnancy-associated hemolytic uremic syndromerevisited in the era of complement gene mutations.J Am Soc Nephrol 21(5):859–867. doi:10.1681/asn.2009070706

Fraser FC, Sajoo A (1995) Teratogenic potential of corti-costeroids in humans. Teratology 51(1):45–46.doi:10.1002/tera.1420510107

Fredi M, Lazzaroni MG, Tani C, Ramoni V, Gerosa M,Inverardi F, Sfriso P, Caramaschi P, Andreoli L, SinicoRA, Motta M, Lojacono A, Trespidi L, Strigini F,Brucato A, Caporali R, Doria A, Guillevin L, MeroniPL, Montecucco C, Mosca M, Tincani A (2015) Sys-temic vasculitis and pregnancy: A multicenter studyon maternal and neonatal outcome of 65 prospectivelyfollowed pregnancies. Autoimmun Rev14(8):686–691. doi:10.1016/j.autrev.2015.03.009


Friedrichs B, Tiemann M, Salwender H, Verpoort K,Wenger MK, Schmitz N (2006) The effects ofrituximab treatment during pregnancy on a neonate.Haematologica 91(10):1426–1427 [Epub 7 Sep 2006]

George JN, Vesely SK, Terrell DR (2004) The OklahomaThrombotic Thrombocytopenic Purpura-HemolyticUremic Syndrome (TTP-HUS) Registry: A communityperspective of patients with clinically diagnosed TTP-HUS. Semin Hematol 41(1):60–67

Greenberg LH, Tanaka KR (1964) Congenital anomaliesprobably induced by cyclophosphamide. JAMA188:423–426

Guller S, Kong L, Wozniak R, Lockwood CJ (1995)Reduction of extracellular matrix protein expressionin human amnion epithelial cells by glucocorticoids:A potential role in preterm rupture of the fetal mem-branes. J Clin Endocrinol Metab 80(7):2244–2250.doi:10.1210/jcem.80.7.7608287

Hallman M (2015) The story of antenatal steroid therapybefore preterm birth. Neonatology 107(4):352–357.doi:10.1159/000381130

Hamilton P, Myers J, Gillham J, Ayers G, Brown N,Venning M (2014) Urinary protein selectivity innephrotic syndrome and pregnancy: Resurrection of abiomarker when renal biopsy is contraindicated. ClinKidney J 7(6):595–598. doi:10.1093/ckj/sfu103

Henderson JT, Whitlock EP, O’Connor E, Senger CA,Thompson JH, Rowland MG (2014) Low-dose aspirinfor prevention of morbidity and mortality from pre-eclampsia: A systematic evidence review for the U.S.Preventive Services Task Force. Ann Intern Med 160(10):695–703. doi:10.7326/M13-2844

Hockel M, Kaufmann R (1986) Placental transfer of classG immunoglobulins treated with beta-propiolactone(beta-PL) for intravenous application – A case report.J Perinat Med 14(3):205–208

HodM, van Dijk DJ, KarpM,Weintraub N, Rabinerson D,Bar J, Peled Y, Erman A, Boner G, Ovadia J (1995)Diabetic nephropathy and pregnancy: The effect ofACE inhibitors prior to pregnancy on fetomaternaloutcome. Nephrol Dial Transplant 10(12):2328–2333

Hofmeyr GJ, Atallah AN, Duley L (2006) Calcium sup-plementation during pregnancy for preventing hyper-tensive disorders and related problems. CochraneDatabase Syst Rev 3:CD001059. doi:10.1002/14651858.CD001059.pub2

Holley JL, Schmidt RJ, Bender FH, Dumler F, Schiff M(1997) Gynecologic and reproductive issues in womenon dialysis. Am J Kidney Dis 29(5):685–690

Hou SH, Grossman S, Molitch ME (1985) Hyper-prolactinemia in patients with renal insufficiency andchronic renal failure requiring hemodialysis or chronicambulatory peritoneal dialysis. Am J Kidney Dis6(4):245–249

Hviid A, Molgaard-Nielsen D (2011) Corticosteroid useduring pregnancy and risk of orofacial clefts. CMAJ183(7):796–804. doi:10.1503/cmaj.101063

Iaccarino L, Ghirardello A, Zen M, Villalta D, Tincani A,Punzi L, Doria A (2012) Polarization of TH2 response

is decreased during pregnancy in systemic lupuserythematosus. Reumatismo 64(5):314–320.doi:10.4081/reumatismo.2012.314

Imbasciati E, Gregorini G, Cabiddu G, Gammaro L,Ambroso G, Del Giudice A, Ravani P (2007) Preg-nancy in CKD stages 3 to 5: Fetal and maternal out-comes. Am J Kidney Dis 49(6):753–762. doi:10.1053/j.ajkd.2007.03.022

Imbasciati E, Tincani A, Gregorini G, Doria A, Moroni G,Cabiddu G, Marcelli D (2009) Pregnancy in womenwith pre-existing lupus nephritis: Predictors of fetal andmaternal outcome. Nephrol Dial Transplant24(2):519–525. doi:10.1093/ndt/gfn348

Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E(2010) The importance of the level of maternal anti-Ro/SSA antibodies as a prognostic marker of the develop-ment of cardiac neonatal lupus erythematosus: A pro-spective study of 186 antibody-exposed fetuses andinfants. J Am Coll Cardiol 55(24):2778–2784.doi:10.1016/j.jacc.2010.02.042

Jain AB, Reyes J, Marcos A, Mazariegos G, Eghtesad B,Fontes PA, Cacciarelli TV, Marsh JW, de Vera ME,Rafail A, Starzl TE, Fung JJ (2003) Pregnancy afterliver transplantation with tacrolimus immunosuppres-sion: A single center’s experience update at 13 years.Transplantation 76(5):827–832. doi:10.1097/01.TP.0000084823.89528.89

Jain AB, Shapiro R, Scantlebury VP, Potdar S, Jordan ML,Flohr J, Marcos A, Fung JJ (2004) Pregnancy afterkidney and kidney-pancreas transplantation undertacrolimus: A single center’s experience. Transplanta-tion 77(6):897–902

Jones DC, Hayslett JP (1996) Outcome of pregnancy inwomen with moderate or severe renal insufficiency. NEngl J Med 335(4):226–232

Jungers P, Houillier P, Forget D, Labrunie M, Skhiri H,Giatras I, Descamps-Latscha B (1995) Influence ofpregnancy on the course of primary chronic glomeru-lonephritis. Lancet 346(8983):1122–1124

Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D(2000) Review of the course and outcome of 100 preg-nancies in 84 women treated with tacrolimus. Trans-plantation 70(12):1718–1721

Kamel H, Navi BB, Sriram N, Hovsepian DA, DevereuxRB, Elkind MS (2014) Risk of a thrombotic event afterthe 6-week postpartum period. N Engl J Med370(14):1307–1315. doi:10.1056/NEJMoa1311485

Katon W, Russo J, Gavin A (2014) Predictors of postpar-tum depression. J Women’s Health (2002)23(9):753–759. doi:10.1089/jwh.2014.4824

Kelly RJ, Hochsmann B, Szer J, Kulasekararaj A, deGuibert S, Roth A, Weitz IC, Armstrong E, RisitanoAM, Patriquin CJ, Terriou L, Muus P, Hill A, TurnerMP, Schrezenmeier H, Peffault de Latour R (2015)Eculizumab in pregnant patients with paroxysmal noc-turnal hemoglobinuria. N Engl J Med 373(11):1032–1039. doi:10.1056/NEJMoa1502950

Khalafallah AA, Dennis AE, Ogden K, Robertson I,Charlton RH, Bellette JM, Shady JL, Blesingk N,


Ball M (2012) Three-year follow-up of a randomisedclinical trial of intravenous versus oral iron for anaemiain pregnancy. BMJ Open 2(5). doi:10.1136/bmjopen-2012-000998

KimMY, Buyon JP, Guerra MM, Rana S, Zhang D, LaskinCA, Petri M, Lockshin MD, Sammaritano LR, BranchDW, Porter TF, Merrill JT, Stephenson MD, Gao Q,Karumanchi SA, Salmon JE (2016) Angiogenic factorimbalance early in pregnancy predicts adverse out-comes in patients with lupus and antiphospholipid anti-bodies: Results of the PROMISSE study. Am J ObstetGynecol 214(1):108.e101–108.e114. doi:10.1016/j.ajog.2015.09.066

Kirshon B,Wasserstrum N,Willis R, Herman GE,McCabeER (1988) Teratogenic effects of first-trimester cyclo-phosphamide therapy. Obstet Gynecol 72(3 Pt2):462–464

Koh JH, Ko HS, Lee J, Jung SM, Kwok SK, Ju JH, ParkSH (2015) Pregnancy and patients with preexistinglupus nephritis: 15 years of experience at a single centerin Korea. Lupus 24(7):764–772. doi:10.1177/0961203315572715

Koukoura O, Mantas N, Linardakis H, Hajiioannou J,Sifakis S (2008) Successful term pregnancy in a patientwith Wegener’s granulomatosis: Case report and liter-ature review. Fertil Steril 89(2):457 e451–455.doi:10.1016/j.fertnstert.2007.03.054

Lamarque V, Leleu MF, Monka C, Krupp P (1997) Anal-ysis of 629 pregnancy outcomes in transplant recipientstreated with Sandimmun. Transplant Proc 29(5):2480

Lee YH, Song GG (2015) Relative efficacy and safety oftacrolimus, mycophenolate mofetil, and cyclophospha-mide as induction therapy for lupus nephritis: A Bayes-ian network meta-analysis of randomized controlledtrials. Lupus 24(14):1520–1528. doi:10.1177/0961203315595131

Lee T, Biddle AK, Lionaki S, Derebail VK, Barbour SJ,Tannous S, Hladunewich MA, Hu Y, Poulton CJ,Mahoney SL, Charles Jennette J, Hogan SL, Falk RJ,Cattran DC, Reich HN, Nachman PH (2014) Personal-ized prophylactic anticoagulation decision analysis inpatients with membranous nephropathy. Kidney Int 85(6):1412–1420. doi:10.1038/ki.2013.476

Li DK, Yang C, Andrade S, Tavares V, Ferber JR (2011)Maternal exposure to angiotensin converting enzymeinhibitors in the first trimester and risk ofmalformations in offspring: A retrospective cohortstudy. BMJ 343:d5931. doi:10.1136/bmj.d5931

Lim VS, Henriquez C, Sievertsen G, Frohman LA (1980)Ovarian function in chronic renal failure: Evidencesuggesting hypothalamic anovulation. Ann InternMed 93(1):21–27

Limardo M, Imbasciati E, Ravani P, Surian M, Torres D,Gregorini G, Magistroni R, Casellato D, Gammaro L,Pozzi C (2010) Pregnancy and progression of IgAnephropathy: Results of an Italian multicenter study.Am J Kidney Dis 56(3):506–512. doi:10.1053/j.ajkd.2010.03.033

Lindheimer MD, Davison JM (1987) Renal biopsy duringpregnancy: ‘to b . . . or not to b . . .?’. Br J ObstetGynaecol 94(10):932–934

Lionaki S, Derebail VK, Hogan SL, Barbour S, Lee T,Hladunewich M, Greenwald A, Hu Y, Jennette CE,Jennette JC, Falk RJ, Cattran DC, Nachman PH,Reich HN (2012) Venous thromboembolism in patientswith membranous nephropathy. Clin J Am Soc Nephrol7(1):43–51. doi:10.2215/CJN.04250511

Liu Y, Ma X, Lv J, Shi S, Liu L, Chen Y, Zhang H (2014)Risk factors for pregnancy outcomes in patients withIgA nephropathy: A matched cohort study. Am J Kid-ney Dis 64(5):730–736. doi:10.1053/j.ajkd.2014.06.021

Lockwood CJ, Radunovic N, Nastic D, Petkovic S, AignerS, Berkowitz GS (1996) Corticotropin-releasing hor-mone and related pituitary-adrenal axis hormones infetal and maternal blood during the second half ofpregnancy. J Perinat Med 24(3):243–251

Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E,Murphy KE, Menzies J, Sanchez J, Singer J, Gafni A,Gruslin A, Helewa M, Hutton E, Lee SK, Lee T, LoganAG, Ganzevoort W, Welch R, Thornton JG, MoutquinJM (2015) Less-tight versus tight control of hyperten-sion in pregnancy. N Engl J Med 372(5):407–417.doi:10.1056/NEJMoa1404595

Magee LA, CHIPS Study Group, von Dadelszen P, SingerJ, Lee T, Rey E, Ross S, Asztalos E, Murphy KE,Menzies J, Sanchez J, Gafni A, Gruslin A, Helewa M,Hutton E, Koren G, Lee SK, Logan AG, GanzevoortJW, Welch R, Thornton JG, Moutquin JM (2016) Dolabetalol and methyldopa have different effects onpregnancy outcome? Analysis of data from the Controlof Hypertension In Pregnancy Study (CHIPS) trial.BJOG 123(7):1143–1151. doi:10.1111/1471-0528.13569

Masuyama H, Nobumoto E, Okimoto N, Inoue S, SegawaT, Hiramatsu Y (2012) Superimposed preeclampsia inwomen with chronic kidney disease. Gynecol ObstetInvestig 74(4):274–281. doi:10.1159/000339935

Matsubara S, Muto S (2012) Good obstetric outcome ofconsecutive pregnancies in a woman with Alport syn-drome. Arch Gynecol Obstet 286(1):261–262.doi:10.1007/s00404-012-2225-6

Matsuo K, Tudor EL, Baschat AA (2007) Alport syndromeand pregnancy. Obstet Gynecol 109(2 Pt2):531–532.doi:10.1097/01.AOG.0000240141.26395.82

McGrogan A, Franssen CF, de Vries CS (2011) The inci-dence of primary glomerulonephritis worldwide: A sys-tematic review of the literature. Nephrol DialTransplant 26(2):414–430. doi:10.1093/ndt/gfq665

Meti S, Paneesha S, Patni S (2010) Successful pregnancyin a case of congenital thrombotic thrombocytopenicpurpura. J Obstet Gynaecol 30(5):519–521.doi:10.3109/01443615.2010.487171

Mok CC, Ying KY, Ng WL, Lee KW, To CH, Lau CS,Wong RW, Au TC (2006) Long-term outcome of dif-fuse proliferative lupus glomerulonephritis treated with


cyclophosphamide. Am J Med 119(4):355 e325–333.doi:10.1016/j.amjmed.2005.08.045

Morais SA, Isenberg DA (2016) A study of the influence ofethnicity on serology and clinical features in lupus.Lupus. doi:10.1177/0961203316645204

Moretti ME, Sgro M, Johnson DW, Sauve RS, WoolgarMJ, Taddio A, Verjee Z, Giesbrecht E, Koren G, Ito S(2003) Cyclosporine excretion into breast milk. Trans-plantation 75(12):2144–2146. doi:10.1097/01.tp.0000066352.86763.d0

Munkhaugen J, Lydersen S, Romundstad PR,Wideroe TE,Vikse BE, Hallan S (2009) Kidney function and futurerisk for adverse pregnancy outcomes: A population-based study from HUNT II, Norway. Nephrol DialTransplant 24(12):3744–3750. doi:10.1093/ndt/gfp320

Murphy KE, Hannah ME, Willan AR, Hewson SA,Ohlsson A, Kelly EN, Matthews SG, Saigal S, AsztalosE, Ross S, Delisle MF, Amankwah K, Guselle P, GafniA, Lee SK, Armson BA (2008) Multiple courses ofantenatal corticosteroids for preterm birth (MACS): Arandomised controlled trial. Lancet 372(9656):2143–2151. doi:10.1016/s0140-6736(08)61929-7

Murray CL, Reichert JA, Anderson J, Twiggs LB (1984)Multimodal cancer therapy for breast cancer in the firsttrimester of pregnancy. A case report. JAMA 252(18):2607–2608

Nelson DB (2003) Minimal change glomerulopathy inpregnancy. Nephrol Nurs J 30(1):45–50, 55–46, 122

Nielsen LR, Damm P, Mathiesen ER (2009) Improvedpregnancy outcome in type 1 diabetic women withmicroalbuminuria or diabetic nephropathy: Effect ofintensified antihypertensive therapy? Diabetes Care32(1):38–44. doi:10.2337/dc08-1526

Norgard B, Pedersen L, Fonager K, Rasmussen SN,Sorensen HT (2003) Azathioprine, mercaptopurineand birth outcome: A population-based cohort study.Aliment Pharmacol Ther 17(6):827–834

Oh HJ, Han SH, Yoo DE, Kim SJ, Park JT, Kim JK, YooTH, Kang SW, Choi KH (2011) Reduced pre-preg-nancy proteinuria is associated with improving postna-tal maternal renal outcomes in IgA nephropathywomen. Clin Nephrol 76(6):447–454

Oktem O, Guzel Y, Aksoy S, Aydin E, Urman B (2015)Ovarian function and reproductive outcomes of femalepatients with systemic lupus erythematosus and thestrategies to preserve their fertility. Obstet GynecolSurv 70(3):196–210. doi:10.1097/OGX.0000000000000160

Ope-Adenuga S, Moretti M, Lakhi N (2015) Managementof Membranous Glomerulonephritis in Pregnancy: Amultidisciplinary challenge. Case Rep Obstet Gynecol2015:839376. doi:10.1155/2015/839376

OstensenM, Khamashta M, LockshinM, Parke A, BrucatoA, Carp H, Doria A, Rai R, Meroni P, Cetin I, DerksenR, Branch W, Motta M, Gordon C, Ruiz-Irastorza G,Spinillo A, Friedman D, Cimaz R, Czeizel A, Piette JC,Cervera R, Levy RA, Clementi M, De Carolis S, Petri

M, Shoenfeld Y, Faden D, Valesini G, Tincani A (2006)Anti-inflammatory and immunosuppressive drugs andreproduction. Arthritis Res Ther 8(3):209. doi:ar1957[pii]. 10.1186/ar1957

Packham DK, North RA, Fairley KF, Whitworth JA,Kincaid-Smith P (1987) Membranous glomerulone-phritis and pregnancy. Clin Nephrol 28(2):56–64

Patel T, Fenves A, Colbert G (2012) The de novo diagnosisof systemic lupus erythematosus and lupus nephritisduring pregnancy. Proc (Bayl Univ Med Cent)25(2):129–131

Perez-Aytes A, Ledo A, Boso V, Saenz P, Roma E, PovedaJL, Vento M (2008) In utero exposure tomycophenolate mofetil: A characteristic phenotype?Am J Med Genet A 146A(1):1–7. doi:10.1002/ajmg.a.32117

Perni U, Sison C, Sharma V, Helseth G, Hawfield A,Suthanthiran M, August P (2012) Angiogenic factorsin superimposed preeclampsia: A longitudinal study ofwomen with chronic hypertension during pregnancy.Hypertension 59(3):740–746. doi:10.1161/hypertensionaha.111.181735

Piccoli GB, Attini R, Vasario E, Conijn A, Biolcati M,D’Amico F, Consiglio V, Bontempo S, Todros T(2010) Pregnancy and chronic kidney disease: A chal-lenge in all CKD stages. Clin J Am Soc Nephrol5(5):844–855. doi:10.2215/cjn.07911109

Piccoli GB, Cabiddu G, Attini R, Vigotti FN, Maxia S,Lepori N, Tuveri M, Massidda M, Marchi C, Mura S,Coscia A, Biolcati M, Gaglioti P, Nichelatti M, Pibiri L,Chessa G, Pani A, Todros T (2015) Risk of adversepregnancy outcomes in women with CKD. J Am SocNephrol 26(8):2011–2022. doi:10.1681/asn.2014050459

Piccoli GB, Daidola G, Attini R, Parisi S, Fassio F, NarettoC, Deagostini MC, Castelluccia N, Ferraresi M,Roccatello D, Todros T (2013a) Kidney biopsy in preg-nancy: Evidence for counselling? A systematic narra-tive review. BJOG 120(4):412–427. doi:10.1111/1471-0528.12111

Piccoli GB, Gaglioti P, Attini R, Parisi S, Bossotti C,Olearo E, Oberto M, Ferraresi M, Rolfo A, Versino E,Biolcati M, Todros T (2013b) Pre-eclampsia or chronickidney disease? The flow hypothesis. Nephrol DialTransplant 28(5):1199–1206. doi:10.1093/ndt/gfs573

Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, CooperGS (2010) Understanding the epidemiology and pro-gression of systemic lupus erythematosus. SeminArthritis Rheum 39(4):257–268. doi:10.1016/j.semarthrit.2008.10.007

Pregnancy and renal disease (1975) Lancet 2(7939):801–802Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E

(2013) Prevention of perinatal death and adverse peri-natal outcome using low-dose aspirin: A meta-analysis.Ultrasound Obstet Gynecol 41(5):491–499.doi:10.1002/uog.12421

Rolfo A, Attini R, Nuzzo AM, Piazzese A, Parisi S,Ferraresi M, Todros T, Piccoli GB (2013) Chronic


kidney disease may be differentially diagnosed frompreeclampsia by serum biomarkers. Kidney Int 83(1):177–181. doi:10.1038/ki.2012.348

Ruiz-Irastorza G, Khamashta MA (2005) Management ofthrombosis in antiphospholipid syndrome and systemiclupus erythematosus in pregnancy. Ann N YAcad Sci1051:606–612. doi:10.1196/annals.1361.105

Saavedra MA, Cruz-Reyes C, Vera-Lastra O, Romero GT,Cruz-Cruz P, Arias-Flores R, Jara LJ (2012) Impact ofprevious lupus nephritis on maternal and fetal out-comes during pregnancy. Clin Rheumatol31(5):813–819. doi:10.1007/s10067-012-1941-4

Saha MT, Saha HH, Niskanen LK, Salmela KT, PasternackAI (2002) Time course of serum prolactin and sexhormones following successful renal transplantation.Nephron 92(3):735–737. doi:64079

Savige J, Rana K, Tonna S, Buzza M, Dagher H, Wang YY(2003) Thin basement membrane nephropathy. KidneyInt 64(4):1169–1178. doi:10.1046/j.1523-1755.2003.00234.x

Schramm C, Herkel J, Beuers U, Kanzler S, Galle PR,Lohse AW (2006) Pregnancy in autoimmune hepatitis:Outcome and risk factors. Am J Gastroenterol 101(3):556–560. doi:10.1111/j.1572-0241.2006.00479.x

Schubiger G, Flury G, Nussberger J (1988) Enalapril forpregnancy-induced hypertension: Acute renal failure ina neonate. Ann Intern Med 108(2):215–216

Sebestyen A, Varbiro S, Sara L, Deak G, Kerkovits L,Szabo I, Kiss I, Paulin F (2008) Successful manage-ment of pregnancy with nephrotic syndrome due topreexisting membranous glomerulonephritis: A casereport. Fetal Diagn Ther 24(3):186–189. doi:10.1159/000151336

Servais A, Devillard N, Fremeaux-Bacchi V, Hummel A,Salomon L, Contin-Bordes C, Gomer H, Legendre C,Delmas Y (2016) Atypical haemolytic uraemic syndromeand pregnancy: Outcome with ongoing eculizumab.Nephrol Dial Transplant. doi:10.1093/ndt/gfw314

Shaheen FA, al-Sulaiman MH, al-Khader AA (1993)Long-term nephrotoxicity after exposure to cyclospor-ine in utero. Transplantation 56(1):224–225

Shimizu A, Takei T, Moriyama T, Itabashi M, Uchida K,Nitta K (2015) Effect of pregnancy and delivery on therenal function and the prognosis of patients withchronic kidney disease stage 3 caused by immunoglob-ulin A nephropathy. Intern Med 54(24):3127–3132.doi:10.2169/internalmedicine.54.5071

Shotan A, Widerhorn J, Hurst A, Elkayam U (1994) Risksof angiotensin-converting enzyme inhibition duringpregnancy: Experimental and clinical evidence, poten-tial mechanisms, and recommendations for use. Am JMed 96(5):451–456

Singh N, Varshney P, Tripathi R, Mala YM, Tyagi S (2013)Safety and efficacy of low molecular weight heparintherapy during pregnancy: Three year experience at atertiary care center. J Obstet Gynaecol India63(6):373–377. doi:10.1007/s13224-013-0412-4

Slone D, Siskind V, Heinonen OP, Monson RR, KaufmanDW, Shapiro S (1976) Aspirin and congenitalmalformations. Lancet 1(7974):1373–1375

Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM,Garovic VD (2010) A systematic review and meta-analysis of pregnancy outcomes in patients with sys-temic lupus erythematosus and lupus nephritis. Clin JAm Soc Nephrol 5(11):2060–2068. doi:10.2215/cjn.00240110

Soma-Pillay P, Nene Z, Mathivha TM, Macdonald AP(2011) The effect of warfarin dosage on maternal andfetal outcomes in pregnant women with prosthetic heartvalves. Obstet Med 4(1):24–27. doi:10.1258/om.2010.100067

Stehman-Breen C, Miller L, Fink J, Schwartz SM (2000)Pre-eclampsia and premature labour among pregnantwowen with haematuria. Paediatr Perinat Epidemiol14(2):136–140

Stehman-Breen CO, Levine RJ, Qian C, Morris CD,Catalano PM, Curet LB, Sibai BM (2002) Increasedrisk of preeclampsia among nulliparous pregnantwomen with idiopathic hematuria. Am J ObstetGynecol 187(3):703–708. doi:S0002937802001916[pii]

Stuart MJ, Gross SJ, Elrad H, Graeber JE (1982) Effects ofacetylsalicylic-acid ingestion on maternal and neonatalhemostasis. N Engl J Med 307(15):909–912.doi:10.1056/NEJM198210073071502

Tabacova S, Little R, Tsong Y, Vega A, Kimmel CA (2003)Adverse pregnancy outcomes associated with maternalenalapril antihypertensive treatment. Pharmacoe-pidemiol Drug Saf 12(8):633–646. doi:10.1002/pds.796

Thewissen L, Pistorius L, Baerts W, Naulaers G, Van Bel F,Lemmers P (2016) Neonatal haemodynamic effectsfollowing foetal exposure to labetalol in hypertensivedisorders of pregnancy. J Matern Fetal NeonatalMed:1–6. doi:10.1080/14767058.2016.1193145

Thomson B, Joseph G, Clark WF, Hladunewich M, PatelA, Blake P, Eastabrook G, Matsui D, Sharma A, HouseA (2014) Maternal, pregnancy and fetal outcomes in denovo anti-glomerular basement membrane antibodydisease in pregnancy: A systematic review. Clin Kid-ney J 7(5):450–456. doi:10.1093/ckj/sfu086

Toledo TM, Harper RC, Moser RH (1971) Fetal effectsduring cyclophosphamide and irradiation therapy. AnnIntern Med 74(1):87–91

Tong A, Brown MA, Winkelmayer WC, Craig JC,Jesudason S (2015) Perspectives on pregnancy inwomen with CKD: A semistructured interview study.Am J Kidney Dis 66(6):951–961. doi:10.1053/j.ajkd.2015.08.023

Transplantation EEGoR (2002) European best practiceguidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.10.Pregnancy in renal transplant recipients. Nephrol DialTransplant 17(Suppl 4):50–55

Tsakonas E, Joseph L, Esdaile JM, Choquette D, SenecalJL, Cividino A, Danoff D, Osterland CK, Yeadon C,


Smith CD (1998) A long-term study ofhydroxychloroquine withdrawal on exacerbations insystemic lupus erythematosus. The CanadianHydroxychloroquine Study Group. Lupus 7(2):80–85

van Eps C, Hawley C, Jeffries J, Johnson DW, Campbell S,Isbel N, Mudge DW, Prins J (2012) Changes in serumprolactin, sex hormones and thyroid function with alter-nate nightly nocturnal home haemodialysis. Nephrol-ogy (Carlton) 17(1):42–47. doi:10.1111/j.1440-1797.2011.01520.x

Warren JB, Silver RM (2004) Autoimmune disease inpregnancy: Systemic lupus erythematosus and anti-phospholipid syndrome. Obstet Gynecol Clin N Am31(2):345–372, vi-vii. doi:10.1016/j.ogc.2004.03.007

Wiernik PH, Duncan JH (1971) Cyclophosphamide inhuman milk. Lancet 1(7705):912

Wiznitzer A, Mazor M, Leiberman JR, Bar-Levie Y,Gurman G, Glezerman M (1992) Familial occurrenceof thrombotic thrombocytopenic purpura in two sistersduring pregnancy. Am J Obstet Gynecol 166(1 Pt1):20–21

Xie RH, Guo Y, Krewski D, Mattison D, Walker MC,Nerenberg K, Wen SW (2014) Association betweenlabetalol use for hypertension in pregnancy and adverseinfant outcomes. Eur J Obstet Gynecol Reprod Biol175:124–128. doi:10.1016/j.ejogrb.2014.01.019

Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC,Sennstrom M, Olovsson M, Brennecke SP, Stepan H,Allegranza D, Dilba P, Schoedl M, Hund M, VerlohrenS (2016) Predictive value of the sFlt-1:PlGF ratio inwomen with suspected preeclampsia. N Engl J Med374(1):13–22. doi:10.1056/NEJMoa1414838

Zemlickis D, Lishner M, Degendorfer P, Panzarella T,Sutcliffe SB, Koren G (1992) Fetal outcome after inutero exposure to cancer chemotherapy. Arch InternMed 152(3):573–576

Zemlickis D, Lishner M, Erlich R, Koren G (1993) Tera-togenicity and carcinogenicity in a twin exposed inutero to cyclophosphamide. Teratog CarcinogMutagen13(3):139–143


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